105 results on '"Joan E Wither"'
Search Results
2. 1501 Genetics of age at systemic lupus erythematosus diagnosis
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Janet E Pope, Daniel J Wallace, Murray B Urowitz, Dafna D Gladman, Diane L Kamen, Christine A Peschken, Zahi Touma, Earl D Silverman, Mariko Ishimori, Andrew D Paterson, Deborah M Levy, Sylvia Kamphuis, Linda T Hiraki, Marisa S Klein-Gitelman, Jingjing Cao, Declan Webber, Daniela Dominguez, Andrea M Knight, Joan E Wither, Raffaella Carlomagno, Fangming Liao, Caroline Jefferies, Chia-Chi J Lee, and Karen B Onel more...
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Immunologic diseases. Allergy ,RC581-607 - Published
- 2021
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Catalog
3. Impaired B cell anergy is not sufficient to breach tolerance to nuclear antigen in Vκ8/3H9 lupus-prone mice.
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Kieran P Manion, Yuriy Baglaenko, Nan-Hua Chang, Nafiseh Talaei, and Joan E Wither
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Medicine ,Science - Abstract
BackgroundSystemic lupus erythematosus (SLE) is a severe autoimmune disease in which immune tolerance defects drive production of pathogenic anti-nuclear autoantibodies. Anergic B cells are considered a potential source of these autoantibodies due to their autoreactivity and overrepresentation in SLE patients. Studies of lupus-prone mice have shown that genetic defects mediating autoimmunity can breach B cell anergy, but how this breach occurs with regards to endogenous nuclear antigen remains unclear. We investigated whether B and T cell defects in congenic mice (c1) derived from the lupus-prone New Zealand Black strain can breach tolerance to nuclear self-antigen in the presence of knock-in genes (Vκ8/3H9; dKI) that generate a ssDNA-reactive, anergic B cell population.MethodsFlow cytometry was used to assess splenic B and T cells from 8-month-old c1 dKI mice and serum autoantibodies were measured by ELISA. dKI B cells stimulated in vitro with anti-IgM were assessed for proliferation and activation by examining CFSE decay and CD86. Cytokine-producing T cells were identified by flow cytometry following culture of dKI splenocytes with PMA and ionomycin. dKI B cells from 6-8-week-old mice were adoptively transferred into 4-month-old wild type recipients and assessed after 7 days via flow cytometry and immunofluorescence microscopy.Resultsc1 dKI mice exhibited B cell proliferation indicative of impaired anergy, but had attenuated autoantibodies and germinal centres compared to wild type littermates. This attenuation appeared to stem from a decrease in PD-1hi T helper cells in the dKI strains, as c1 dKI B cells were recruited to germinal centres when adoptively transferred into c1 wild type mice.ConclusionAnergic, DNA-specific autoreactive B cells only seem to drive profound autoimmunity in the presence of concomitant defects in the T cell subsets that support high-affinity plasma cell production. more...
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- 2020
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4. Evaluation of Progression From Preclinical to Systemic Autoimmune Rheumatic Disease: Novel Use of the European Alliance of Associations for Rheumatology/American College of Rheumatology Systemic Lupus Erythematosus Classification Criteria as an Outcome Measure
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Sindhu R. Johnson, Hana Alahmari, Dennisse Bonilla, Zareen Ahmad, Arthur Bookman, Linda T. Hiraki, Earl Silverman, Zahi Touma, Mohammad Movahedi, and Joan E. Wither
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Diseases of the musculoskeletal system ,RC925-935 - Abstract
Objective Our objective was to evaluate the development of a systemic autoimmune rheumatic disease (SARD) in undifferentiated and asymptomatic individuals with antinuclear antibodies (ANAs). We comparatively evaluated those who did and did not develop a SARD and fulfillment of classification criteria. Methods We conducted a cohort study of undifferentiated and asymptomatic patients with ANAs who were assessed for the development of a SARD. The primary outcome was a diagnosis of a SARD over a two‐year period. We assessed fulfillment of classification criteria. Risk ratios (RRs) were used to evaluate differences among those who did and did not progress to a SARD. Results We evaluated 207 asymptomatic ANA‐positive or undifferentiated patients, of whom 23 (11%) progressed to a SARD, whereas 187 (89%) did not progress. Progressors developed systemic lupus erythematosus (SLE) (n = 11 [48%]), Sjögren disease (n = 5 [22%]), systemic sclerosis (n = 3 [13%]), rheumatoid arthritis (n = 1 [4%]), and from ANA‐positive to undifferentiated connective tissue disease (n = 3 [13%]). Fever (RR 0.89, 95% confidence interval [CI] 0.8–0.93) and antiphospholipid antibodies (RR 0.89, 95% CI 0.87–0.93) occurred less frequently, whereas arthritis (RR 1.74, 95% CI 1.20–2.55) occurred more frequently in progressors. Progressors to SLE had arthritis (91%), whereas none developed delirium, psychosis, or nephritis. Among patients with SLE, 100% fulfilled the EULAR/American College of Rheumatology (ACR) SLE criteria (sensitivity 91.7%, specificity 100%), whereas 73% fulfilled the 1997 ACR SLE criteria (sensitivity 81.8%, specificity 98.9%). Conclusion Most undifferentiated/asymptomatic individuals with ANA do not progress to a SARD over a two‐year period. SLE progressors appear to have mild disease in the short term. The EULAR/ACR SLE criteria have improved ability to identify those who develop SLE. more...
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- 2024
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5. Identification of a neutrophil-related gene expression signature that is enriched in adult systemic lupus erythematosus patients with active nephritis: Clinical/pathologic associations and etiologic mechanisms.
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Joan E Wither, Stephenie D Prokopec, Babak Noamani, Nan-Hua Chang, Dennisse Bonilla, Zahi Touma, Carmen Avila-Casado, Heather N Reich, James Scholey, Paul R Fortin, Paul C Boutros, and Carolina Landolt-Marticorena more...
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Medicine ,Science - Abstract
Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN. In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited. more...
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- 2018
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6. Multiple tolerance defects contribute to the breach of B cell tolerance in New Zealand Black chromosome 1 congenic mice.
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Nan-Hua Chang, Kieran P Manion, Christina Loh, Evelyn Pau, Yuriy Baglaenko, and Joan E Wither
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Medicine ,Science - Abstract
Lupus is characterized by a loss of B cell tolerance leading to autoantibody production. In this study, we explored the mechanisms underlying this loss of tolerance using B6 congenic mice with an interval from New Zealand Black chromosome 1 (denoted c1(96-100)) sufficient for anti-nuclear antibody production. Transgenes for soluble hen egg white lysozyme (sHEL) and anti-HEL immunoglobulin were crossed onto this background and various tolerance mechanisms examined. We found that c1(96-100) mice produced increased levels of IgM and IgG anti-HEL antibodies compared to B6 mice and had higher proportions of germinal center B cells and long-lived plasma cells, suggesting a germinal center-dependent breach of B cell anergy. Consistent with impaired anergy induction, c1(96-100) double transgenic B cells showed enhanced survival and CD86 upregulation. Hematopoietic chimeric sHEL mice with a mixture of B6 and c1(96-100) HEL transgenic B cells recapitulated these results, suggesting the presence of a B cell autonomous defect. Surprisingly, however, there was equivalent recruitment of B6 and c1(96-100) B cells into germinal centers and differentiation to splenic plasmablasts in these mice. In contrast, there were increased proportions of c1(96-100) T follicular helper cells and long-lived plasma cells as compared to their B6 counterparts, suggesting that both B and T cell defects are required to breach germinal center tolerance in this model. This possibility was further supported by experiments showing an enhanced breach of anergy in double transgenic mice with a longer chromosome 1 interval with additional T cell defects. more...
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- 2017
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7. IL-10 Production Is Critical for Sustaining the Expansion of CD5+ B and NKT Cells and Restraining Autoantibody Production in Congenic Lupus-Prone Mice.
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Yuriy Baglaenko, Kieran P Manion, Nan-Hua Chang, Eric Gracey, Christina Loh, and Joan E Wither
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Medicine ,Science - Abstract
The development and progression of systemic lupus erythematosus is mediated by the complex interaction of genetic and environmental factors. To decipher the genetics that contribute to pathogenesis and the production of pathogenic autoantibodies, our lab has focused on the generation of congenic lupus-prone mice derived from the New Zealand Black (NZB) strain. Previous work has shown that an NZB-derived chromosome 4 interval spanning 32 to 151 Mb led to expansion of CD5+ B and Natural Killer T (NKT) cells, and could suppress autoimmunity when crossed with a lupus-prone mouse strain. Subsequently, it was shown that CD5+ B cells but not NKT cells derived from these mice could suppress the development of pro-inflammatory T cells. In this paper, we aimed to further resolve the genetics that leads to expansion of these two innate-like populations through the creation of additional sub-congenic mice and to characterize the role of IL-10 in the suppression of autoimmunity through the generation of IL-10 knockout mice. We show that expansion of CD5+ B cells and NKT cells localizes to a chromosome 4 interval spanning 91 to 123 Mb, which is distinct from the region that mediates the majority of the suppressive phenotype. We also demonstrate that IL-10 is critical to restraining autoantibody production and surprisingly plays a vital role in supporting the expansion of innate-like populations. more...
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- 2016
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8. T cell and dendritic cell abnormalities synergize to expand pro-inflammatory T cell subsets leading to fatal autoimmunity in B6.NZBc1 lupus-prone mice.
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Nafiseh Talaei, Yui-Ho Cheung, Carolina Landolt-Marticorena, Babak Noamani, Timothy Li, and Joan E Wither
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Medicine ,Science - Abstract
We have previously shown that B6 congenic mice with a New Zealand Black chromosome 1 (c1) 96-100 cM interval produce anti-nuclear Abs and that at least two additional genetic loci are required to convert this subclinical disease to fatal glomerulonephritis in mice with a c1 70-100 cM interval (c1(70-100)). Here we show that the number of T follicular helper and IL-21-, IFN-γ-, and IL-17-secreting CD4(+) T cells parallels disease severity and the number of susceptibility loci in these mice. Immunization of pre-autoimmune mice with OVA recapitulated these differences. Differentiation of naïve T cells in-vitro under polarizing conditions and in-vivo following adoptive transfer of OVA-specific TCR transgenic cells into c1(70-100) or B6 recipient mice, revealed T cell functional defects leading to increased differentiation of IFN-γ- and IL-17-producing cells in the 96-100 cM and 88-96 cM intervals, respectively. However, in-vivo enhanced differentiation of pro-inflammatory T cell subsets was predominantly restricted to c1(70-100) recipient mice, which demonstrated altered dendritic cell function, with increased production of IL-6 and IL-12. The data provide support for the role of pro-inflammatory T cells in the conversion of subclinical disease to fatal autoimmunity and highlight the importance of synergistic interactions between individual susceptibility loci in this process. more...
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- 2013
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9. TLR tolerance reduces IFN-alpha production despite plasmacytoid dendritic cell expansion and anti-nuclear antibodies in NZB bicongenic mice.
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Evelyn Pau, Yui-Ho Cheung, Christina Loh, Ginette Lajoie, and Joan E Wither
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Medicine ,Science - Abstract
Genetic loci on New Zealand Black (NZB) chromosomes 1 and 13 play a significant role in the development of lupus-like autoimmune disease. We have previously shown that C57BL/6 (B6) congenic mice with homozygous NZB chromosome 1 (B6.NZBc1) or 13 (B6.NZBc13) intervals develop anti-nuclear antibodies and mild glomerulonephritis (GN), together with increased T and B cell activation. Here, we produced B6.NZBc1c13 bicongenic mice with both intervals, and demonstrate several novel phenotypes including: marked plasmacytoid and myeloid dendritic cell expansion, and elevated IgA production. Despite these changes, only minor increases in anti-nuclear antibody production were seen, and the severity of GN was reduced as compared to B6.NZBc1 mice. Although bicongenic mice had increased levels of baff and tnf-α mRNA in their spleens, the levels of IFN-α-induced gene expression were reduced. Splenocytes from bicongenic mice also demonstrated reduced secretion of IFN-α following TLR stimulation in vitro. This reduction was not due to inhibition by TNF-α and IL-10, or regulation by other cellular populations. Because pDC in bicongenic mice are chronically exposed to nuclear antigen-containing immune complexes in vivo, we examined whether repeated stimulation of mouse pDC with TLR ligands leads to impaired IFN-α production, a phenomenon termed TLR tolerance. Bone marrow pDC from both B6 and bicongenic mice demonstrated markedly inhibited secretion of IFN-α following repeated stimulation with a TLR9 ligand. Our findings suggest that the expansion of pDC and production of anti-nuclear antibodies need not be associated with increased IFN-α production and severe kidney disease, revealing additional complexity in the regulation of autoimmunity in systemic lupus erythematosus. more...
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- 2012
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10. Assessing the Utility of the Montreal Cognitive Assessment in Screening for Cognitive Impairment in Patients With Systemic Lupus Erythematosus
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Oshrat E. Tayer‐Shifman, Kimberley Yuen, Robin Green, Mahta Kakvan, Patricia Katz, Kathleen S. Bingham, Juan Pablo Diaz‐Martinez, Lesley Ruttan, Joan E. Wither, Maria Carmela Tartaglia, Jiandong Su, Dennisse Bonilla, May Y. Choi, Simone Appenzeller, Michelle Barraclough, Dorcas E. Beaton, and Zahi Touma more...
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Rheumatology - Abstract
Screening for cognitive impairment (CI) in systemic lupus erythematosus (SLE) relies on the American College of Rheumatology (ACR) neuropsychological battery (NB). By studying the concurrent criterion validity, our goal was to assess the Montreal Cognitive Assessment (MoCA) as a screening tool for CI compared to the ACR-NB and to evaluate the added value of the MoCA to the Automated Neuropsychological Assessment Metrics (ANAM).A total of 285 adult SLE patients were administered the ACR-NB, MoCA, and ANAM. For the ACR-NB, patients were classified as having CI if there was a Z score of ≤-1.5 in ≥2 domains. The area under the curve (AUC) and sensitivities/specificities were determined. A discriminant function analysis was applied to assess the ability of the MoCA to differentiate between CI, undetermined CI, and non-CI patients.CI was not accurately identified by the MoCA compared to the ACR-NB (AUC of 0.66). Sensitivity and specificity were poor at 50% and 69%, respectively, for the cutoff of 26, and 80% and 45%, respectively, for the cutoff of 28. The MoCA had a low ability to identify CI status. The addition of the MoCA to the ANAM led to improvement on the AUC by only 2.5%.The MoCA does not have adequate concurrent criterion validity to accurately identify CI in patients with SLE. The low specificity of the MoCA may lead to overdiagnosis and concern among patients. Adding the MoCA to the ANAM does not substantially improve the accuracy of the ANAM. These results do not support using the MoCA as a screening tool for CI in patients with SLE. more...
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- 2022
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11. Association of mycophenolate and azathioprine use with cognitive function in systemic lupus
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Chrisanna Dobrowolski, John McGinley, Melissa Fazzari, Jiandong Su, Kathleen S Bingham, Nicole Anderson, Lesley Ruttan, Dorcas E Beaton, Joan E Wither, Maria Carmela Tartaglia, Mahta Kakvan, Dennisse Bonilla, May Y Choi, Marvin J Fritzler, Juan Pablo Diaz Martinez, Patricia Katz, Robin Green, Chaim Putterman, and Zahi Touma more...
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Rheumatology ,Pharmacology (medical) - Abstract
Objectives Cognitive dysfunction (CD) is a common manifestation of SLE that can have detrimental consequences for those affected. To date, no treatments have been approved for SLE-CD. This study aims to assess the association of azathioprine (AZA) and mycophenolate (MMF) use with SLE-CD, given that these medications have demonstrated neuroprotective qualities in prior studies. Methods Consecutive adult SLE patients presenting to a single healthcare center were considered for participation. The ACR neuropsychological battery for SLE was administered to consenting patients at 0, 6 and 12 months. Scores were compared with age- and sex-matched controls. Primary outcome was CD, defined as a z-score ≤−1.5 in two or more cognitive domains. Mixed-effects logistic regression models were constructed to estimate the odds of CD with respect to AZA and MMF use. Results A total of 300 participants representing 676 patient visits completed the study; 114 (38%) met criteria for CD at baseline. The cumulative AZA dose (g/kg) was associated with reduced odds of CD [odds ratio (OR) 0.76 (95% CI 0.58, 0.98), P = 0.04]. Years of AZA treatment was also associated with reduced odds of CD [OR 0.72 (95% CI 0.54, 0.97), P = 0.03]. MMF use was not associated with CD. Conclusion AZA use was associated with significantly lower odds of SLE-CD, while MMF use was not. Additional studies are warranted to further investigate the relationship of AZA and SLE-CD. more...
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- 2022
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12. Elevated levels of interferon‐α act directly on B cells to breach multiple tolerance mechanisms promoting autoantibody production
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Dario M. Ferri, Carol Nassar, Kieran P. Manion, Michael Kim, Yuriy Baglaenko, Carolina Muñoz‐Grajales, and Joan E. Wither
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Rheumatology ,Immunology ,Immunology and Allergy - Published
- 2023
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13. Metrics and definitions used in the assessment of cognitive impairment in systemic lupus erythematosus: A systematic review
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Melanie Anderson, Victoria Lee-Kim, Lesley Ruttan, Marvin J. Fritzler, Dorcas E. Beaton, Maria Carmela Tartaglia, Robin Green, Kathleen Bingham, Patricia P. Katz, May Y. Choi, Zahi Touma, Moe Zandy, Kimberley Yuen, and Joan E. Wither more...
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Adult ,Ovid medline ,Screening test ,PsycINFO ,Neuropsychological Tests ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Cognitive Dysfunction ,030212 general & internal medicine ,Neuropsychological assessment ,skin and connective tissue diseases ,Cognitive impairment ,030203 arthritis & rheumatology ,Systemic lupus erythematosus ,medicine.diagnostic_test ,business.industry ,Neuropsychological battery ,medicine.disease ,Benchmarking ,Anesthesiology and Pain Medicine ,business ,Clinical psychology - Abstract
Objective To review: 1) degree of conformity to the American College of Rheumatology neuropsychological battery (ACR-NB) among studies that used a NB, 2) review definitions of cognitive impairment (CI) from studies that used a NB, and 3) characterize measurement tools used to assess CI in systemic lupus erythematosus (SLE). Methods The literature search was conducted in Ovid Medline, Embase, and PsycINFO for articles on CI in adult SLE patients. We reviewed studies that used a NB and compared their tests to the ACR-NB to assess the degree of conformity. Definitions of CI from studies that used a NB were reviewed when sufficient information was available. We reviewed and categorized CI measurement tools into four broad categories: NB, screening, incomplete/mixed batteries, and computerized batteries. Results Of 8727 references, 118 were selected for detailed review and 97 were included in the final analysis. Of 43 studies that used a NB, none of the studies used the ACR-NB exactly as published. Many studies supplemented with other tests. Overall, there was inconsistent use of ACR-NB tests. Definitions for CI varied, with cut-offs ranging from 1 to 3 standard deviations below normative values on domains/tests varying in type and number. The most frequently used measurement tool for assessing CI in SLE was a NB. Use of screening tests and computerized batteries have also increased over the last decade. Conclusion The assessment and definition of CI in SLE remains heterogeneous. A consensus meeting to address existing inconsistencies should be considered to harmonize the field of CI in SLE. more...
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- 2021
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14. The liver and muscle secreted Hfe2-protein maintains blood brain barrier integrity
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Angeliki M. Nikolakopoulou, Dene Ringuette, Jason Charish, Joan E. Wither, Alireza P. Shabanzadeh, Seunggi Lee, Horea Rus, Bernhard K. Mueller, Hidekiyo Harada, Jean-François Cloutier, Peter L. Carlen, Philippe P. Monnier, Peter V. DiStefano, Michal Syonov, Thomas Wälchli, Yuriy Baglaenko, Suzie Dufour, Robin J. Vigouroux, Jason E. Fish, Xue Fan Wang, and Berislav V. Zlokovic more...
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medicine.anatomical_structure ,nervous system ,Chemistry ,cardiovascular system ,medicine ,Blood–brain barrier ,Cell biology - Abstract
Liver failure causes blood-brain-barrier (BBB) breakdown leading to central nervous system damage, however the mechanisms whereby the liver influences BBB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BBB integrity. We developed light-sheet imaging for three-dimensional study of BBB function. We show that liver- or muscle-specific knockout of Hfe2 induces BBB breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits. In healthy animals, soluble Hfe2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells and the ensuing BBB disruption. Hfe2 administration in an animal model of multiple sclerosis prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BBB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BBB dysfunction such as multiple sclerosis. more...
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- 2022
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15. The baseline interferon signature predicts disease severity over the subsequent 5 years in systemic lupus erythematosus
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Lloyd Mai, Babak Noamani, Arundip Asaduzzaman, Zahi Touma, Joan E. Wither, Paul R. Fortin, Murray B. Urowitz, and Dafna D. Gladman
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0301 basic medicine ,Oncology ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Severity of Illness Index ,Correlation ,03 medical and health sciences ,0302 clinical medicine ,Systemic lupus erythematosus ,Disease severity ,Prednisone ,Interferon ,Internal medicine ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Disease course ,030203 arthritis & rheumatology ,Receiver operating characteristic ,business.industry ,Rheumatology ,Pathophysiology ,030104 developmental biology ,Cross-Sectional Studies ,Interferon Type I ,SLEDAI-2K ,Biomarker (medicine) ,lcsh:RC925-935 ,business ,Immunosuppressive Agents ,medicine.drug ,Research Article - Abstract
Objectives Type I interferons (IFNs) play an important role in the pathophysiology of systemic lupus erythematosus (SLE). While cross-sectional data suggest an association between IFN-induced gene expression and SLE disease activity, interest in this as a biomarker of flare has been tempered by a lack of fluctuation with disease activity in the majority of patients. This led us to question whether IFN-induced gene expression might instead be a biomarker of overall disease severity, with patients with high levels spending more time in an active disease state. Methods Levels of five interferon-responsive genes were measured in the whole peripheral blood at baseline visit for 137 SLE patients subsequently followed for 5 years. Log transformed values were summed to yield a composite IFN5 score, and the correlation with various disease outcomes examined. Receiver operator characteristic analyses were performed for outcomes of interest. Kaplan-Meier curves were generated to compare the proportion of flare-free patients with high and low IFN5 scores over time. Results The baseline IFN5 score was positively correlated with the adjusted mean SLE disease activity index-2000, number of flares, adjusted mean prednisone dose, and number of new immunosuppressive medications over the subsequent 5 years. Optimal cut-offs for the IFN5 score were determined using Youden’s index and predicted more severe outcomes with 57–67% accuracy. A high baseline IFN5 level was associated with a significantly increased risk of subsequent flare. Conclusions Measurement of the type I IFN signature is a useful tool for predicting the subsequent disease activity course. more...
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- 2021
16. Prevalence and metric of depression and anxiety in systemic lupus erythematosus: A systematic review and meta-analysis
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William A. Fung, Jiandong Su, Zahi Touma, Elvira Bangert, Mitra Moazzami, Maryana Kravtsenyuk, Ahmed T. Moustafa, Mohamed Hassanein, Sherief Marzouk, Lisa Engel, Lihi Eder, and Joan E. Wither
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medicine.medical_specialty ,business.industry ,Beck Anxiety Inventory ,Beck Depression Inventory ,Rating scales for depression ,medicine.disease ,Anesthesiology and Pain Medicine ,Rheumatology ,Meta-analysis ,Internal medicine ,Epidemiology ,medicine ,Anxiety ,medicine.symptom ,business ,Anxiety disorder ,Depression (differential diagnoses) - Abstract
Objectives To systematically review and synthesize literature on 1) the overall prevalence of depression and anxiety in SLE patients in identified studies, and 2) the pooled prevalence per metrics of depression and anxiety in adult SLE patients. Methods This review used (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) PRISMA guidelines and in-depth searches in four databases (1954-2016; Ovid-based Medline, Embase, PsycINFO and CINAHL) to identify articles on the prevalence of depression and/or anxiety in adult SLE patients. Included studies were critically appraised and analyzed. The prevalence of depression and anxiety was studied for all included studies, and whenever possible, pooled prevalence (PP) was determined for more commonly used metrics. Statistical and publication bias was assessed using funnel plots. Result A total of 3103 references were identified, 226 were selected for detailed review and 72 were included in the final analysis. Overall Prevalence The depression PP, obtained from 69 studies representing 23,386 SLE patients, was 35.0% (95% CI: 29.9%-40.3%). The anxiety PP, obtained from 38 studies representing 4439 SLE patients, was 25.8% (95% CI: 19.2%-32.9%). Prevalence per metrics used The more commonly used instruments included the Centre for Epidemiological Studies - Depression (CES-D), Beck Depression Inventory (BDI), Beck Anxiety Inventory (BAI), Hospital Anxiety and Depression Scales (HADS-A/D), and Hamilton Rating Scales for Depression/Anxiety (HAM-D/A)]. The CES-D was utilized in 13 studies including 1856 SLE patients; depression PP was 41.5% (95% CI: 35.1%-48.1%). The BDI was utilized in 14 studies including 1355 SLE patients and the BAI in 3 studies including 489 patients; depression PP was 39.9% (95% CI: 31.1%-49.1) and anxiety PP was 38.4% (95% CI: 34.2%-42.8%). The HADS-D was utilized in 14 studies including 1238 SLE patients and the HADS-A in 12 studies including 1099 patients respectively; it's depression PP was 24.4% (95% CI: 19.1%-30.1%) and anxiety PP was 38.3% (95% CI: 29.1%-47.9%). The HAM-D was utilized in 4 studies including 267 SLE patients and the HAM-A in 4 studies including 213 patients respectively; its depression PP was 40.0% (95% CI: 23.0%-59.0%) and anxiety PP was 39.0% (95% CI: 32.0%-45.0%). Conclusion There was high variability in the prevalence of depression and anxiety, ranging from 8.7%-78.6% and 1.1%-71.4%, respectively. This could be attributed to the lack of consistency in the metrics used and its definition for depression and anxiety in SLE. Studies that used a specific metric, such as the CES-D, BDI or HAM-D, yielded similar depression prevalence. The HADS-D had the lowest prevalence. All metrics of anxiety yielded similar anxiety prevalence. more...
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- 2020
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17. Altered Balance of Pro-Inflammatory Immune Cells to T Regulatory Cells Differentiates Symptomatic From Asymptomatic Individuals With Anti-Nuclear Antibodies
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Rashi Gupta, Emma Vanlieshout, Kieran Manion, Dennisse Bonilla, Michael Kim, Carolina Muñoz-Grajales, Carol Nassar, Sindhu R. Johnson, Linda T. Hiraki, Zareen Ahmad, Zahi Touma, Arthur Bookman, and Joan E. Wither more...
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Antibodies, Antinuclear ,Rheumatic Diseases ,Immunology ,Immunology and Allergy ,Humans ,Autoimmunity ,T-Lymphocytes, Regulatory ,Autoimmune Diseases - Abstract
Systemic Autoimmune Rheumatic Diseases (SARDs) are characterized by the production of anti-nuclear antibodies (ANAs). ANAs are also seen in healthy individuals and can be detected years before disease onset in SARD. Both the immunological changes that promote development of clinical symptoms in SARD and those that prevent autoimmunity in asymptomatic ANA+ individuals (ANA+ NS) remain largely unexplored. To address this question, we used flow cytometry to examine peripheral blood immune populations in ANA+ individuals, with and without SARD, including 20 individuals who subsequently demonstrated symptom progression. Several immune populations were expanded in ANA+ individuals with and without SARD, as compared with ANA- healthy controls, particularly follicular and peripheral T helper, and antibody-producing B cell subsets. In ANA+ NS individuals, there were significant increases in T regulatory subsets and TGF-ß1 that normalized in SARD patients, whereas in SARD patients there were increases in Th2 and Th17 helper cell levels as compared with ANA+ NS individuals, resulting in a shift in the balance between inflammatory and regulatory T cell subsets. Patients with SARD also had increases in the proportion of pro-inflammatory innate immune cell populations, such as CD14+ myeloid dendritic cells, and intermediate and non-classical monocytes, as compared to ANA+ NS individuals. When comparing ANA+ individuals without SARD who progressed clinically over the subsequent 2 years with those who did not, we found that progressors had significantly increased T and B cell activation, as well as increased levels of LAG3+ T regulatory cells and TGF-ß1. Collectively, our findings suggest that active immunoregulation prevents clinical autoimmunity in ANA+ NS and that this becomes impaired in patients who progress to SARD, resulting in an imbalance favoring inflammation. more...
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- 2022
18. Validation of the automated neuropsychological assessment metrics for assessing cognitive impairment in systemic lupus erythematosus
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Kimberley Yuen, Dorcas Beaton, Kathleen Bingham, Patricia Katz, Jiandong Su, Juan Pablo Diaz Martinez, Maria Carmela Tartaglia, Lesley Ruttan, Joan E. Wither, Mahta Kakvan, Nicole Anderson, Dennisse Bonilla, May Y. Choi, Marvin J. Fritzler, Robin Green, and Zahi Touma more...
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Adult ,screening ,lupus ,Neuropsychological Tests ,CART analysis ,Benchmarking ,ANAM ,Rheumatology ,systemic lupus erythematosus ,Papers ,Humans ,Lupus Erythematosus, Systemic ,Cognitive Dysfunction ,cognitive impairment - Abstract
Objective We previously demonstrated the utility of the Automated Neuropsychological Assessment Metrics (ANAM) for screening cognitive impairment (CI) in patients with systemic lupus erythematosus (SLE) and developed composite indices for interpreting ANAM results. Our objectives here were to provide further support for the ANAM’s concurrent criterion validity against the American College of Rheumatology neuropsychological battery (ACR-NB), identify the most discriminatory subtests and scores of the ANAM for predicting CI, and provide a new approach to interpret ANAM results using Classification and Regression Tree (CART) analysis. Methods 300 adult SLE patients completed an adapted ACR-NB and ANAM on the same day. As per objectives, six models were built using combinations of ANAM subtests and scores and submitted to CART analysis. Area under the curve (AUC) was calculated to evaluate the ANAM’s criterion validity compared to the adapted ACR-NB; the most discriminatory ANAM subtests and scores in each model were selected, and performance of models with the highest AUCs were compared to our previous composite indices; decision trees were generated for models with the highest AUCs. Results Two models had excellent AUCs of 86 and 89%. Eight most discriminatory ANAM subtests and scores were identified. Both models demonstrated higher AUCs against our previous composite indices. An adapted decision tree was created to simplify the interpretation of ANAM results. Conclusion We provide further validity evidence for the ANAM as a valid CI screening tool in SLE. The decision tree improves interpretation of ANAM results, enhancing clinical utility. more...
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- 2022
19. 601 An imbalance between regulatory and pro-inflammatory T cell subsets distinguishes symptomatic from asymptomatic individuals with anti-nuclear antibodies
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Arthur Bookman, Joan E. Wither, Linda T Hiraki, Zareen Ahmad, Emma Vanlieshout, Dennisse Bonilla, Kieran P. Manion, Rashi Gupta, Michael Kim, Sindhu R. Johnson, and Zahi Touma
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medicine.anatomical_structure ,Anti-nuclear antibody ,business.industry ,T cell ,Immunology ,Medicine ,medicine.symptom ,Immunologic diseases. Allergy ,RC581-607 ,business ,Asymptomatic - Published
- 2021
20. 1117 SLE phenotypes formed from machine learning and their associations with cognitive impairment
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Lauren Erdman, Jiandong Su, P.P. Katz, Marvin J. Fritzler, Dorcas E. Beaton, Ben Parker, Ian N Bruce, Andrea M. Knight, Mahta Kakvan, Maria Carmela Tartaglia, Zahi Touma, May Y. Choi, Robin Green, Dennisse Bonilla, Juan Pablo Diaz-Martinez, Lesley Ruttan, Joan E. Wither, Michelle Barraclough, and Kathleen Bingham more...
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Immunologic diseases. Allergy ,RC581-607 ,Psychology ,Cognitive impairment ,Neuroscience ,Phenotype - Published
- 2021
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21. 1501 Genetics of age at systemic lupus erythematosus diagnosis
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Sylvia Kamphuis, Declan Webber, Daniela Dominguez, Andrea M. Knight, Mariko L. Ishimori, Karen Onel, Jingjing Cao, Joan E. Wither, Chia-Chi J Lee, Deborah M. Levy, Andrew D. Paterson, Earl D. Silverman, Diane L. Kamen, Caroline A. Jefferies, Zahi Touma, Raffaella L Carlomagno, Janet E. Pope, Murray B. Urowitz, Christine A. Peschken, Dafna D. Gladman, Marisa S. Klein-Gitelman, Daniel J. Wallace, Linda T. Hiraki, and Fangming Liao more...
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Genetics ,Immunologic diseases. Allergy ,RC581-607 ,Biology - Published
- 2021
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22. Serological abnormalities that predict progression to systemic autoimmune rheumatic diseases in antinuclear antibody–positive individuals
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Carolina Muñoz-Grajales, Dennisse Bonilla, Linda T. Hiraki, Arthur Bookman, Andrzej Chruscinski, Joan E. Wither, Sindhu R. Johnson, Zareen Ahmad, Paul C. Boutros, Stephenie D. Prokopec, and Zahi Touma more...
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Adult ,Male ,Screening techniques ,Anti-nuclear antibody ,Clinical Sciences ,Immunology ,SLE ,antinuclear antibodies ,Asymptomatic ,Autoimmune Disease ,Antibodies ,Serology ,Autoimmune Diseases ,Young Adult ,Rheumatology ,Antigen ,Clinical Research ,Predictive Value of Tests ,Antinuclear ,Rheumatic Diseases ,medicine ,2.1 Biological and endogenous factors ,Humans ,Pharmacology (medical) ,Antinuclear antibody positive ,Aetiology ,screening and diagnosis ,business.industry ,Prevention ,Inflammatory and immune system ,Undifferentiated connective tissue disease ,Clinical Science ,Middle Aged ,medicine.disease ,4.1 Discovery and preclinical testing of markers and technologies ,Arthritis & Rheumatology ,Ro52 antigen ,Detection ,Increased risk ,Antibodies, Antinuclear ,Public Health and Health Services ,Disease Progression ,Female ,microarray analysis ,medicine.symptom ,business ,4.2 Evaluation of markers and technologies - Abstract
Objective We investigated the autoantibody (autoAb) profiles in ANA+ individuals lacking systemic autoimmune rheumatic disease (SARD) and early SARD patients to determine the key differences between these groups and identify factors that are associated with an increased risk of symptomatic progression within the next 2 years in ANA+ individuals. Methods Using custom antigen (Ag) microarrays, 144 IgM and IgG autoAbs were surveyed in 84 asymptomatic and 123 symptomatic (48 UCTD and 75 SARD patients) ANA+ individuals. AutoAbs were compared in ANA+ individuals lacking a SARD diagnosis with ≥2 years follow-up (n = 52), including all those who demonstrated progression (n = 14) during this period, with changes over time assessed in a representative subset. Results We show that ANA+ individuals have autoAb to many self-Ags that are not being captured by current screening techniques and very high levels of these autoAbs are predominantly restricted to early SARD patients, with SLE patients displaying reactivity to many more autoAgs than the other groups. In general, the symptoms that developed in progressors mirrored those seen in SARD patients with similar patterns of autoAbs. Only anti-Ro52 Abs were found to predict progression (positive predictive value 46%, negative predictive value 89%). Surprisingly, over 2 years of follow-up the levels of autoAbs remained remarkably stable regardless of whether individuals progressed or not. Conclusion Our findings strongly argue that development of assays with an expanded set of auto-Ags and enhanced dynamic range would improve the diagnostic and prognostic ability of autoAb testing. more...
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- 2021
23. Longitudinal relationships between cognitive domains and depression and anxiety symptoms in systemic lupus erythematosus
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Zahi Touma, Dorcas E. Beaton, May Y. Choi, P.P. Katz, Robin Green, Maria Carmela Tartaglia, Dennisse Bonilla, Nicole Anderson, Marvin J. Fritzler, Mahta Kakvan, Lesley Ruttan, JuanPablo DiazMartinez, Jiandong Su, Kathleen Bingham, and Joan E. Wither more...
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Longitudinal study ,business.industry ,Working memory ,Depression ,Beck Anxiety Inventory ,Neuropsychology ,Cognition ,Anxiety ,Neuropsychological Tests ,Cognitive test ,Anesthesiology and Pain Medicine ,Rheumatology ,Medicine ,Humans ,Lupus Erythematosus, Systemic ,medicine.symptom ,business ,Cognition Disorders ,Depression (differential diagnoses) ,Clinical psychology - Abstract
Objectives To examine i) the relationship between neuropsychological performance and depression and anxiety over time, and ii) the overlap between classification of cognitive dysfunction, anxiety, and depression in SLE. Methods 301 patients with SLE were included. Cognition was measured using a modified version of the ACR neuropsychological battery; cognitive dysfunction was defined as z-scores ≤-1.5 on ≥2 domains. Depression and anxiety were measured using the Beck Depression Inventory-II and the Beck Anxiety Inventory, respectively. All measures were assessed at baseline, 6, and 12 months. Their relationships were analyzed using Multiple Factor Analysis (MFA). Results Anxiety and depression and neuropsychological performance were stable across time. Factor analysis identified two dimensions explaining 42.2% of the variance in neuropsychological performance. The first dimension (33.1% of the variance) included primarily complex cognitive tests measuring executive function; verbal, visual, and working memory; and complex processing speed. The second dimension (9.1% of the variance) included primarily measures of simple information processing speed or motor dexterity. Anxiety and depression scores were consistently related to the first cognitive dimension. There was substantial overlap in participants classified with cognitive dysfunction and anxiety and depression. Conclusions Depression and anxiety symptoms in SLE patients are related to a cognitive dimension incorporating memory, executive function and complex processing speed in a stable manner across one year. Many patients with cognitive dysfunction exhibit clinically significant anxiety and depression. Further research should examine whether cognition improves when anxiety and depression are treated and mechanistic links between anxiety and depression and cognitive dysfunction in SLE. more...
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- 2021
24. Introduction: Metrics and Domains Measured in SLE
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Diane Lacaille, Jorge Sanchez-Guerrero, Dorcas E. Beaton, Taneisha K. McGhie, Joan E. Wither, and Zahi Touma
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Systemic lupus erythematosus ,business.industry ,Clinical settings ,Cognition ,medicine.disease ,Disease activity ,Quality of life (healthcare) ,immune system diseases ,medicine ,Anxiety ,medicine.symptom ,skin and connective tissue diseases ,business ,Construct (philosophy) ,Depression (differential diagnoses) ,Clinical psychology - Abstract
Chapter 1 provides an overview of the five core domains for the appropriate assessment of patients with systemic lupus erythematosus (SLE) for research and clinical settings: disease activity, chronic damage resulting from lupus activity or its treatment, health-related quality of life (HRQoL), adverse events, and economic impact. Emerging concepts in SLE such as frailty are also introduced along with deep insights on selected existing concepts, in particular cognition, depression, and anxiety as well as fatigue. Having explored what needs to be measured in SLE, this chapter then outlines the decision-making process by which candidate instruments are identified and determined to be a match for the target construct (e.g., disease activity). more...
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- 2021
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25. Apoptotic cell–induced AhR activity is required for immunological tolerance and suppression of systemic lupus erythematosus in mice and humans
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Reema Deol, Tiago Medina, Rahul Shinde, Marie Jo Halaby, Yuriy Baglaenko, Zahi Touma, Sathi Babu Chodisetti, Kieran P. Manion, Haiyun Liu, Maria Eldh, Sara Lamorte, Kapil Chaudhary, Andreas Kloetgen, Drew Wallace, Kebria Hezaveh, Tracy L. McGaha, Ankur Chakravarthy, Aristotelis Tsirigos, David H. Munn, Joan E. Wither, Susanne Gabrielsson, Michael P. Madaio, Daniel D. De Carvalho, and Buvana Ravishankar more...
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0301 basic medicine ,medicine.medical_treatment ,Immunology ,Cell ,Apoptosis ,Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Immune Tolerance ,medicine ,Animals ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Transcription factor ,Macrophages ,Peripheral tolerance ,TLR9 ,respiratory system ,respiratory tract diseases ,3. Good health ,030104 developmental biology ,Cytokine ,medicine.anatomical_structure ,Receptors, Aryl Hydrocarbon ,Toll-Like Receptor 9 ,030220 oncology & carcinogenesis ,Signal Transduction - Abstract
The transcription factor AhR modulates immunity at multiple levels. Here we report that phagocytes exposed to apoptotic cells exhibited rapid activation of AhR, which drove production of the cytokine IL-10. Activation of AhR was dependent on interactions between apoptotic-cell DNA and the pattern-recognition receptor TLR9 that was required for the prevention of immune responses to DNA and histones in vivo. Moreover, disease progression in mouse systemic lupus erythematosus (SLE) correlated with strength of the AhR signal, and the disease course could be altered by modulation of AhR activity. Deletion of AhR in the myeloid lineage caused systemic autoimmunity in mice, and an enhanced AhR transcriptional signature correlated with disease in patients with SLE. Thus, AhR activity induced by apoptotic cell phagocytes maintains peripheral tolerance. more...
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- 2018
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26. Insight into intraindividual variability across neuropsychological tests and its association with cognitive dysfunction in patients with lupus
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Dennisse Bonilla, Jennifer Wei He, Nicole Anderson, Juan Pablo Diaz Martinez, Zahi Touma, Lesley Ruttan, Marvin J. Fritzler, Maria Carmela Tartaglia, Dorcas E. Beaton, Jiandong Su, Robin Green, Patricia P. Katz, May Y. Choi, Mahta Kakvan, Joan E. Wither, and Kathleen Bingham more...
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Adult ,medicine.medical_specialty ,Immunology ,Neuropsychological Tests ,psychology ,050105 experimental psychology ,03 medical and health sciences ,0302 clinical medicine ,systemic lupus erythematosus ,Quality of life ,Internal medicine ,Covariate ,Humans ,Medicine ,Cognitive Dysfunction ,autoimmune diseases ,0501 psychology and cognitive sciences ,Association (psychology) ,outcome assessment ,Depression (differential diagnoses) ,030203 arthritis & rheumatology ,Systemic lupus erythematosus ,Depression ,business.industry ,05 social sciences ,Neuropsychology ,Cognition ,General Medicine ,RC581-607 ,medicine.disease ,Epidemiology and Outcomes ,health care ,Logistic Models ,quality of life ,Anxiety ,Immunologic diseases. Allergy ,medicine.symptom ,business - Abstract
ObjectiveDispersion, or variability in an individual’s performance across multiple tasks at a single assessment visit, has been associated with cognitive dysfunction (CD) in many neurodegenerative and neurodevelopmental disorders. We aimed to compute a dispersion score using neuropsychological battery (NB) tests and determine its association with CD in patients with SLE.MethodsCD was defined as a z-score of ≤−1.5 on ≥2 domains of the NB. To compute a type of dispersion score known as the intraindividual SD (ISD), the SD of age-adjusted and sex-adjusted z-scores was calculated for each visit in each patient. To estimate the association between ISD and cognitive status (CD and non-CD), we used multilevel logistic regression, adjusting for clinically important covariates.ResultsA total of 301 adult patients with SLE completed the NB at baseline, 187 of whom were reassessed at 6 months and 189 at 12 months. CD was observed in 35.2% of patients at baseline, 27.8% at 6 months and 28.0% at 12 months. Prior to covariate adjustment, the mean ISD for non-CD was 1.10±0.31 compared with 1.50±0.70 for CD. After adjusting for ethnicity, education, employment, socioeconomic status and anxiety/depression, there was a statistically significant association between ISD and CD (OR for one-unit increase in ISD: 13.56, 95% CI 4.80 to 38.31; OR for 1/10th-unit increase in ISD: 1.30, 95% CI 1.17 to 1.44). Findings were valid across multiple sensitivity analyses.ConclusionThis is the first study to show that patients with SLE who were classified as having CD by the NB had more variability across the NB tests (ie, higher ISD score) compared with those who were not classified as having CD. more...
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- 2021
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27. Invariant NKT Cell Activation Is Potentiated by Homotypic trans-Ly108 Interactions
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Joan E. Wither, Kieran P. Manion, Thierry Mallevaey, Mayra Cruz Tleugabulova, Dario Ferri, Nafiseh Talaei, Nan-Hua Chang, Eric Gracey, and Yuriy Baglaenko
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0301 basic medicine ,Chemokine ,biology ,Cell growth ,Effector ,Immunology ,Cell ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,medicine.anatomical_structure ,CD1D ,MHC class I ,biology.protein ,medicine ,Immunology and Allergy ,Cell activation ,Receptor ,030215 immunology - Abstract
Invariant NKT (iNKT) cells are innate lymphocytes that respond to glycolipids presented by the MHC class Ib molecule CD1d and are rapidly activated to produce large quantities of cytokines and chemokines. iNKT cell development uniquely depends on interactions between double-positive thymocytes that provide key homotypic interactions between signaling lymphocyte activation molecule (SLAM) family members. However, the role of SLAM receptors in the differentiation of iNKT cell effector subsets and activation has not been explored. In this article, we show that C57BL/6 mice containing the New Zealand Black Slam locus have profound alterations in Ly108, CD150, and Ly9 expression that is associated with iNKT cell hyporesponsiveness. This loss of function was only apparent when dendritic cells and iNKT cells had a loss of SLAM receptor expression. Using small interfering RNA knockdowns and peptide-blocking strategies, we demonstrated that trans-Ly108 interactions between dendritic cells and iNKT cells are critical for robust activation. LY108 costimulation similarly increased human iNKT cell activation. Thus, in addition to its established role in iNKT cell ontogeny, Ly108 regulates iNKT cell function in mice and humans. more...
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- 2017
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28. Validity Evidence for the Use of Automated Neuropsychologic Assessment Metrics As a Screening Tool for Cognitive Impairment in Systemic Lupus Erythematosus
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Dennisse Bonilla, Lesley Ruttan, Moe Zandy, Zahi Touma, Sabrina Lombardi, Mahta Kakvan, May Y. Choi, Joan E. Wither, Maria Carmela Tartaglia, Jiandong Su, Nicole Anderson, Robin Green, Oshrat E Tayer-Shifman, Dorcas E. Beaton, and Marvin J. Fritzler more...
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Adult ,Diagnostic Screening Programs ,Male ,medicine.medical_specialty ,Adolescent ,Audiology ,Neuropsychological Tests ,Logistic regression ,03 medical and health sciences ,Automation ,Young Adult ,0302 clinical medicine ,Cognition ,Rheumatology ,Predictive Value of Tests ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Screening tool ,Cognitive Dysfunction ,Neuropsychological assessment ,Cognitive impairment ,Aged ,030203 arthritis & rheumatology ,Systemic lupus erythematosus ,medicine.diagnostic_test ,Adult patients ,Receiver operating characteristic ,business.industry ,Reproducibility of Results ,Gold standard (test) ,Middle Aged ,medicine.disease ,Female ,business - Abstract
OBJECTIVE Screening for cognitive impairment in systemic lupus erythematosus (SLE) conventionally relies on the American College of Rheumatology (ACR) neuropsychologic battery (NB), which is not universally available. To develop a more accessible screening approach, we assessed validity of the Automated Neuropsychological Assessment Metrics (ANAM). Using the ACR NB as the gold standard for cognitive impairment classification, the objectives were 1) to measure overall discriminative validity of the ANAM for cognitive impairment versus no cognitive impairment, 2) to identify ANAM subtests and scores that best differentiate patients with cognitive impairment from those with no cognitive impairment, and 3) to derive ANAM composite indices and cutoffs. METHODS A total of 211 consecutive adult patients, female and male, with SLE were administered the ANAM and ACR NB. 1) For overall discriminative validity of the ANAM, we compared patients with cognitive impairment versus those with no cognitive impairment on 4 scores. 2) Six ANAM models using different scores were developed, and the most discriminatory subtests were selected using logistic regression analyses. The area under the receiver operating characteristic curve (AUC) was calculated to establish ANAM validity against the ACR NB. 3) ANAM composite indices and cutoffs were derived for the best models, and sensitivities and specificities were calculated. RESULTS Patients with no cognitive impairment performed better on most ANAM subtests, supporting ANAM's discriminative validity. Cognitive impairment could be accurately identified by selected ANAM subtests with top models, demonstrating excellent AUCs of 81% and 84%. Derived composite indices and cutoffs demonstrated sensitivity of 78-80% and specificity of 70%. CONCLUSION This study provides support for ANAM's discriminative validity for cognitive impairment and utility for cognitive screening in adult SLE. Derived composite indices and cutoffs enhance clinical applicability. more...
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- 2019
29. Fatigue severity in anti-nuclear antibody-positive individuals does not correlate with pro-inflammatory cytokine levels or predict imminent progression to symptomatic disease
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Dennisse Bonilla, Waleed Hafiz, Sindhu R. Johnson, Larissa Lisnevskaia, Earl D. Silverman, Ariana Bregasi, Carolina Landolt-Marticorena, Arthur Bookman, Joan E. Wither, Babak Noamani, and Rawad Nori
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musculoskeletal diseases ,Adult ,Male ,medicine.medical_specialty ,lcsh:Diseases of the musculoskeletal system ,Fibromyalgia ,Anti-nuclear antibody ,medicine.medical_treatment ,Inflammation ,Disease ,Severity of Illness Index ,Autoimmune Diseases ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Internal medicine ,Rheumatic Diseases ,medicine ,Humans ,030212 general & internal medicine ,Fatigue ,Aged ,Autoantibodies ,030203 arthritis & rheumatology ,biology ,business.industry ,Undifferentiated connective tissue disease ,Middle Aged ,medicine.disease ,Systemic autoimmune rheumatic disease ,Rheumatology ,3. Good health ,Cytokine ,Antibodies, Antinuclear ,biology.protein ,Disease Progression ,Cytokines ,Female ,Antibody ,medicine.symptom ,lcsh:RC925-935 ,Inflammation Mediators ,business ,Risk Reduction Behavior ,Forecasting ,Research Article - Abstract
Background Fatigue is a common symptom of systemic autoimmune rheumatic disease (SARD). Patients with SARD have a protracted pre-clinical phase during which progressive immunologic derangements occur culminating in disease. In this study, we sought to determine when fatigue develops and whether its presence correlates with inflammatory factors or predicts disease progression. Methods Anti-nuclear antibody (ANA)-negative healthy controls (HCs) and ANA-positive participants with no criteria, at least one clinical criteria (undifferentiated connective tissue disease, UCTD), or meeting SARD classification criteria were recruited. Fatigue was assessed using a modified version of the FACIT-F questionnaire and the presence of fibromyalgia determined using a questionnaire based on the modified 2010 ACR criteria. Peripheral blood expression of five IFN-induced genes was quantified by NanoString and the levels of IL-1β, IL-6, or TNF-α by ELISA. Results Fatigue was as prevalent and severe in individuals lacking SARD criteria as it was in UCTD and SARD. Overall, ~ 1/3 of ANA+ subjects met fibromyalgia criteria, with no differences between sub-groups. Although fatigue was more severe in these individuals, those lacking fibromyalgia remained significantly more fatigued than ANA− HC. However, even in these subjects, fatigue correlated with the widespread pain index and symptom severity scores on the fibromyalgia questionnaire. Fatigue was not associated with elevated cytokine levels in any of the ANA+ sub-groups and did not predict imminent disease progression. Conclusions Fatigue is common in ANA+ individuals lacking sufficient criteria for a SARD diagnosis, correlates with fibromyalgia-related symptoms, and is not associated with inflammation or predictive of disease progression. more...
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- 2019
30. 60 Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset with SLE
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Declan Webber, Dafna D. Gladman, Linda T Hiraki, Joan E. Wither, Deborah M. Levy, Jingjing Cao, Murray B. Urowitz, Zahi Touma, Andrew D. Paterson, Lawrence Ng, Earl D. Silverman, and Daniela Dominguez more...
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030203 arthritis & rheumatology ,medicine.medical_specialty ,business.industry ,Lupus nephritis ,Single-nucleotide polymorphism ,Human leukocyte antigen ,medicine.disease ,Tertiary care ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,Funding source ,Internal medicine ,Cohort ,medicine ,Genetic predisposition ,030212 general & internal medicine ,skin and connective tissue diseases ,business - Abstract
Background Lupus nephritis (LN) is one of the most common and severe manifestations of systemic lupus erythematosus (SLE). We tested the association of SLE-risk loci with LN risk in childhood- (cSLE) and adult-onset SLE (aSLE). Methods Two Toronto-based tertiary care SLE cohorts included cSLE (diagnosed Results Of 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk (OR=1.26; 95% CI: 1.09, 1.46, p=0.0006) as was increasing HLA GRS in Europeans (OR=1.55; 95% CI: 1.07, 2.25; p=0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. Conclusions We observed an association between known SLE-risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future directions will include incorporating SLE-risk SNPs specific to non-European ancestral groups and validating findings in an independent cohort. Funding Source(s): Dr. Hiraki: Canadian Institute of Health Research (CIHR) Project Scheme grant more...
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- 2019
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31. Development, Sensibility, and Validity of a Systemic Autoimmune Rheumatic Disease Case Ascertainment Tool
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Susan M. Armstrong, Carolina Landolt-Marticorena, Aileen M. Davis, Joan E. Wither, Sindhu R. Johnson, and Alan M. Borowoy
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Adult ,Male ,medicine.medical_specialty ,Immunology ,Subgroup analysis ,Sensitivity and Specificity ,Polymyositis ,Autoimmune Diseases ,03 medical and health sciences ,0302 clinical medicine ,Rheumatology ,Rheumatic Diseases ,Surveys and Questionnaires ,Internal medicine ,medicine ,Humans ,Immunology and Allergy ,030212 general & internal medicine ,Medical diagnosis ,Myositis ,030203 arthritis & rheumatology ,business.industry ,Medical record ,Middle Aged ,Dermatomyositis ,medicine.disease ,Case ascertainment ,Rheumatoid arthritis ,Physical therapy ,Feasibility Studies ,Female ,business - Abstract
Objective.Case ascertainment through self-report is a convenient but often inaccurate method to collect information. The purposes of this study were to develop, assess the sensibility, and validate a tool to identify cases of systemic autoimmune rheumatic diseases (SARD) in the outpatient setting.Methods.The SARD tool was administered to subjects sampled from specialty clinics. Determinants of sensibility — comprehensibility, feasibility, validity, and acceptability — were evaluated using a numeric rating scale from 1–7. Comprehensibility was evaluated using the Flesch Reading Ease and the Flesch-Kincaid Grade Level. Self-reported diagnoses were validated against medical records using Cohen’s κ statistic.Results.There were 141 participants [systemic lupus erythematosus (SLE), systemic sclerosis (SSc), rheumatoid arthritis, Sjögren syndrome (SS), inflammatory myositis (polymyositis/dermatomyositis; PM/DM), and controls] who completed the questionnaire. The Flesch Reading Ease score was 77.1 and the Flesch-Kincaid Grade Level was 4.4. Respondents endorsed (mean ± SD) comprehensibility (6.12 ± 0.92), feasibility (5.94 ± 0.81), validity (5.35 ± 1.10), and acceptability (3.10 ± 2.03). The SARD tool had a sensitivity of 0.91 (95% CI 0.88–0.94) and a specificity of 0.99 (95% CI 0.96–1.00). The agreement between the SARD tool and medical record was κ = 0.82 (95% CI 0.77–0.88). Subgroup analysis by SARD found κ coefficients for SLE to be κ = 0.88 (95% CI 0.79–0.97), SSc κ = 1.0 (95% CI 1.0–1.0), PM/DM κ = 0.72 (95% CI 0.49–0.95), and SS κ = 0.85 (95% CI 0.71–0.99). The screening questions had sensitivity ranging from 0.96 to 1.0 and specificity ranging from 0.88 to 1.0.Conclusion.This SARD case ascertainment tool has demonstrable sensibility and validity. The use of both screening and confirmatory questions confers added accuracy. more...
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- 2016
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32. Association of systemic lupus erythematosus (SLE) genetic susceptibility loci with lupus nephritis in childhood-onset and adult-onset SLE
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Declan Webber, Andrew D. Paterson, Earl D. Silverman, Lawrence Ng, Zahi Touma, Daniela Dominguez, Linda T. Hiraki, Deborah M. Levy, Murray B. Urowitz, Dafna D. Gladman, Joan E. Wither, and Jingjing Cao more...
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0301 basic medicine ,Adult ,Male ,medicine.medical_specialty ,Adolescent ,Genotype ,Lupus nephritis ,Single-nucleotide polymorphism ,Human leukocyte antigen ,Polymorphism, Single Nucleotide ,White People ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Rheumatology ,Risk Factors ,Internal medicine ,Epidemiology ,medicine ,Genetic predisposition ,Odds Ratio ,Humans ,Lupus Erythematosus, Systemic ,Pharmacology (medical) ,Genetic Predisposition to Disease ,Age of Onset ,Child ,030203 arthritis & rheumatology ,business.industry ,Odds ratio ,medicine.disease ,Lupus Nephritis ,3. Good health ,030104 developmental biology ,Logistic Models ,Genetic Loci ,Cohort ,Female ,business - Abstract
ObjectiveLN is one of the most common and severe manifestations of SLE. Our aim was to test the association of SLE risk loci with LN risk in childhood-onset SLE (cSLE) and adult-onset SLE (aSLE).MethodsTwo Toronto-based tertiary care SLE cohorts included cSLE (diagnosed ResultsOf 1237 participants, 572 had cSLE (41% with LN) and 665 had aSLE (30% with LN). Increasing non-HLA GRS was significantly associated with increased LN risk [odds ratio (OR) = 1.26; 95% CI 1.09, 1.46; P = 0.0006], as was increasing HLA GRS in Europeans (OR = 1.55; 95% CI 1.07, 2.25; P = 0.03). There was a trend for stronger associations between both GRSs and LN risk in Europeans with cSLE compared with aSLE. When restricting cases to proliferative LN, the magnitude of these associations increased for both the non-HLA (OR = 1.30; 95% CI 1.10, 1.52; P = 0.002) and HLA GRS (OR = 1.99; 95% CI 1.29, 3.08; P = 0.002).ConclusionWe observed an association between known SLE risk loci and LN risk in children and adults with SLE, with the strongest effect observed among Europeans with cSLE. Future studies will include SLE-risk single nucleotide polymorphisms specific to non-European ancestral groups and validate findings in an independent cohort. more...
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- 2019
33. The presence of anti-nuclear antibodies alone is associated with changes in B cell activation and T follicular helper cells similar to those in systemic autoimmune rheumatic disease
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Sindhu R. Johnson, Babak Noamani, Kieran P. Manion, Sina Rusta-Sellehy, Arthur Bookman, Yuriy Baglaenko, Carolina Landolt-Marticorena, Dennisse Bonilla, Joan E. Wither, Larissa Lisnevskaia, Waleed Hafiz, Earl D. Silverman, Nan-Hua Chang, and Dario Ferri more...
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Male ,0301 basic medicine ,lcsh:Diseases of the musculoskeletal system ,Anti-nuclear antibody ,Lymphocyte Activation ,Arthritis, Rheumatoid ,Cohort Studies ,0302 clinical medicine ,immune system diseases ,Medicine ,skin and connective tissue diseases ,B-Lymphocytes ,B cell ,biology ,Undifferentiated connective tissue disease ,T-Lymphocytes, Helper-Inducer ,Middle Aged ,Anti-nuclear antibodies ,3. Good health ,medicine.anatomical_structure ,Antibodies, Antinuclear ,Female ,medicine.symptom ,Antibody ,Research Article ,Adult ,musculoskeletal diseases ,medicine.medical_specialty ,T cell ,Plasma Cells ,Asymptomatic ,Autoimmune Diseases ,03 medical and health sciences ,Rheumatic Diseases ,Internal medicine ,Humans ,B-cell activating factor ,Aged ,030203 arthritis & rheumatology ,business.industry ,medicine.disease ,Systemic autoimmune rheumatic disease ,Rheumatology ,stomatognathic diseases ,030104 developmental biology ,Immunology ,biology.protein ,lcsh:RC925-935 ,business - Abstract
Background Diagnosis of systemic autoimmune rheumatic diseases (SARD) relies on the presence of hallmark anti-nuclear antibodies (ANA), many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals, most of whom will not develop SARD. Here, we examined a unique cohort of asymptomatic ANA+ individuals to determine whether they share any of the cellular immunologic features seen in SARD. Methods Healthy ANA− controls and ANA+ (ANA ≥1:160 by immunofluorescence) participants with no SARD criteria, with at least one criterion (undifferentiated connective tissue disease (UCTD)), or meeting SARD classification criteria were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry and transcript levels of BAFF, interferon (IFN)-induced and plasma cell-expressed genes were quantified by NanoString. Results A number of the immunologic abnormalities seen in SARD, including changes in peripheral B (switched memory) and T (iNKT, T regulatory, activated memory T follicular helper) subsets and B cell activation, were also seen in asymptomatic ANA+ subjects and those with UCTD. The extent of these immunologic changes correlated with ANA titer or the number of different specific ANAs produced. Principal component analysis of the cellular data indicated that a significant proportion of asymptomatic ANA+ subjects and subjects with UCTD clustered with patients with early SARD, rather than ANA− healthy controls. Conclusions ANA production is associated with altered T and B cell activation even in asymptomatic individuals. Some of the currently accepted cellular features of SARD may be associated with ANA production rather than the immunologic events that cause symptoms in SARD. Electronic supplementary material The online version of this article (10.1186/s13075-018-1752-3) contains supplementary material, which is available to authorized users. more...
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- 2018
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34. AI-09 T follicular helper (Tfh) cells are increased in asymptomatic anti-nuclear antibody (ANA)+ individuals and appear to play a role in epitope spreading
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Larissa Lisnevskaia, Earl D. Silverman, Babak Noamani, Zahi Touma, Sina Rusta-Sellehy, Ariana Karanxha, Waleed Hafiz, Carolina Landolt-Marticorena, Nan-Hua Chang, Sindhu R. Johnson, Joan E. Wither, Kieran P. Manion, Dennisse Bonilla, Arthur Bookman, Yuriy Baglaenko, and Dario Ferri more...
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CD86 ,Anti-nuclear antibody ,medicine.diagnostic_test ,business.industry ,FOXP3 ,Immunofluorescence ,Asymptomatic ,Flow cytometry ,stomatognathic diseases ,Immune system ,immune system diseases ,Immunology ,medicine ,medicine.symptom ,skin and connective tissue diseases ,business ,Memory B cell - Abstract
Background The diagnosis of Systemic Autoimmune Rheumatic Diseases (SARD), including Systemic Lupus Erythematosus (SLE), relies on the presence of ANAs, many of which can be detected years before clinical manifestations. However, ANAs are also seen in healthy individuals most of whom will not develop SARD. A number of cellular immune changes are seen in SARD, and thus could constitute potential biomarkers/treatment targets for SARD, however it is not known at what point in disease progression these develop. Methods Healthy ANA- controls (n=32) and ANA+ (≥1:160 by immunofluorescence) participants with no (asymptomatic ANA+, n=61), at least one (UCTD, n=35), or meeting SARD classification criteria (n=59) were recruited. Peripheral blood cellular immunological changes were assessed by flow cytometry. Results Consistent with previous reports, SARD patients had increased proportions of activated B cells (CD86+ or CD95+) and in the SLE patient subset there were increased proportions of plasma cells/plasmablasts, as compared to ANA- controls. SARD patients also had reduced proportions of iNKT and IFN-γ producing cells, as well as, increased proportions of memory Tfh (CD4+CXCR5hiPD1hi) and T regulatory (Treg, CD4+FOXP3+HELIOS+) cells, especially in the SLE and Sjogren’s Disease patient subsets. In asymptomatic ANA+ individuals and UCTD patients, similar increases in the proportion of activated B cells, Tfh, and Treg cells, and decreases in the proportion of iNKT and IFN-γ producing cells were seen to those in SARD. In asymptomatic ANA+ individuals and SARD patients, the extent of serologic changes (number of specific ANAs detected by Bioplex® 2200 ANA screening system) positively correlated with activation in the switched memory B cell compartment and the proportion of Tfh cells, with the later being an independent predictor of serologic status in a multivariate analysis. However, significantly elevated levels of Tfh cells could still be seen in asymptomatic ANA+ individuals who lacked specific ANAs. Consistent with a role for Tfh cell in ANA production there was a strong correlation between the proportion of Tfh and plasma cells in asymptomatic ANA+ individuals. In preliminary studies, the majority of Tfh cells in asymptomatic ANA+ and UCTD patients were Tfh2 cells, with a trend to increased proportions of Tfh2 cells and decreased proportions Tfh17 cells as compared to active SLE patients. Conclusions Tfh cells appear to play an important role in the development of a positive ANA and in the epitope spreading that may accompany disease progression, and therefore constitute a promising target for treatment of early disease. more...
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- 2018
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35. CS-37 Prevalence of cognitive impairment in systemic lupus erythematosus assessed by a comprehensive neuropsychological battery
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Dorcas E. Beaton, Marvin J. Fritzler, Dennise Bonilla, Sabrina Lombardi, Jiandong Su, Lisa Engel, Zahi Touma, Lesley Ruttan, Robin Green, Kenneth Colosimo, Nicole Anderson, Michelle Vitti, Joan E. Wither, and Carmela Tartaglia more...
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medicine.medical_specialty ,business.industry ,Sample size determination ,Internal medicine ,Neuropsychology ,Medicine ,Verbal fluency test ,In patient ,Cognition ,Neuropsychological battery ,business ,Single Center ,Cognitive impairment - Abstract
Background Cognitive impairment (CI) is a common neurobehavioural manifestation of systemic lupus erythematosus (SLE). In our recent systematic review, the prevalence of CI was 38% (95% CI 33% to 43%) with a wide variation (15%–79%), which may be due to differences in CI definitions and selection of neuropsychological tests across studies. We aim to report the prevalence of CI in a large cohort using a comprehensive battery (CB) of tests in which we operationalized the classification of CI. Methods Consecutive consenting SLE patients, aged 18–65 years, who attended a single center (Jul 2016-Feb 2018) were recruited. Patients were administered a CB that evaluates the major cognitive domains: Manual motor speed and dexterity, simple attention and processing speed, visual-spatial construction, verbal fluency, learning and memory (visuospatial and memory), executive functioning (untimed and timed). Patient scores were compared to a normative sample of age- and gender-matched healthy controls to obtain z-scores. CI was operationalized on the CB as a z-score of ≤−1.5 (as compared to controls) on ≥2 domains or z≤−2.0 on ≥1 domain. Descriptive statistics were used. Results Of the 199 patients (89% female), the mean age at SLE diagnosis was 28.3±10.4 and disease duration at enrolment was 14.3±10.2 years. The prevalence of CI was 37.7% (z≤−1.5 in ≥2 domains) and 49.8% (z≤−2.0 in ≥1 domains). Prevalence of patients with domain z-scores of ≤−1.5 and ≤−2.0 varied from 3.0%–46.2% and 0.5%–25.1% respectively (figure 1). The most affected domain was learning and memory (visuospatial and memory) in 92 (46.2%) patients based on z≤−1.5 on ≥2 subtests and 50 (25.1%) patients based on z≤−2.0 in ≥1 subtest. Conclusion Prevalence of CI using our CB ranged between 37.7%–49.8% (z≤−1.5 in≥2 domains and z≤−2.0 in≥1 domains respectively), which was higher than the pooled prevalence from previous reports of 38%. These differences in CI prevalence across studies could be attributed to different factors including the heterogeneity in patients’ demographics/comorbidities, sample size, the use of different metrics to determine CI, and the lack of a standardized definition of CI. Further studies are required to identify the best definition for CI and its metrics. Acknowledgment This project is funded by the Arthritis Society and the Physicians’ Services Incorporated Foundation. more...
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- 2018
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36. Identification of the SLAM Adapter Molecule EAT-2 as a Lupus-Susceptibility Gene That Acts through Impaired Negative Regulation of Dendritic Cell Signaling
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Nafiseh Talaei, Kieran P. Manion, Tao Yu, Rod Bremner, and Joan E. Wither
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Cellular differentiation ,T cell ,CD40 Ligand ,Molecular Sequence Data ,Immunology ,Congenic ,Lymphocyte Activation ,p38 Mitogen-Activated Protein Kinases ,Interleukin-12 Subunit p35 ,Proinflammatory cytokine ,Mice ,medicine ,Animals ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,RNA, Small Interfering ,Cells, Cultured ,Adaptor Proteins, Signal Transducing ,Gene knockdown ,CD40 ,Base Sequence ,Mice, Inbred NZB ,biology ,JNK Mitogen-Activated Protein Kinases ,Cell Differentiation ,Dendritic Cells ,Dendritic cell ,Th1 Cells ,Molecular biology ,Coculture Techniques ,medicine.anatomical_structure ,Antibodies, Antinuclear ,biology.protein ,Female ,RNA Interference ,Signal transduction ,Signal Transduction - Abstract
We showed previously that C57BL/6 congenic mice with an introgressed homozygous 70 cM (125.6 Mb) to 100 cM (179.8 Mb) interval on c1 from the lupus-prone New Zealand Black (NZB) mouse develop high titers of antinuclear Abs and severe glomerulonephritis. Using subcongenic mice, we found that a genetic locus in the 88–96 cM region was associated with altered dendritic cell (DC) function and synergized with T cell functional defects to promote expansion of pathogenic proinflammatory T cell subsets. In this article, we show that the promoter region of the NZB gene encoding the SLAM signaling pathway adapter molecule EWS-activated transcript 2 (EAT-2) is polymorphic, which results in an ∼70% reduction in EAT-2 in DC. Silencing of the EAT-2 gene in DC that lacked this polymorphism led to increased production of IL-12 and enhanced differentiation of T cells to a Th1 phenotype in T cell–DC cocultures, reproducing the phenotype observed for DC from congenic mice with the NZB c1 70–100 cM interval. SLAM signaling was shown to inhibit production of IL-12 by CD40L-activated DCs. Consistent with a role for EAT-2 in this inhibition, knockdown of EAT-2 resulted in increased production of IL-12 by CD40-stimulated DC. Assessment of downstream signaling following CD40 cross-linking in the presence or absence of SLAM cross-linking revealed that SLAM coengagement blocked activation of p38 MAPK and JNK signaling pathways in DC, which was reversed in DC with the NZB EAT-2 allele. We conclude that EAT-2 negatively regulates cytokine production in DC downstream of SLAM engagement and that a genetic polymorphism that disturbs this process promotes the development of lupus. more...
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- 2015
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37. Interferon-α induces altered transitional B cell signaling and function in Systemic Lupus Erythematosus
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Nan-Hua Chang, Paul R. Fortin, Julie J. Kim, Murray B. Urowitz, Joan E. Wither, Carolina Landolt-Marticorena, Timothy T. Li, and Dafna D. Gladman
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Adult ,Male ,Cell signaling ,Adolescent ,Immunology ,Cell ,Naive B cell ,B-Lymphocyte Subsets ,Syk ,Apoptosis ,Young Adult ,medicine ,Humans ,Lupus Erythematosus, Systemic ,Syk Kinase ,Immunology and Allergy ,Phosphorylation ,Receptor ,Cells, Cultured ,B cell ,Cell Proliferation ,B-Lymphocytes ,Systemic lupus erythematosus ,biology ,Intracellular Signaling Peptides and Proteins ,Interferon-alpha ,Cell Differentiation ,Protein-Tyrosine Kinases ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,Immunoglobulin M ,biology.protein ,Cancer research ,Female ,Antibody ,Signal Transduction - Abstract
Previous studies suggest that the B cells of patients with Systemic Lupus Erythematosus (SLE) are hyper-responsive to BCR crosslinking; however, it has been unclear whether this is the result of altered B cell signaling or differences in various B cell subpopulations in SLE patients as compared to healthy controls. Here we have developed a novel Phosflow technique that permits examination of cell signaling in distinct B cell subpopulations stratified based upon developmental stage and cell surface IgM levels, which we use to show that the naïve B cells of SLE patients are hyper-responsive to IgM receptor crosslinking, resulting in increased SYK phosphorylation. We further demonstrate that this hyper-responsiveness is most marked in the transitional B cell subset and that it is associated with altered function, resulting in decreased apoptosis and increased proliferation of these cells. Examination of repeated samples from the same patients revealed that the hyper-responsiveness fluctuated over time, suggesting that it may be mediated by pro-inflammatory factors rather than genetic variations between patients. In support of this concept, incubation of healthy control B cells with IFN-α or SLE plasma induced the hyper-responsive phenotype, which was blocked by anti-IFN-α antibody. Furthermore, no obvious correlation was seen between genetic variants that are proposed to alter BCR signaling and the increased SYK phosphorylation. The findings suggest that pro-inflammatory factors, in particular Type I IFNs, modulate B cell function in SLE in a way that could contribute to the breach of tolerance in this condition. more...
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- 2015
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38. Anti-dsDNA and Antichromatin Antibody Isotypes in Serologically Active Clinically Quiescent Systemic Lupus Erythematosus
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Joan E. Wither, Timothy Li, Murray B. Urowitz, Dominique Ibañez, Amanda Steiman, and Dafna D. Gladman
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Adult ,Male ,Immunology ,Subclass ,Serology ,Disease activity ,Rheumatology ,Humans ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Medicine ,skin and connective tissue diseases ,Aged ,Autoantibodies ,biology ,business.industry ,Autoantibody ,DNA ,Igg subclasses ,Middle Aged ,Isotype ,Chromatin ,Immunoglobulin Isotypes ,biology.protein ,Female ,Anti dsdna ,Antibody ,business - Abstract
Objective.Serologically active clinically quiescent (SACQ) patients with systemic lupus erythematosus (SLE) are clinically quiescent despite serologic activity. Since studies suggest that antichromatin antibodies are more sensitive than anti-dsDNA antibodies in detecting active SLE, and that immunoglobulin (Ig) G, in particular complement-fixing subclasses, may be more pathogenic than IgM, we investigated the levels of anti-dsDNA and antichromatin isotypes in SACQ patients as compared to non-SACQ patients with SLE.Methods.Levels of IgM, IgA, IgG, and IgG1–4 antichromatin and anti-dsDNA were measured by ELISA. SACQ was defined as ≥ 2 years with the SLE Disease Activity Index 2000 (SLEDAI-2K) at 2 or 4 from serologic activity, during which patients could be taking antimalarials, but not corticosteroids or immunosuppressives. Unselected non-SACQ patients with SLE were used as comparators. SACQ patient serum samples were further stratified based on subsequent development of flare, defined as clinical SLEDAI-2K ≥ 1 and/or treatment initiation. Nonparametric statistics were used, and generalized estimating equations were applied to account for multiple samples in the same patient.Results.SACQ patients’ complement-fixing antichromatin and anti–dsDNA IgG subclasses were significantly higher than those of non-SACQ patients. When the sample drawn latest in a SACQ period was analyzed, there was no difference between antichromatin or anti-dsDNA isotype or IgG subclass levels between patients who flared and those who remained SACQ, nor were consistent trends seen when samples were examined during SACQ and flare in the same patient.Conclusion.The SACQ phenotype does not arise from a lack of pathogenic anti-dsDNA and/or antichromatin autoantibodies. Neither increases in antichromatin nor anti-dsDNA isotype or IgG subclass levels were predictive of or coincident with flare in SACQ patients. more...
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- 2015
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39. Genetic engineering in primary human B cells with CRISPR-Cas9 ribonucleoproteins
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Juan Carlos Zúñiga-Pflücker, Theodore L. Roth, Joan E. Wither, Dario Ferri, Alexander Marson, Kristina W. Rosbe, Chung-An M. Wu, Christopher D.C. Allen, Yuriy Baglaenko, and Patrick M. Brauer
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0301 basic medicine ,Adult ,Adolescent ,Sialic Acid Binding Ig-like Lectin 2 ,Immunology ,Palatine Tonsil ,Computational biology ,Biology ,Article ,Genome engineering ,Cell Line ,Homology directed repair ,03 medical and health sciences ,Gene Knockout Techniques ,Young Adult ,Genome editing ,medicine ,Immunology and Allergy ,CRISPR ,Humans ,Gene knockout ,B cell ,Ribonucleoprotein ,B-Lymphocytes ,Cas9 ,Recombinational DNA Repair ,030104 developmental biology ,medicine.anatomical_structure ,Ribonucleoproteins ,Mutation ,CRISPR-Cas Systems ,Genetic Engineering - Abstract
Genome editing in human cells with targeted nucleases now enables diverse experimental and therapeutic genome engineering applications, but extension to primary human B cells remains limited. Here we report a method for targeted genetic engineering in primary human B cells, utilizing electroporation of CRISPR-Cas9 ribonucleoproteins (RNPs) to introduce gene knockout mutations at protein-coding loci with high efficiencies that in some cases exceeded 80%. Further, we demonstrate knock-in editing of targeted nucleotides with efficiency exceeding 10% through co-delivery of oligonucleotide templates for homology directed repair. We delivered Cas9 RNPs in two distinct in vitro culture systems to achieve editing in both undifferentiated B cells and activated B cells undergoing differentiation, reflecting utility in diverse experimental conditions. In summary, we demonstrate a powerful and scalable research tool for functional genetic studies of human B cell biology that may have further applications in engineered B cell therapeutics. more...
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- 2018
40. Identification of a neutrophil-related gene expression signature that is enriched in adult systemic lupus erythematosus patients with active nephritis: Clinical/pathologic associations and etiologic mechanisms
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Carolina Landolt-Marticorena, Heather N. Reich, James W. Scholey, Dennisse Bonilla, Babak Noamani, Paul C. Boutros, Paul R. Fortin, Stephenie D. Prokopec, Nan-Hua Chang, Joan E. Wither, Zahi Touma, Carmen Avila-Casado, and Zhou, Xu-jie more...
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0301 basic medicine ,Male ,Kidney Disease ,Physiology ,Microarrays ,Neutrophils ,Biopsy ,Lupus nephritis ,Gene Expression ,lcsh:Medicine ,Cell Count ,Biochemistry ,Transcriptome ,White Blood Cells ,0302 clinical medicine ,Animal Cells ,Medicine and Health Sciences ,Medicine ,lcsh:Science ,screening and diagnosis ,Multidisciplinary ,Proteinuria ,medicine.diagnostic_test ,Middle Aged ,Lupus Nephritis ,Body Fluids ,3. Good health ,Detection ,Blood ,Bioassays and Physiological Analysis ,Biomarker (medicine) ,Female ,Renal biopsy ,Cellular Types ,Anatomy ,medicine.symptom ,Nephritis ,Research Article ,Adult ,General Science & Technology ,Immune Cells ,Immunology ,Lupus ,Surgical and Invasive Medical Procedures ,Research and Analysis Methods ,Systemic Lupus Erythematosus ,Autoimmune Disease ,Autoimmune Diseases ,03 medical and health sciences ,Young Adult ,Rheumatology ,Clinical Research ,Genetics ,Humans ,030203 arthritis & rheumatology ,Blood Cells ,Lupus Erythematosus ,business.industry ,Gene Expression Profiling ,Inflammatory and immune system ,lcsh:R ,Biology and Life Sciences ,Cell Biology ,medicine.disease ,4.1 Discovery and preclinical testing of markers and technologies ,Gene expression profiling ,030104 developmental biology ,Clinical Immunology ,lcsh:Q ,Interferons ,Clinical Medicine ,business ,Biomarkers - Abstract
Both a lack of biomarkers and relatively ineffective treatments constitute impediments to management of lupus nephritis (LN). Here we used gene expression microarrays to contrast the transcriptomic profiles of active SLE patients with and without LN to identify potential biomarkers for this condition. RNA isolated from whole peripheral blood of active SLE patients was used for transcriptomic profiling and the data analyzed by linear modeling, with corrections for multiple testing. Results were validated in a second cohort of SLE patients, using NanoString technology. The majority of genes demonstrating altered transcript abundance between patients with and without LN were neutrophil-related. Findings in the validation cohort confirmed this observation and showed that levels of RNA abundance in renal remission were similar to active patients without LN. In secondary analyses, RNA abundance correlated with disease activity, hematuria and proteinuria, but not renal biopsy changes. As abundance levels of the individual transcripts correlated strongly with each other, a composite neutrophil score was generated by summing all levels before examining additional correlations. There was a modest correlation between the neutrophil score and the blood neutrophil count, which was largely driven by the dose of glucocorticosteroids and not the proportion of low density and/or activated neutrophils. Analysis of longitudinal data revealed no correlation between baseline neutrophil score or changes over the first year of follow-up with subsequent renal flare or treatment outcomes, respectively. The findings argue that although the neutrophil score is associated with LN, its clinical utility as a biomarker may be limited. more...
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- 2018
41. A tyrosine sulfation-dependent HLA-I modification identifies memory B cells and plasma cells
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Paolo Campisi, Theresa Holler, Leslie Y. T. Leung, Chunxia Zou, Jonathan St-Germain, Joan E. Wither, Eyal Grunebaum, Srijit Khan, Justin Chan, Christopher W. Cairo, Alexander F. Palazzo, Max D. Cooper, Yanling Liu, Götz R. A. Ehrhardt, Evan J. Propst, Michael F. Moran, Mengyao Shi, Amit Bar-Or, and Judi Yang more...
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0301 basic medicine ,Tyrosine sulfation ,Multiple Sclerosis ,Plasma Cells ,Immunology ,Immunoglobulin Variable Region ,Human leukocyte antigen ,03 medical and health sciences ,0302 clinical medicine ,Antigen ,Animals ,Humans ,Lupus Erythematosus, Systemic ,14. Life underwater ,Tyrosine ,Memory B cell ,Cells, Cultured ,Research Articles ,B-Lymphocytes ,Multidisciplinary ,Cluster of differentiation ,biology ,Chemistry ,Histocompatibility Antigens Class I ,Antibodies, Monoclonal ,Lampreys ,SciAdv r-articles ,3. Good health ,Cell biology ,Receptors, Antigen ,030104 developmental biology ,Monoclonal ,biology.protein ,Antibody ,human activities ,Immunologic Memory ,030215 immunology ,Research Article - Abstract
We identify a cell type–specific modification of HLA-I using lamprey VLR antibodies as a new class of research reagents., Memory B cells and plasma cells are antigen-experienced cells tasked with the maintenance of humoral protection. Despite these prominent functions, definitive cell surface markers have not been identified for these cells. We report here the isolation and characterization of the monoclonal variable lymphocyte receptor B (VLRB) N8 antibody from the evolutionarily distant sea lamprey that specifically recognizes memory B cells and plasma cells in humans. Unexpectedly, we determined that VLRB N8 recognizes the human leukocyte antigen–I (HLA-I) antigen in a tyrosine sulfation–dependent manner. Furthermore, we observed increased binding of VLRB N8 to memory B cells in individuals with autoimmune disorders multiple sclerosis and systemic lupus erythematosus. Our study indicates that lamprey VLR antibodies uniquely recognize a memory B cell– and plasma cell–specific posttranslational modification of HLA-I, the expression of which is up-regulated during B cell activation. more...
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- 2017
42. Immunoglobulin G Subclass Analysis in Psoriatic Arthritis
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Arane Thavaneswaran, Dafna D. Gladman, Joan E. Wither, Vinod Chandran, Fawnda Pellett, Amir Haddad, and Fatima Abji
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Adult ,Male ,Immunology ,Abnormal erythrocyte sedimentation rate ,Blood Sedimentation ,Comorbidity ,Monoclonal Gammopathy of Undetermined Significance ,Immunoglobulin G ,Subclass ,Cohort Studies ,Uveitis ,Psoriatic arthritis ,Rheumatology ,Rheumatic Diseases ,Prevalence ,medicine ,Humans ,Immunology and Allergy ,Longitudinal Studies ,Aged ,biology ,medicine.diagnostic_test ,business.industry ,Arthritis, Psoriatic ,C-reactive protein ,Gamma globulin ,Middle Aged ,Inflammatory Bowel Diseases ,medicine.disease ,C-Reactive Protein ,Serum protein electrophoresis ,Disease Progression ,biology.protein ,Female ,business ,Biomarkers ,Monoclonal gammopathy of undetermined significance - Abstract
Objective.The occurrence of monoclonal gammopathy of undetermined significance (MGUS) is common in chronic immune mediated disorders. This increased monoclonal antibody production could result from chronic stimulation of lymphocytes, with the immunoglobulin G (IgG) subtype accounting for the majority of cases in psoriatic arthritis (PsA). We aimed to identify IgG subclass profiles in patients with PsA and to determine association with specific disease characteristics.Methods.Serum samples from 221 patients with PsA from a single cohort were analyzed for their serum IgG subclass levels. All patients fulfilled the ClASsification for Psoriatic ARthritis (CASPAR) criteria and were followed at 6-month to 12-month intervals according to a standard protocol. MGUS was defined as the occurrence of a discrete band in the gammaglobulin region on at least 2 separate serum protein electrophoresis tests performed 6 months apart. Patients with high abnormal IgG subclass levels were compared to patients with normal levels using descriptive tests.Results.Elevations of IgG1-4 were common in PsA, with ∼20%–49% of patients having elevations of each subclass, IgG2 being the most common subclass abnormality. However, no clinical-serological correlation was found in the group with abnormal IgG2 levels. Of the 38 patients with MGUS, elevations in IgG1 were most common. Patients with an abnormal IgG1 subclass level were more likely to have a discrete band in the gammaglobulin region, higher prevalence of MGUS, and abnormal erythrocyte sedimentation rate or C-reactive protein levels.Conclusion.Determination of the IgG subclass concentration in PsA did not seem to add any significant value in identifying specific disease manifestations. However, this study provides insight into the pathological process leading to MGUS in PsA. more...
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- 2014
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43. Anti-nucleosome antibodies outperform traditional biomarkers as longitudinal indicators of disease activity in systemic lupus erythematosus
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Stephenie D. Prokopec, Timothy Li, Stacey Morrison, Wendy Lou, James W. Scholey, Carolina Landolt-Marticorena, Paul C. Boutros, Dafna D. Gladman, Heather Reich, Murray B. Urowitz, Joan E. Wither, and Paul R. Fortin more...
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Adult ,Male ,Time Factors ,Adolescent ,Cross-sectional study ,Sensitivity and Specificity ,Severity of Illness Index ,Young Adult ,Rheumatology ,Severity of illness ,Humans ,Lupus Erythematosus, Systemic ,Medicine ,Pharmacology (medical) ,Longitudinal Studies ,Prospective Studies ,Young adult ,skin and connective tissue diseases ,Prospective cohort study ,Aged ,biology ,business.industry ,Anti-dsDNA antibodies ,Complement C3 ,DNA ,Middle Aged ,Clinical Science ,Antibodies, Anti-Idiotypic ,Nucleosomes ,Cross-Sectional Studies ,Immunology ,biology.protein ,Biomarker (medicine) ,Female ,Analysis of variance ,Antibody ,business ,Biomarkers - Abstract
Objective. The aim of this study was to determine whether anti-nucleosome antibodies function as activity-specific biomarkers in SLE. Methods. Fifty-one patients were recruited and followed prospectively with periodic clinical and biochemical assessments over a 14-month period. Disease activity was determined by the SLEDAI-2K. Anti-nucleosome antibody levels were measured by an ELISA and its utility as an activity-specific biomarker as compared with that of anti-dsDNA antibodies and C3 was assessed both at baseline and in longitudinal analysis. Results. Anti-nucleosome antibodies were significantly elevated in SLE patients vs controls and showed a moderate positive correlation with disease activity. The utility of anti-nucleosome antibodies in identifying patients with active disease in a cross-sectional analysis was comparable to that of anti-dsDNA antibodies and C3. Analysis of variance demonstrated that the level of anti-nucleosome antibodies and C3 varied significantly with changes in disease activity over time. Changes in clinical state were not mirrored by changes in anti-dsDNA antibodies. In time-dependent analysis, anti-nucleosome antibodies showed a better fit over time than anti-dsDNA antibodies and C3. In pairwise comparisons, C3 and anti-nucleosome antibodies outperformed other models, including the conventional pairing of C3 and anti-dsDNA antibodies, however, no biomarker alone or as a group accurately predicted impending remissions or exacerbations. Conclusion. Anti-nucleosome antibodies demonstrate greater fidelity as a biomarker for changes in SLE disease activity than traditional biomarkers, supporting the routine monitoring of this antibody in clinical practice. more...
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- 2014
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44. Rethinking Lupus Nephritis Classification on a Molecular Level
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Jianying Zhang, Paul C. Boutros, Ana Malvar, Carmen Avila-Casado, Valeria Alberton, Joan E. Wither, Brad H. Rovin, Heather N. Reich, Lianbo Yu, Salem Almaani, James W. Scholey, Samir V. Parikh, and Stephenie D. Prokopec more...
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Nephrology ,medicine.medical_specialty ,Pathology ,Kidney Disease ,mRNA ,Clinical Sciences ,Lupus nephritis ,Lupus ,lcsh:Medicine ,Disease ,Autoimmune Disease ,Article ,Correlation ,03 medical and health sciences ,0302 clinical medicine ,Clinical Research ,Internal medicine ,Biopsy ,RPS classification ,2.1 Biological and endogenous factors ,Medicine ,Aetiology ,ISN/RPS classification ,ISN ,Cancer ,030304 developmental biology ,lupus nephritis ,030203 arthritis & rheumatology ,0303 health sciences ,Kidney ,medicine.diagnostic_test ,business.industry ,lcsh:R ,General Medicine ,medicine.disease ,Phenotype ,3. Good health ,medicine.anatomical_structure ,Renal pathology ,business - Abstract
The International Society of Nephrology/Renal Pathology Society (ISN/RPS) lupus nephritis (LN) classification is under reconsideration, given challenges with inter-rater reliability and resultant inconsistent relationship with treatment response. Integration of molecular classifiers into histologic evaluation can improve diagnostic precision and identify therapeutic targets. This study described the relationship between histological and molecular phenotypes and clinical responses in LN. Renal compartmental mRNA abundance was measured in 54 biopsy specimens from LN patients and correlated to ISN/RPS classification and individual histologic lesions. A subset of transcripts was also evaluated in sequential biopsies of a separate longitudinal cohort of 36 patients with paired samples obtained at the time of flare and at follow up. Unsupervised clustering based on mRNA abundance did not demonstrate a relationship with the (ISN/RPS) classification, nor did univariate statistical analysis. Exploratory analyses suggested a correlation with individual histologic lesions. Glomerular FN1 (fibronectin), SPP1 (secreted phosphoprotein 1), and LGALS3 (galectin 3) abundance correlated with disease activity and changed following treatment. Exploratory analyses suggested relationships between specific transcripts and individual histologic lesions, with the important representation of interferon-regulated genes. Our findings suggested that the current LN classification could be refined by the inclusion of molecular descriptors. Combining molecular and pathologic kidney biopsy phenotypes may hold promise to better classify disease and identify actionable treatment targets and merits further exploration in larger cohorts. more...
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- 2019
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45. Transancestral mapping and genetic load in systemic lupus erythematosus
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László Kovács, Helle Laustrup, Michael F. Seldin, Jeffrey C. Edberg, Swapan K. Nath, John D. Reveille, Diane L. Kamen, Quan Zhen Li, Guillermo A. Berbotto, Betty P. Tsao, Lennart Truedsson, Dafna D. Gladman, Mario H. Cardiel, Robert R. Graham, Chaim O. Jacob, Carlos Vasconcelos, Iñigo de la Rúa Figueroa, Mary E. Comeau, Deborah S. Cunninghame Graham, Iva Gunnarsson, Rosalind Ramsey-Goldman, Ignacio García-De La Torre, Luis J. Catoggio, Miranda C. Marion, Pedro Miranda, John D. Rioux, Laura E. Schanberg, Jorge R. Oksenberg, Earl D. Silverman, David R. McWilliams, Solbritt Rantapää Dahlqvist, Jennifer A. Croker, Raffaella Scorza, Carl D. Langefeld, Susan D. Thompson, Edward K. Wakeland, Elizabeth E. Brown, Berta Martins da Silva, Christopher Sjöwall, Kenneth M. Kaufman, Jennifer Huggins, Johan Frostegård, Lars Rönnblom, Joan E. Wither, Joseph M. McCune, Laurie P Russell, Sandra D'Alfonso, Johanna K. Sandling, Timothy W. Behrens, Mercedes A. García, Andrea Doria, Vicente Baca, Joel M. Guthridge, Bernardo A. Pons-Estel, José Francisco Moctezuma, Bernard Lauwerys, Sergio Toloza, Timothy D. Howard, Kathy L. Sivils, Hannah C. Ainsworth, Patrick M. Gaffney, David L. Morris, Jorge A. Esquivel-Valerio, Christian A. Pineau, Michelle Petri, Elisabet Svenungsson, Daniel J. Wallace, Norberto Ortego-Centeno, Robert P. Kimberly, Jonas Carlsson Almlöf, Gary S. Gilkeson, Lorena Orozco, Peter K. Gregersen, Judith A. James, Teresa Tusié-Luna, Paul R. Fortin, Marc Bijl, Jennifer A. Kelly, Timothy B. Niewold, Ricard Cervera, Timothy J. Vyse, Javier Martín, Prithvi Raj, Barry I. Freedman, Eduardo Acevedo-Vásquez, Carlos A. Aguilar-Salinas, Paula S. Ramos, Emőke Endreffy, Michael H. Weisman, Leah C. Kottyan, Janet E. Pope, Ann-Christine Syvänen, Joan T. Merrill, Hermine I. Brunner, Luis M. Vilá, Anders A. Bengtsson, Graciela S. Alarcón, Marta E. Alarcón-Riquelme, Jorge M. Cucho-Venegas, John B. Harley, Cees G. M. Kallenberg, Marco A. Maradiaga-Ceceña, David R. Karp, Lindsey A. Criswell, José Mario Sabio, Tushar Bhangale, Hugo R. Scherbarth, Alejandra Babini, UCL - SSS/IREC/RUMA - Pôle de Pathologies rhumatismales, UCL - (SLuc) Service de rhumatologie, Universitat de Barcelona, and Translational Immunology Groningen (TRIGR) more...
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0301 basic medicine ,Genetics and Molecular Biology (all) ,Medicin och hälsovetenskap ,Multifactorial Inheritance ,Autoimmune diseases ,General Physics and Astronomy ,Genome-wide association study ,VARIANTS ,Medical and Health Sciences ,Biochemistry ,DISEASE ,0302 clinical medicine ,Human genetics ,HLA Antigens ,immune system diseases ,Genotype ,Lupus Erythematosus, Systemic ,03.02. Klinikai orvostan ,Age of Onset ,skin and connective tissue diseases ,Sequence Deletion ,Genetics ,REVISED CRITERIA ,Genètica humana ,Multidisciplinary ,Malalties autoimmunitàries ,Chemistry (all) ,Hispanic or Latino ,3. Good health ,Genetic load ,SHARED EPITOPE HYPOTHESIS ,HLA ,Estudi de casos ,CAUCASIAN POPULATIONS ,Medical genetics ,Genetic Load ,Medical Genetics ,medicine.medical_specialty ,SUSCEPTIBILITY LOCI ,Science ,Black People ,Human leukocyte antigen ,Biology ,Polymorphism, Single Nucleotide ,Article ,White People ,General Biochemistry, Genetics and Molecular Biology ,PHYLOGENETIC TREES ,03 medical and health sciences ,Physics and Astronomy (all) ,Journal Article ,medicine ,Humans ,GENOME-WIDE ASSOCIATION ,American Indian or Alaska Native ,Medicinsk genetik ,030203 arthritis & rheumatology ,Lupus erythematosus ,Case-control study ,General Chemistry ,medicine.disease ,RHEUMATOID-ARTHRITIS ,Mutagenesis, Insertional ,Logistic Models ,030104 developmental biology ,Lupus eritematós ,Case-Control Studies ,Immunology ,Case studies ,Biochemistry, Genetics and Molecular Biology (all) ,Anti-SSA/Ro autoantibodies - Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with marked gender and ethnic disparities. We report a large transancestral association study of SLE using Immunochip genotype data from 27,574 individuals of European (EA), African (AA) and Hispanic Amerindian (HA) ancestry. We identify 58 distinct non-HLA regions in EA, 9 in AA and 16 in HA (∼50% of these regions have multiple independent associations); these include 24 novel SLE regions (P, Systemic lupus erythematosus (SLE) is an autoimmune disease with a strong ethnic and gender bias. In a transancestral genetic association study, Langefeld et al. identify 24 novel regions associated with risk to lupus and propose a cumulative hits hypothesis for loci conferring risk to SLE. more...
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- 2017
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46. Invariant NKT Cell Activation Is Potentiated by Homotypic
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Yuriy, Baglaenko, Mayra, Cruz Tleugabulova, Eric, Gracey, Nafiseh, Talaei, Kieran Patricia, Manion, Nan-Hua, Chang, Dario Michael, Ferri, Thierry, Mallevaey, and Joan E, Wither
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Cell Differentiation ,Dendritic Cells ,Lymphocyte Activation ,Mice, Inbred C57BL ,Mice ,Gene Expression Regulation ,Signaling Lymphocytic Activation Molecule Family Member 1 ,Signaling Lymphocytic Activation Molecule Family ,Animals ,Antigens, Ly ,Cytokines ,Humans ,Natural Killer T-Cells ,Antigens, CD1d ,RNA, Small Interfering - Abstract
Invariant NKT (iNKT) cells are innate lymphocytes that respond to glycolipids presented by the MHC class Ib molecule CD1d and are rapidly activated to produce large quantities of cytokines and chemokines. iNKT cell development uniquely depends on interactions between double-positive thymocytes that provide key homotypic interactions between signaling lymphocyte activation molecule (SLAM) family members. However, the role of SLAM receptors in the differentiation of iNKT cell effector subsets and activation has not been explored. In this article, we show that C57BL/6 mice containing the New Zealand Black more...
- Published
- 2016
47. Evaluation of Clinical Outcomes and Renal Vascular Pathology among Patients with Lupus
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Ellie Aghdassi, Andrew M. Herzenberg, James W. Scholey, Claire E.H. Barber, Heather N. Reich, Jonathan Yip, David B. Thomas, Samih H. Nasr, Murray B. Urowitz, Joan E. Wither, Gan Qian, Wendy Lou, Paul R. Fortin, Jiandong Su, and Dafna D. Gladman more...
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Adult ,medicine.medical_specialty ,Pathology ,Time Factors ,Thrombotic microangiopathy ,Epidemiology ,Lupus nephritis ,Renal function ,Blood Pressure ,Kidney ,Critical Care and Intensive Care Medicine ,Severity of Illness Index ,Gastroenterology ,Young Adult ,Internal medicine ,Confidence Intervals ,Odds Ratio ,medicine ,Humans ,Clinical significance ,Prospective Studies ,Renal Insufficiency, Chronic ,Peripheral Vascular Diseases ,Transplantation ,Sclerosis ,Systemic lupus erythematosus ,Thrombotic Microangiopathies ,business.industry ,Original Articles ,Middle Aged ,medicine.disease ,Lupus Nephritis ,Proteinuria ,medicine.anatomical_structure ,Blood pressure ,Nephrology ,Multivariate Analysis ,Disease Progression ,Blood Vessels ,business ,Nephritis ,Glomerular Filtration Rate - Abstract
The objective of this study was to determine the clinical significance of renal vascular lesions in lupus nephritis.Renal vascular lesions defined as thrombotic microangiopathy, lupus vasculopathy, uncomplicated vascular immune deposits, and arterial sclerosis were evaluated in relation to renal and vascular morbidity and overall mortality.Biopsies from 161 patients revealed thrombotic microangiopathy (13), lupus vasculopathy (5), and arterial sclerosis (93). No renal vascular lesions were found in 24.8% of patients. At the time of biopsy, arterial sclerosis or lupus vasculopathy patients were older (arterial sclerosis=37.9±13.0 and lupus vasculopathy=44.4±8.9 versus controls=33.1±8.9 years, P0.05), and the mean arterial pressure was higher in all groups compared with controls. Nephritis subtype, activity indices, and proteinuria were similar between groups, estimated GFR was lower in arterial sclerosis (70.5±33.3 versus 84.5±26.6 ml/min per 1.73 m(2), P=0.03), and chronicity index (thrombotic microangiopathy=3.5, lupus vasculopathy=4.5, and arterial sclerosis=2.5) was higher in all renal vascular lesions subgroups versus controls (1.0, P0.05). In 133 patients with similar follow-up, the association between renal vascular lesions and vascular events was significant (Fisher exact test, P=0.002) and remained so after multivariate analysis (exact conditional scores test, P=0.04), where the difference between arterial sclerosis and uncomplicated vascular immune deposits was most noticeable (odds ratio [95% confidence interval]=8.35[0.98, 83.12], P=0.05). The associations between renal vascular lesions, renal outcomes, and death were not significant, likely because of insufficient power.Renal vascular lesions are common in SLE patients with nephritis and may be associated with arterial vascular events. more...
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- 2012
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48. Epistatic Suppression of Fatal Autoimmunity in New Zealand Black Bicongenic Mice
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Yuriy Baglaenko, Ginette Lajoie, Timothy Li, Yui-Ho Cheung, Christina Loh, Joan E. Wither, Nan-Hua Chang, and Evelyn Pau
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T-Lymphocytes ,Immunology ,Congenic ,Fluorescent Antibody Technique ,Autoimmunity ,chemical and pharmacologic phenomena ,Lymphocyte Activation ,medicine.disease_cause ,Proinflammatory cytokine ,Pathogenesis ,Interferon-gamma ,Mice ,Mice, Congenic ,immune system diseases ,medicine ,Animals ,Lupus Erythematosus, Systemic ,Immunology and Allergy ,Cells, Cultured ,Autoantibodies ,B-Lymphocytes ,Polymorphism, Genetic ,Systemic lupus erythematosus ,Mice, Inbred NZB ,biology ,Epistasis, Genetic ,Flow Cytometry ,medicine.disease ,Natural killer T cell ,Lupus Nephritis ,Chromosome 4 ,Immunoglobulin G ,CD1D ,biology.protein ,Natural Killer T-Cells ,Receptors, Complement 3d ,Antigens, CD1d - Abstract
Numerous mapping studies have implicated genetic intervals from lupus-prone New Zealand Black (NZB) chromosomes 1 and 4 as contributing to lupus pathogenesis. By introgressing NZB chromosomal intervals onto a non–lupus-prone B6 background, we determined that: NZB chromosome 1 congenic mice (denoted B6.NZBc1) developed fatal autoimmune-mediated kidney disease, and NZB chromosome 4 congenic mice (denoted B6.NZBc4) exhibited a marked expansion of B1a and NKT cells in the surprising absence of autoimmunity. In this study, we sought to examine whether epistatic interactions between these two loci would affect lupus autoimmunity by generating bicongenic mice that carry both NZB chromosomal intervals. Compared with B6.NZBc1 mice, bicongenic mice demonstrated significantly decreased mortality, kidney disease, Th1-biased IgG autoantibody isotypes, and differentiation of IFN-γ–producing T cells. Furthermore, a subset of bicongenic mice exhibited a paucity of CD21+CD1d+ B cells and an altered NKT cell activation profile that correlated with greater disease inhibition. Thus, NZBc4 contains suppressive epistatic modifiers that appear to inhibit the development of fatal NZBc1 autoimmunity by promoting a shift away from a proinflammatory cytokine profile, which in some mice may involve NKT cells. more...
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- 2011
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49. An intrinsic B-cell defect supports autoimmunity in New Zealand black chromosome 13 congenic mice
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Nan-Hua Chang, Evelyn Pau, Joan E. Wither, and Christina Loh
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Cell Survival ,T-Lymphocytes ,Transgene ,Immunology ,B-Lymphocyte Subsets ,Congenic ,Receptors, Antigen, B-Cell ,Autoimmunity ,Cell Count ,Mice, Transgenic ,Biology ,Lymphocyte Activation ,medicine.disease_cause ,Mice ,Immune system ,Antigen ,Animals, Congenic ,medicine ,Animals ,Immunology and Allergy ,Bone Marrow Transplantation ,Cell Proliferation ,Clonal Anergy ,B-Lymphocytes ,Transplantation Chimera ,Mice, Inbred NZB ,Autoantibody ,Receptor editing ,Cell Differentiation ,Dendritic Cells ,Chromosomes, Mammalian ,Molecular biology ,Toll-Like Receptor 3 ,Mice, Inbred C57BL ,Poly I-C ,Antibodies, Antinuclear ,biology.protein ,Female ,Muramidase ,Antibody ,Spleen ,Signal Transduction - Abstract
Introgression of a New Zealand Black (NZB) chromosome 13 interval onto a C57BL/6 (B6) background (B6.NZBc13) is sufficient to produce many hallmarks of lupus, including high-titre anti-chromatin antibody production, abnormal B- and T-cell activation, and renal disease. In this study we sought to characterize the immune defects leading to these abnormalities. By generating hematopoietic chimeras and BCR transgenic mice, we show that the congenic autoimmune phenotype can be transferred by BM cells and requires the presence of autoreactive B cells. Using the hen egg white lysozyme immunoglobulin transgenic mouse model, we demonstrate that B-cell anergy, deletion, and receptor editing are intact. Nevertheless, congenic B cells exhibit altered peripheral B-cell selection, as demonstrated by enhanced survival and activation of endogenous B cells with autoreactivity to chromatin and Sm/ribonucleoprotein. Given the autoantibody specificities to nuclear antigens, TLR signalling was assessed. B6.NZBc13 B cells were hyper-responsive to poly(I:C), a TLR3 ligand, demonstrating enhanced proliferation and survival as compared to B6 B cells. Our findings indicate the presence of an intrinsic B-cell defect on NZB chromosome 13 that results in hyper-responsiveness to a dsRNA analogue and implicates its potential supporting role in the generation of autoimmunity in B6.NZBc13 mice. more...
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- 2010
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50. Adults With Systemic Lupus Erythematosus Have High Cognitive Impairment Rates: Role for Cognitive Rehabilitation?
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Jiandong Su, Carmela Tartaglia, Lisa Engel, Dennisse Bonilla, Joan E. Wither, Sabrina Lombardi, Kenneth Colosimo, Robin Green, Lesley Ruttan, Michelle Vitti, and Nicole D. Anderson
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medicine.medical_specialty ,Physical medicine and rehabilitation ,business.industry ,Rehabilitation ,medicine ,Physical Therapy, Sports Therapy and Rehabilitation ,Cognitive rehabilitation therapy ,Cognitive impairment ,business - Published
- 2018
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