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51. High Systemic Type I Interferon Activity Is Associated With Active Class III/IV Lupus Nephritis

Author

Iwamoto, Taro, Dorschner, Jessica M., Selvaraj, Shanmugapriya, Mezzano, Valeria, Jensen, Mark A., Vsetecka, Danielle, Amin, Shreyasee, Makol, Ashima, Osborn, Thomas, Moder, Kevin, Chowdhary, Vaidehi R., Izmirly, Peter, Belmont, H. Michael, Clancy, Robert M., Buyon, Jill P., Wu, Ming, Loomis, Cynthia A., and Niewold, Timothy B.

Abstract

ObjectivePrevious studies suggest a link between high serum type I interferon (IFN) and lupus nephritis (LN). We determined whether serum IFN activity is associated with subtypes of LN and studied renal tissues and cells to understand the effect of IFN in LN.MethodsTwo hundred and twenty-one patients with systemic lupus erythematosus were studied. Serum IFN activity was measured by WISH bioassay. mRNA in situ hybridization was used in renal tissue to measure expression of the representative IFN-induced gene, IFN-induced protein with tetratricopeptide repeats-1 (IFIT1), and the plasmacytoid dendritic cell (pDC) marker gene C-type lectin domain family-4 member C (CLEC4C). Podocyte cell line gene expression was measured by real-time PCR.ResultsClass III/IV LN prevalence was significantly increased in patients with high serum IFN compared with those with low IFN (odds ratio 5.40, P= 0.009). In multivariate regression models, type I IFN was a stronger predictor of class III/IV LN than complement C3 or anti-dsDNA antibody, and could account for the association of these variables with LN. IFIT1expression was increased in all classes of LN, but most in the glomerular areas of active class III/IV LN kidneys. IFIT1expression was not closely colocalized with pDCs. IFN directly activated podocyte cell lines to induce chemokines and proapoptotic molecules.ConclusionSystemic high IFN is involved in the pathogenesis of severe LN. We did not find colocalization of pDCs with IFN signature in renal tissue, and instead observed the greatest intensity of the IFN signature in glomerular areas, which could suggest a blood source of IFN.

Published
2022
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55. The role of nitric oxide in the pathogenesis of preeclampsia

Author

Seligman, Susan P., Buyon, Jill P., Clancy, Robert M., Young, Bruce K., and Abramson, Steven B.

Subjects
Preeclampsia -- Development and progression, Nitric oxide -- Physiological aspects, Health
Abstract

Pregnant women with preeclampsia may have lower levels of nitric oxide in their blood than pregnant women with normal blood pressure. Nitric oxide is a powerful blood vessel dilator that also inhibits platelet aggregation and adhesion to the cells lining blood vessels. Hypertension and vasoendothelial cell damage are significant features of preeclampsia. Twenty-six women with preeclampsia in the third trimester and 26 similar women with normal blood pressure had blood drawn and analyzed for nitric oxide. The mean serum level of nitric oxide was decreased in the preeclamptic women (20.04 micromoles/L vs. 27.38 micromoles/L). Nitric oxide levels bore an inverse relationship with systolic and diastolic blood pressure within the preeclamptic group.

Published
1994

57. A protective Langerhans cell–keratinocyte axis that is dysfunctional in photosensitivity

Author

Shipman, William D., primary, Chyou, Susan, additional, Ramanathan, Anusha, additional, Izmirly, Peter M., additional, Sharma, Sneh, additional, Pannellini, Tania, additional, Dasoveanu, Dragos C., additional, Qing, Xiaoping, additional, Magro, Cynthia M., additional, Granstein, Richard D., additional, Lowes, Michelle A., additional, Pamer, Eric G., additional, Kaplan, Daniel H., additional, Salmon, Jane E., additional, Mehrara, Babak J., additional, Young, James W., additional, Clancy, Robert M., additional, Blobel, Carl P., additional, and Lu, Theresa T., additional

Published
2018
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60. Clinical and pathologic implications of extending the spectrum of maternal autoantibodies reactive with ribonucleoproteins associated with cutaneous and now cardiac neonatal lupus from SSA/Ro and SSB/La to U1RNP

Author

Izmirly, Peter M., primary, Halushka, Marc K., additional, Rosenberg, Avi Z., additional, Whelton, Sean, additional, Rais-Bahrami, Khodayar, additional, Nath, Dilip S., additional, Parton, Hilary, additional, Clancy, Robert M., additional, Rasmussen, Sara, additional, Saxena, Amit, additional, and Buyon, Jill P., additional

Published
2017
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64. Digestion of Chromatin in Apoptotic Cell Microparticles Prevents Autoimmunity

Author

Sisirak, Vanja, primary, Sally, Benjamin, additional, D’Agati, Vivette, additional, Martinez-Ortiz, Wilnelly, additional, Özçakar, Z. Birsin, additional, David, Joseph, additional, Rashidfarrokhi, Ali, additional, Yeste, Ada, additional, Panea, Casandra, additional, Chida, Asiya Seema, additional, Bogunovic, Milena, additional, Ivanov, Ivaylo I., additional, Quintana, Francisco J., additional, Sanz, Inaki, additional, Elkon, Keith B., additional, Tekin, Mustafa, additional, Yalçınkaya, Fatoş, additional, Cardozo, Timothy J., additional, Clancy, Robert M., additional, Buyon, Jill P., additional, and Reizis, Boris, additional

Published
2016
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67. Systemic lupus erythematosus and the risk of perioperative major adverse cardiovascular events.

Author

Smilowitz, Nathaniel R., Katz, Gregory, Buyon, Jill P., Clancy, Robert M., and Berger, Jeffrey S.

Abstract

Systemic lupus erythematosus (SLE) is a significant risk factor for cardiovascular disease. The relationship between SLE and perioperative cardiovascular risks following non-cardiac surgery is uncertain. We investigated associations between a diagnosis of SLE and outcomes following major non-cardiac surgery in a large national database from the United States. Patients age ≥ 18 years requiring major non-cardiac surgery were identified from Healthcare Cost and Utilization Project's National Inpatient Sample data from 2004 to 2014. Systemic lupus erythematosus and perioperative major adverse cardiovascular events (MACE; myocardial infarction, ischemic stroke or death) were defined by ICD-9 diagnosis codes. Perioperative MACE were reported for SLE patients stratified by age and sex. From 2004 to 2014, a total of 17,853,194 hospitalizations for major non-cardiac surgery met study inclusion criteria. SLE was identified in 70,578 (0.4%) hospitalizations. Overall, the frequency of perioperative MACE was higher in patients with vs. without SLE [2.4 vs. 2.0%, p < 0.001; adjusted OR (aOR) 1.25; 95% CI 1.18-1.31]. Perioperative MACE associated with SLE was largely driven by increased death (aOR 1.58 95% CI 1.40-1.77) and myocardial infarction (aOR 1.32; 95% CI 1.05-1.66) in younger patients with SLE. The increased risk of perioperative MACE associated with SLE in younger patients was attenuated with increasing age. A diagnosis of SLE is associated with increased risk of perioperative MACE, particularly among younger patients. Efforts to improve the perioperative management and outcomes of patients with SLE are needed. [ABSTRACT FROM AUTHOR]

Published
2018
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70. Anti-La/SSB antiidiotypic antibodies in maternal serum - A marker of low risk for neonatal lupus in an offspring

Author

Stea, Eleni A. Routsias, John G. Clancy, Robert M. Buyon, Jill P. Moutsopoulos, Haralampos M. Tzioufas, Athanasios G.

Abstract

Objective. The anti-La/SSB response to major B cell epitopes of La/SSB can be blocked by an active idiotypic/antiidiotypic network, which can be identified using synthetic complementary epitopes deduced from the sequence of the major B cell epitopes of the molecule. This study evaluated the role of this network in pregnant women with anti-Ro/SSA and/or anti-La/SSB antibodies in the development of neonatal lupus syndrome (NLS). Methods. Sixty-three serum samples collected from anti-Ro/anti-La-positive women during pregnancy or within 6 months after delivery were obtained from the Research Registry for Neonatal Lupus and the PR Interval Dexamethasone Evaluation study. These samples, as well as 30 sera from healthy individuals, were tested in a blinded manner by enzyme-linked immunosorbent assay against, synthetic peptides corresponding to major B cell epitopes and complementary epitopes of La/SSB. Results. Sera from mothers giving birth to a healthy child and having no history of a child with NLS exhibited higher antiidiotypic antibody activity compared with mothers carrying a child with NLS (P < 0.0001) or mothers giving birth to a healthy child but who previously gave birth to a child with NLS (P 0.0151). Sera from mothers of healthy children, which exhibited no apparent epitope activity against amino acids 349-364, revealed a significantly greater frequency of hidden anti-349-364aa epitope responses, blocked by antiidiotypic antibodies, as compared with sera from women pregnant with an affected child (P = 0.0094). Conclusion. The presence of antiidiotypic antibodies to autoantibodies against La/SSB may protect the fetus by blocking pathogenic maternal autoantibodies. Testing for these antiidiotypic responses may be useful in predicting a decreased risk of NLS.

Published
2006

71. Association of Natural Killer Cell Ligand Polymorphism HLA-C Asn80Lys With the Development of Anti- SSA/Ro-Associated Congenital Heart Block.

Author

Ainsworth, Hannah C., Marion, Miranda C., Bertero, Tiziana, Brucato, Antonio, Cimaz, Rolando, Costedoat‐Chalumeau, Nathalie, Fredi, Micaela, Gaffney, Patrick, Kelly, Jennifer, Levesque, Kateri, Maltret, Alice, Morel, Nathalie, Ramoni, Veronique, Ruffatti, Amelia, Langefeld, Carl D., Buyon, Jill P., and Clancy, Robert M.

Subjects
GENETICS of autoimmune diseases, ALLELES, AUTOIMMUNE diseases, SIBLINGS, CONGENITAL heart disease, GENETIC polymorphisms, HEART block, PROBABILITY theory, SEX distribution, LOGISTIC regression analysis, DATA analysis, MICROARRAY technology, ODDS ratio, GENOTYPES, FETUS, GENETICS
Abstract

Objective Fetal exposure to maternal anti- SSA/Ro antibodies is necessary but not sufficient for the development of autoimmune congenital heart block ( CHB), suggesting that other factors, such as fetal genetic predisposition, are important. Given the previously described association between major histocompatibility complex alleles and CHB risk, we undertook the present study to test the hypothesis that a variant form of HLA-C Asn80Lys, which binds with high affinity to an inhibitory killer cell immunoglobulin-like receptor ( KIR) and thus renders natural killer ( NK) cells incapable of restricting inflammation, contributes to the development of CHB. Methods Members of 192 pedigrees in the US and Europe (194 cases of CHB, 91 unaffected siblings, 152 fathers, 167 mothers) and 1,073 out-of-study controls were genotyped on the Immunochip single-nucleotide polymorphism microarray. Imputation was used to identify associations at HLA-C Asn80Lys (Asn, C1; Lys, C2) and KIR. Tests for association were performed using logistic regression. McNemar's test and the pedigree disequilibrium test ( PDT) were used for matched analyses between affected and unaffected children. Results Compared with out-of-study controls of the same sex, the C2 allele was less frequent in the mothers (odds ratio [ OR] 0.63, P = 0.0014) and more frequent in the fathers ( OR 1.40, P = 0.0123), yielding a significant sex-by-C2 interaction ( P = 0.0002). The C2 allele was more frequent in affected siblings than in unaffected siblings ( OR 3.67, P = 0.0025), which was consistent with the PDT results ( P = 0.016); these results were observed in both sexes and across the US and European cohorts. There was no difference in the frequency of the inhibitory KIR genotype ( KIR AA) between affected and unaffected children ( P = 0.55). Conclusion These data establish C2 as a novel genetic risk factor associated with CHB. This observation supports a model in which fetuses with C2 ligand expression and maternal anti- SSA/Ro positivity may have impaired NK cell surveillance, resulting in unchecked cardiac inflammation and scarring. [ABSTRACT FROM AUTHOR]

Published
2017
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73. Ro60 requires Y3 RNA for cell surface exposure and inflammation associated with cardiac manifestations of neonatal lupus

Author

Reed, Joanne H, Sim, Soyeong, Wolin, Sandra L, Clancy, Robert M, Buyon, Jill P, Reed, Joanne H, Sim, Soyeong, Wolin, Sandra L, Clancy, Robert M, and Buyon, Jill P

Abstract

Cardiac neonatal lupus (NL) is presumed to arise from maternal autoantibody targeting an intracellular ribonucleoprotein, Ro60, which binds noncoding Y RNA and only becomes accessible to autoantibodies during apoptosis. Despite the importance of Ro60 trafficking in the development of cardiac NL, the mechanism underlying cell surface exposure is unknown. To evaluate the influence of Y RNA on the subcellular location of Ro60 during apoptosis and activation of macrophages, stable Ro60 knockout murine fibroblasts expressing wild-type or mutated FLAG-Ro60 were assessed. FLAG3-Ro60(K170A R174A) binds Y RNA, whereas FLAG3-Ro60(H187S) does not bind Y RNA; fibroblasts expressing these constructs showed equivalent intracellular expression of Ro60. In contrast, apoptotic fibroblasts containing FLAG3-Ro60(K170A R174A) were bound by anti-Ro60, whereas FLAG3-Ro60(H187S) was not surface expressed. RNA interference of mY3 RNA in wild-type fibroblasts inhibited surface translocation of Ro60 during apoptosis, whereas depletion of mY1 RNA did not affect Ro60 exposure. Furthermore, Ro60 was not exposed following overexpression of mY1 in the mY3-depleted fibroblasts. In an in vitro model of anti-Ro60–mediated injury, Y RNA was shown to be an obligate factor for TLR-dependent activation of macrophages challenged with anti-Ro60–opsonized apoptotic fibroblasts. Murine Y3 RNA is a necessary factor to support the surface translocation of Ro60, which is pivotal to the formation of immune complexes on apoptotic cells and a TLR-dependent proinflammatory cascade. Accordingly, the Y3 RNA moiety of the Ro60 ribonucleoprotein imparts a critical role in the pathogenicity of maternal anti-Ro60 autoantibodies.

Published
2013

74. Umbilical cord blood levels of maternal antibodies reactive with p200 and full-length Ro 52 in the assessment of risk for cardiac manifestations of neonatal Lupus

Author

Reed, Joanne H, Clancy, Robert M, Lee, Kristen H, Saxena, Amit, Izmirly, Peter M, Buyon, Jill P, Reed, Joanne H, Clancy, Robert M, Lee, Kristen H, Saxena, Amit, Izmirly, Peter M, and Buyon, Jill P

Abstract

Objective Maternal anti-Ro autoantibodies are associated with cardiac manifestations of neonatal lupus (cardiac NL), yet only 2% of women with this reactivity have an affected child. Identification of a more specific marker would channel intense monitoring to fetuses at greater risk. This study aimed to determine whether autoantibodies against Ro 52 amino acids 200–239 (p200) confer added risk over autoantibodies to full-length Ro 52, Ro 60, or La. Methods Anti-Ro–exposed pregnancies resulting in cardiac NL or no cardiac manifestations were identified from the Research Registry for Neonatal Lupus and the PR Interval and Dexamethasone Evaluation study. Umbilical cord (n = 123) and maternal (n = 115) samples were evaluated by enzyme-linked immunosorbent assay. Results The frequencies of p200, Ro 52, Ro 60, and La autoantibodies were not significantly different between affected and unaffected children. However, neonatal anti–Ro 52 and Ro 60 titers were highest in cardiac NL and their unaffected siblings compared to unaffected neonates without a cardiac NL sibling. Although both maternal anti–Ro 52 and p200 autoantibodies were less than 50% specific for cardiac NL, anti-p200 was the least likely of the Ro autoantibodies to be false-positive in mothers who have never had an affected child. Titers of anti–Ro 52 and p200 did not differ during a cardiac NL or unaffected pregnancy from the same mother. Conclusion Maternal reactivity to p200 does not confer an added risk to fetal conduction defects over full-length Ro 52 or Ro 60 autoantibodies. Mothers who may never be at risk for having an affected child have lower anti–Ro 60 titers and may require less stringent echocardiographic monitoring compared to women with high-titer autoantibodies.

Published
2012

78. Dysregulation of the Microvasculature in Nonlesional Non-Sun-exposed Skin of Patients with Lupus Nephritis

Author

IZMIRLY, PETER M., primary, SHVARTSBEYN, MARIANNA, additional, MEEHAN, SHANE, additional, FRANKS, ANDREW, additional, BRAUN, ALAN, additional, GINZLER, ELLEN, additional, XU, SHERRY X., additional, YEE, HERMAN, additional, RIVERA, TANIA, additional, ESMON, CHARLES, additional, BARISONI, LAURA, additional, MERRILL, JOAN T., additional, BUYON, JILL P., additional, and CLANCY, ROBERT M., additional

Published
2012
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90. Reply

Author

Clancy, Robert M., primary and Buyon, Jill P., additional

Published
2005
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