70 results on '"Romberg N"'
Search Results
2. M164 NOVEL ERBIN VARIANT AND ASSOCIATED SEVERE ECZEMA IN A 3-MONTH-OLD
- Author
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Nguyen, K., primary, Heimall, J., additional, Henrickson, S., additional, Khurana, M., additional, Romberg, N., additional, Treat, J., additional, Brown-Whitehorn, T., additional, and Sun, D., additional
- Published
- 2021
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3. Lentiviral-mediated gene therapy restores B cell tolerance in Whiskott-Aldrich syndrome patients
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Pala F., Morbach H., Castiello M. C., Schickel J. N., Scaramuzza S., Chamberlain N., Cassani B., Glauzy S., Romberg N., Candotti F., Bosticardo M., Villa A., Meffre E., AIUTI , ALESSANDRO, Pala, F., Morbach, H., Castiello, M. C., Schickel, J. N., Scaramuzza, S., Chamberlain, N., Cassani, B., Glauzy, S., Romberg, N., Candotti, F., Aiuti, Alessandro, Bosticardo, M., Villa, A., and Meffre, E.
- Published
- 2015
4. Newborn screening for severe combined immunodeficiency in 11 screening programs in the United States
- Author
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Kwan, A, Abraham, RS, Currier, R, Brower, A, Andruszewski, K, Abbott, JK, Baker, M, Ballow, M, Bartoshesky, LE, Bonilla, FA, Brokopp, C, Brooks, E, Caggana, M, Celestin, J, Church, JA, Comeau, AM, Connelly, JA, Cowan, MJ, Cunningham-Rundles, C, Dasu, T, Dave, N, De La Morena, MT, Duffner, U, Fong, CT, Forbes, L, Freedenberg, D, Gelfand, EW, Hale, JE, Hanson, IC, Hay, BN, Hu, D, Infante, A, Johnson, D, Kapoor, N, Kay, DM, Kohn, DB, Lee, R, Lehman, H, Lin, Z, Lorey, F, Abdel-Mageed, A, Manning, A, McGhee, S, Moore, TB, Naides, SJ, Notarangelo, LD, Orange, JS, Pai, SY, Porteus, M, Rodriguez, R, Romberg, N, Routes, J, Ruehle, M, Rubenstein, A, Saavedra-Matiz, CA, Scott, G, Scott, PM, Secord, E, Seroogy, C, Shearer, WT, Siegel, S, Silvers, SK, Stiehm, ER, Sugerman, RW, Sullivan, JL, Tanksley, S, Tierce, ML, Verbsky, J, Vogel, B, Walker, R, Walkovich, K, Walter, JE, Wasserman, RL, Watson, MS, Weinberg, GA, Weiner, LB, Wood, H, Yates, AB, and Puck, JM
- Abstract
Importance: Newborn screening for severe combined immunodeficiency (SCID) using assays to detect T-cell receptor excision circles (TRECs) began in Wisconsin in 2008, and SCID was added to the national recommended uniform panel for newborn screened disorders in 2010. Currently 23 states, the District of Columbia, and the Navajo Nation conduct population-wide newborn screening for SCID. The incidence of SCID is estimated at 1 in 100 000 births. Objectives: To present data from a spectrum of SCID newborn screening programs, establish population-based incidence for SCID and other conditions with T-cell lymphopenia and document early institution of effective treatments. DESIGN Epidemiological and retrospective observational study. Setting: Representatives in states conducting SCID newborn screening were invited to submit their SCID screening algorithms, test performance data and deidentified clinical and laboratory information regarding infants screened and cases with nonnormal results. Infants born from the start of each participating program from January 2008 through the most recent evaluable date prior to July 2013 were included. Representatives from 10 states plus the Navajo Area Indian Health Service contributed data from 3 030 083 newborns screened with a TREC test. Main Outcomes and Measures: Infants with SCID and other diagnoses of T-cell lymphopenia were classified. Incidence and, where possible, etiologies were determined. Interventions and survival were tracked. Results: Screening detected 52 cases of typical SCID, leaky SCID, and Omenn syndrome, affecting 1 in 58 000 infants (95%CI, 1/46 000-1/80 000). Survival of SCID-affected infants through their diagnosis and immune reconstitution was 87%(45/52), 92%(45/49) for infants who received transplantation, enzyme replacement, and/or gene therapy. Additional interventions for SCID and non-SCID T-cell lymphopenia included immunoglobulin infusions, preventive antibiotics, and avoidance of live vaccines. Variations in definitions and follow-up practices influenced the rates of detection of non-SCID T-cell lymphopenia. Conclusions and Relevance: Newborn screening in 11 programs in the United States identified SCID in 1 in 58 000 infants, with high survival. The usefulness of detection of non-SCID T-cell lymphopenias by the same screening remains to be determined. Copyright © 2014 American Medical Association. All rights reserved.
- Published
- 2014
5. Les mutations de TACI associées aux DICV affectent la sélection et l’activation des lymphocytes B autoréactifs
- Author
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Saadoun, D., primary, Romberg, N., additional, Chamberlain, N., additional, Geha, R., additional, Grimbacher, B., additional, Cunningham Rundles, C., additional, and Meffre, E., additional
- Published
- 2013
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6. A Central B Cell Tolerance Defect In Group Ia CVID Patients
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Romberg, N., primary, Ng, Y., additional, Cunningham-Rundles, C., additional, and Meffre, E., additional
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- 2012
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7. Transmembrane Activator and Calcium-modulator and Cyclophilin Ligand Interactor (TACI) Expression is Essential for Human B-cell Tolerance
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Romberg, N., primary, Saadoun, D., additional, Rachid, R., additional, Geha, R., additional, Grimbacher, B., additional, Cunningham-Rundles, C., additional, and Meffre, E., additional
- Published
- 2010
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8. AIRE expression controls the peripheral selection of autoreactive B cells
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Sng, J, primary, Ayoglu, B, additional, Chen, JW, additional, Schickel, JN, additional, Ferre, EMN, additional, Glauzy, S, additional, Romberg, N, additional, Hoenig, M, additional, Cunningham-Rudles, C, additional, Utz, PJ, additional, Lionakis, MS, additional, and Meffre, E, additional
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9. The common variable immunodeficiency IgM repertoire narrowly recognizes erythrocyte and platelet glycans.
- Author
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Le Coz C, Trofa M, Butler DL, Yoon S, Tian T, Reid W, Cruz Cabrera E, Knox AVC, Khanna C, Sullivan KE, Heimall J, Takach P, Fadugba OO, Lawrence M, Jyonouchi S, Hakonarson H, Wells AD, Handler S, Zur KB, Pillai V, Gildersleeve JC, and Romberg N
- Subjects
- Humans, Male, Female, B-Lymphocyte Subsets immunology, Adult, Immunoglobulin M immunology, Immunoglobulin M blood, Erythrocytes immunology, Common Variable Immunodeficiency immunology, Polysaccharides immunology, Blood Platelets immunology, Autoantibodies immunology, Autoantibodies blood
- Abstract
Background: Autoimmune cytopenias (AICs) regularly occur in profoundly IgG-deficient patients with common variable immunodeficiency (CVID). The isotypes, antigenic targets, and origin(s) of their disease-causing autoantibodies are unclear., Objective: We sought to determine reactivity, clonality, and provenance of AIC-associated IgM autoantibodies in patients with CVID., Methods: We used glycan arrays, patient erythrocytes, and platelets to determine targets of CVID IgM autoantibodies. Glycan-binding profiles were used to identify autoreactive clones across B-cell subsets, specifically circulating marginal zone (MZ) B cells, for sorting and IGH sequencing. The locations, transcriptomes, and responses of tonsillar MZ B cells to different T
H - cell subsets were determined by confocal microscopy, RNA-sequencing, and cocultures, respectively., Results: Autoreactive IgM coated erythrocytes and platelets from many CVID patients with AICs (CVID+AIC). On glycan arrays, CVID+AIC plasma IgM narrowly recognized erythrocytic i antigens and platelet i-related antigens and failed to bind hundreds of pathogen- and tumor-associated carbohydrates. Polyclonal i antigen-recognizing B-cell receptors were highly enriched among CVID+AIC circulating MZ B cells. Within tonsillar tissues, MZ B cells secreted copious IgM when activated by the combination of IL-10 and IL-21 or when cultured with IL-10/IL-21-secreting FOXP3- CD25hi T follicular helper (Tfh) cells. In lymph nodes from immunocompetent controls, MZ B cells, plentiful FOXP3+ regulatory T cells, and rare FOXP3- CD25+ cells that represented likely CD25hi Tfh cells all localized outside of germinal centers. In CVID+AIC lymph nodes, cellular positions were similar but CD25hi Tfh cells greatly outnumbered regulatory cells., Conclusions: Our findings indicate that glycan-reactive IgM autoantibodies produced outside of germinal centers may contribute to the autoimmune pathogenesis of CVID., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.)- Published
- 2024
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10. 3D chromatin-based variant-to-gene maps across 57 human cell types reveal the cellular and genetic architecture of autoimmune disease susceptibility.
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Trang KB, Sharma P, Cook L, Mount Z, Thomas RM, Kulkarni NN, Pahl MC, Pippin JA, Su C, Kaestner KH, O'Brien JM, Wagley Y, Hankenson KD, Jermusyk A, Hoskins JW, Amundadottir LT, Xu M, Brown KM, Anderson SA, Yang W, Titchenell PM, Seale P, Zemel BS, Chesi A, Romberg N, Levings MK, Grant SFA, and Wells AD
- Abstract
A portion of the genetic basis for many common autoimmune disorders has been uncovered by genome-wide association studies (GWAS), but GWAS do not reveal causal variants, effector genes, or the cell types impacted by disease-associated variation. We have generated 3D genomic datasets consisting of promoter-focused Capture-C, Hi-C, ATAC-seq, and RNA-seq and integrated these data with GWAS of 16 autoimmune traits to physically map disease-associated variants to the effector genes they likely regulate in 57 human cell types. These 3D maps of gene cis -regulatory architecture are highly powered to identify the cell types most likely impacted by disease-associated genetic variation compared to 1D genomic features, and tend to implicate different effector genes than eQTL approaches in the same cell types. Most of the variants implicated by these cis -regulatory architectures are highly trait-specific, but nearly half of the target genes connected to these variants are shared across multiple autoimmune disorders in multiple cell types, suggesting a high level of genetic diversity and complexity among autoimmune diseases that nonetheless converge at the level of target gene and cell type. Substantial effector gene sharing led to the common enrichment of similar biological networks across disease and cell types. However, trait-specific pathways representing potential areas for disease-specific intervention were identified. To test this, we pharmacologically validated squalene synthase, a cholesterol biosynthetic enzyme encoded by the FDFT1 gene implicated by our approach in MS and SLE, as a novel immunomodulatory drug target controlling inflammatory cytokine production by human T cells. These data represent a comprehensive resource for basic discovery of gene cis -regulatory mechanisms, and the analyses reported reveal mechanisms by which autoimmune-associated variants act to regulate gene expression, function, and pathology across multiple, distinct tissues and cell types.
- Published
- 2024
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11. PI3Kγ in B cells promotes antibody responses and generation of antibody-secreting cells.
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Lanahan SM, Yang L, Jones KM, Qi Z, Cabrera EC, Cominsky LY, Ramaswamy A, Barmada A, Gabernet G, Uthaya Kumar DB, Xu L, Shan P, Wymann MP, Kleinstein SH, Rao VK, Mustillo P, Romberg N, Abraham RS, and Lucas CL
- Subjects
- Animals, Mice, Humans, Mice, Knockout, Antibody-Producing Cells immunology, Lymphocyte Activation immunology, Mice, Inbred C57BL, Signal Transduction immunology, Memory B Cells immunology, Memory B Cells metabolism, Class Ib Phosphatidylinositol 3-Kinase metabolism, Class Ib Phosphatidylinositol 3-Kinase immunology, Cell Differentiation immunology, B-Lymphocytes immunology, B-Lymphocytes metabolism, Antibody Formation immunology
- Abstract
The differentiation of naive and memory B cells into antibody-secreting cells (ASCs) is a key feature of adaptive immunity. The requirement for phosphoinositide 3-kinase-delta (PI3Kδ) to support B cell biology has been investigated intensively; however, specific functions of the related phosphoinositide 3-kinase-gamma (PI3Kγ) complex in B lineage cells have not. In the present study, we report that PI3Kγ promotes robust antibody responses induced by T cell-dependent antigens. The inborn error of immunity caused by human deficiency in PI3Kγ results in broad humoral defects, prompting our investigation of roles for this kinase in antibody responses. Using mouse immunization models, we found that PI3Kγ functions cell intrinsically within activated B cells in a kinase activity-dependent manner to transduce signals required for the transcriptional program supporting differentiation of ASCs. Furthermore, ASC fate choice coincides with upregulation of PIK3CG expression and is impaired in the context of PI3Kγ disruption in naive B cells on in vitro CD40-/cytokine-driven activation, in memory B cells on toll-like receptor activation, or in human tonsillar organoids. Taken together, our study uncovers a fundamental role for PI3Kγ in supporting humoral immunity by integrating signals instructing commitment to the ASC fate., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)
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- 2024
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12. IL-12 drives the differentiation of human T follicular regulatory cells.
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Castaño D, Wang S, Atencio-Garcia S, Shields EJ, Rico MC, Sharpe H, Bustamante J, Feng A, Le Coz C, Romberg N, Tobias JW, Utz PJ, Henrickson SE, Casanova JL, Bonasio R, and Locci M
- Subjects
- Humans, STAT4 Transcription Factor immunology, STAT4 Transcription Factor genetics, Receptors, Interleukin-12 immunology, Receptors, Interleukin-12 genetics, Female, Male, Interleukin-12 immunology, Cell Differentiation immunology, T-Lymphocytes, Regulatory immunology
- Abstract
T follicular regulatory (T
fr ) cells can counteract the B cell helper activity of T follicular helper (Tfh ) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg ) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr -like cells.- Published
- 2024
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13. 22q11.2 Deletion-Associated Blood-Brain Barrier Permeability Potentiates Systemic Capillary Leak Syndrome Neurologic Features.
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Crockett AM, Kebir H, Anderson SA, Jyonouchi S, Romberg N, and Alvarez JI
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- Humans, Male, Child, Blood-Brain Barrier, Endothelial Cells, Permeability, Inflammation, Capillary Leak Syndrome diagnosis, DiGeorge Syndrome
- Abstract
We present a case study of a young male with a history of 22q11.2 deletion syndrome (22qDS), diagnosed with systemic capillary leak syndrome (SCLS) who presented with acute onset of diffuse anasarca and sub-comatose obtundation. We hypothesized that his co-presentation of neurological sequelae might be due to blood-brain barrier (BBB) susceptibility conferred by the 22q11.2 deletion, a phenotype that we have previously identified in 22qDS. Using pre- and post-intravenous immunoglobulins (IVIG) patient serum, we studied circulating biomarkers of inflammation and assessed the potential susceptibility of the 22qDS BBB. We employed in vitro cultures of differentiated BBB-like endothelial cells derived from a 22qDS patient and a healthy control. We found evidence of peripheral inflammation and increased serum lipopolysaccharide (LPS) alongside endothelial cells in circulation. We report that the patient's serum significantly impairs barrier function of the 22qDS BBB compared to control. Only two other cases of pediatric SCLS with neurologic symptoms have been reported, and genetic risk factors have been suggested in both instances. As the third case to be reported, our findings are consistent with the hypothesis that genetic susceptibility of the BBB conferred by genes such as claudin-5 deleted in the 22q11.2 region promoted neurologic involvement during SCLS in this patient., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2024
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14. Common variable immunodeficiency, cross currents, and prevailing winds.
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Romberg N and Le Coz C
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- Humans, B-Lymphocytes, Reproducibility of Results, Wind, Germinal Center, Common Variable Immunodeficiency genetics
- Abstract
Common variable immunodeficiency (CVID) is a heterogenous disease category created to distinguish late-onset antibody deficiencies from early-onset diseases like agammaglobulinemia or more expansively dysfunctional combined immunodeficiencies. Opinions vary on which affected patients should receive a CVID diagnosis which confuses clinicians and erects reproducibility barriers for researchers. Most experts agree that CVID's most indeliable feature is defective germinal center (GC) production of isotype-switched, affinity-maturated antibodies. Here, we review the biological factors contributing to CVID-associated GC dysfunction including genetic, epigenetic, tolerogenic, microbiome, and regulatory abnormalities. We also discuss the consequences of these biological phenomena to the development of non-infectious disease complications. Finally, we opine on topics and lines of investigation we think hold promise for expanding our mechanistic understanding of this protean condition and for improving the lives of affected patients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2024
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15. NF-κB Signaling is Required for X-Chromosome Inactivation Maintenance Following T cell Activation.
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Forsyth KS, Toothacre NE, Jiwrajka N, Driscoll AM, Shallberg LA, Cunningham-Rundles C, Barmettler S, Farmer J, Verbsky J, Routes J, Beiting DP, Romberg N, May MJ, and Anguera MC
- Abstract
X Chromosome Inactivation (XCI) is a female-specific process which balances X-linked gene dosage between sexes. Unstimulated T cells lack cytological enrichment of Xist RNA and heterochromatic modifications on the inactive X chromosome (Xi), and these modifications become enriched at the Xi after cell stimulation. Here, we examined allele-specific gene expression and the epigenomic profiles of the Xi following T cell stimulation. We found that the Xi in unstimulated T cells is largely dosage compensated and is enriched with the repressive H3K27me3 modification, but not the H2AK119-ubiquitin (Ub) mark, even at promoters of XCI escape genes. Upon CD3/CD28-mediated T cell stimulation, the Xi accumulates H2AK119-Ub and H3K27me3 across the Xi. Next, we examined the T cell signaling pathways responsible for Xist RNA localization to the Xi and found that T cell receptor (TCR) engagement, specifically NF-κB signaling downstream of TCR, is required. Disruption of NF-κB signaling, using inhibitors or genetic deletions, in mice and patients with immunodeficiencies prevents Xist/XIST RNA accumulation at the Xi and alters expression of some X-linked genes. Our findings reveal a novel connection between NF-κB signaling pathways which impact XCI maintenance in female T cells.
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- 2024
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16. Inborn Errors of Immunity and Cytokine Storm Syndromes.
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Reid W and Romberg N
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- Humans, Cytokines immunology, Cytokines metabolism, Animals, Genetic Diseases, Inborn immunology, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn pathology, Cytokine Release Syndrome immunology
- Abstract
Inborn errors of immunity (IEI) are a diverse and growing category of more than 430 chronic disorders that share susceptibilities to infections. Whether the result of a genetic lesion that causes defective granule-dependent cytotoxicity, excessive lymphoproliferation, or an overwhelming infection represents a unique antigenic challenge, IEIs can display a proclivity for cytokine storm syndrome (CSS) development. This chapter provides an overview of CSS pathophysiology as it relates to IEIs. For each IEI, the immunologic defect and how it promotes or discourages CSS phenomena are reviewed. The IEI-associated molecular defects in pathways that are postulated to be critical to CSS physiology (i.e., toll-like receptors, T regulatory cells, the IL-12/IFNγ axis, IL-6) and, whenever possible, review strategies for treating CSS in IEI patients with molecularly directed therapies are highlighted., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2024
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17. Enterobacter cloacae, a Rare Cause of Cervical Lymphadenitis in X-Linked Chronic Granulomatous Disease.
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Penner C, Datta R, Ebube J, and Romberg N
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- Humans, Enterobacter cloacae genetics, Granulomatous Disease, Chronic complications, Granulomatous Disease, Chronic diagnosis, Granulomatous Disease, Chronic genetics, Lymphadenitis diagnosis
- Published
- 2023
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18. Human T follicular helper clones seed the germinal center-resident regulatory pool.
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Le Coz C, Oldridge DA, Herati RS, De Luna N, Garifallou J, Cruz Cabrera E, Belman JP, Pueschl D, Silva LV, Knox AVC, Reid W, Yoon S, Zur KB, Handler SD, Hakonarson H, Wherry EJ, Gonzalez M, and Romberg N
- Subjects
- Humans, B-Lymphocytes, T-Lymphocytes, Regulatory, Clone Cells, T-Lymphocytes, Helper-Inducer, Germinal Center
- Abstract
The mechanisms by which FOXP3
+ T follicular regulatory (Tfr) cells simultaneously steer antibody formation toward microbe or vaccine recognition and away from self-reactivity remain incompletely understood. To explore underappreciated heterogeneity in human Tfr cell development, function, and localization, we used paired TCRVA / TCRVB sequencing to distinguish tonsillar Tfr cells that are clonally related to natural regulatory T cells (nTfr) from those likely induced from T follicular helper (Tfh) cells (iTfr). The proteins iTfr and nTfr cells differentially expressed were used to pinpoint their in situ locations via multiplex microscopy and establish their divergent functional roles. In silico analyses and in vitro tonsil organoid tracking models corroborated the existence of separate Treg -to-nTfr and Tfh-to-iTfr developmental trajectories. Our results identify human iTfr cells as a distinct CD38+ , germinal center-resident, Tfh-descended subset that gains suppressive function while retaining the capacity to help B cells, whereas CD38- nTfr cells are elite suppressors primarily localized in follicular mantles. Interventions differentially targeting specific Tfr cell subsets may provide therapeutic opportunities to boost immunity or more precisely treat autoimmune diseases.- Published
- 2023
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19. Distinct stage-specific transcriptional states of B cells derived from human tonsillar tissue.
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Espinoza DA, Le Coz C, Cruz Cabrera E, Romberg N, Bar-Or A, and Li R
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- Humans, Germinal Center, Receptors, Antigen, B-Cell, Antibody-Producing Cells, Palatine Tonsil, B-Lymphocytes
- Abstract
B cells within secondary lymphoid tissues encompass a diversity of activation states and multiple maturation processes that reflect antigen recognition and transition through the germinal center (GC) reaction, in which mature B cells differentiate into memory and antibody-secreting cells (ASCs). Here, utilizing single-cell RNA-seq, we identify a range of distinct activation and maturation states of tonsil-derived B cells. In particular, we identify what we believe is a previously uncharacterized CCL4/CCL3 chemokine-expressing B cell population with an expression pattern consistent with B cell receptor/CD40 activation. Furthermore, we present a computational method that leverages regulatory network inference and pseudotemporal modeling to identify upstream transcription factor modulation along a GC-to-ASC axis of transcriptional maturation. Our data set provides valuable insight into diverse B cell functional profiles and will be a useful resource for further studies into the B cell immune compartment.
- Published
- 2023
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20. Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.
- Author
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Leiding JW, Vogel TP, Santarlas VGJ, Mhaskar R, Smith MR, Carisey A, Vargas-Hernández A, Silva-Carmona M, Heeg M, Rensing-Ehl A, Neven B, Hadjadj J, Hambleton S, Ronan Leahy T, Meesilpavikai K, Cunningham-Rundles C, Dutmer CM, Sharapova SO, Taskinen M, Chua I, Hague R, Klemann C, Kostyuchenko L, Morio T, Thatayatikom A, Ozen A, Scherbina A, Bauer CS, Flanagan SE, Gambineri E, Giovannini-Chami L, Heimall J, Sullivan KE, Allenspach E, Romberg N, Deane SG, Prince BT, Rose MJ, Bohnsack J, Mousallem T, Jesudas R, Santos Vilela MMD, O'Sullivan M, Pachlopnik Schmid J, Průhová Š, Klocperk A, Rees M, Su H, Bahna S, Baris S, Bartnikas LM, Chang Berger A, Briggs TA, Brothers S, Bundy V, Chan AY, Chandrakasan S, Christiansen M, Cole T, Cook MC, Desai MM, Fischer U, Fulcher DA, Gallo S, Gauthier A, Gennery AR, Gonçalo Marques J, Gottrand F, Grimbacher B, Grunebaum E, Haapaniemi E, Hämäläinen S, Heiskanen K, Heiskanen-Kosma T, Hoffman HM, Gonzalez-Granado LI, Guerrerio AL, Kainulainen L, Kumar A, Lawrence MG, Levin C, Martelius T, Neth O, Olbrich P, Palma A, Patel NC, Pozos T, Preece K, Lugo Reyes SO, Russell MA, Schejter Y, Seroogy C, Sinclair J, Skevofilax E, Suan D, Suez D, Szabolcs P, Velasco H, Warnatz K, Walkovich K, Worth A, Seppänen MRJ, Torgerson TR, Sogkas G, Ehl S, Tangye SG, Cooper MA, Milner JD, and Forbes Satter LR
- Subjects
- Child, Humans, Autoimmunity genetics, Cohort Studies, Gain of Function Mutation, Mutation, STAT3 Transcription Factor genetics, Cell Proliferation, Lymphocytes, Immune System Diseases, Immunologic Deficiency Syndromes genetics
- Abstract
Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., Conclusion: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)
- Published
- 2023
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21. High cost of immunoglobulin replacement therapy: Causes and implications.
- Author
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Sun D and Romberg N
- Subjects
- Humans, Immunization, Passive, Immunoglobulins, Intravenous therapeutic use
- Published
- 2022
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22. Genetic obstacles to developing and tolerizing human B cells.
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Nguyen K, Alsaati N, Le Coz C, and Romberg N
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- Antigens metabolism, Autoantibodies, Germinal Center, Humans, Immune Tolerance genetics, B-Lymphocytes, Receptors, Antigen, B-Cell genetics
- Abstract
Early in development, B cells explosively diversify B-cell receptors (BCRs) to recognize a wide variety of microbial antigens. A variety of developmental and tolerance checkpoints are subsequently deployed at later developmental stages to purge useless or potentially dangerous autoreactive B-cell clones. Once B cells recognize cognate antigens within secondary lymphoid tissues, their BCRs are genetically modified to increase the specificity and strength of antigen binding. Identification and investigation of monogenic inborn errors of immunity (IEI) diseases demonstrate which specific molecules and pathways are essential for developing well-tolerized human B cells. Although rare, IEI patients have provided important mechanistic insights into, and therapeutic clues for, patients afflicted with more common autoantibody associated autoimmune diseases like lupus, rheumatoid arthritis, and type 1 diabetes. This article is categorized under: Immune System Diseases > Stem Cells and Development > Genetics/Genomics/Epigenetics., (© 2022 Wiley Periodicals LLC.)
- Published
- 2022
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23. Implicating effector genes at COVID-19 GWAS loci using promoter-focused Capture-C in disease-relevant immune cell types.
- Author
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Pahl MC, Le Coz C, Su C, Sharma P, Thomas RM, Pippin JA, Cruz Cabrera E, Johnson ME, Leonard ME, Lu S, Chesi A, Sullivan KE, Romberg N, Grant SFA, and Wells AD
- Subjects
- Genome-Wide Association Study, Humans, Inflammation, SARS-CoV-2 genetics, Severity of Illness Index, COVID-19 genetics
- Abstract
Background: SARS-CoV-2 infection results in a broad spectrum of COVID-19 disease, from mild or no symptoms to hospitalization and death. COVID-19 disease severity has been associated with some pre-existing conditions and the magnitude of the adaptive immune response to SARS-CoV-2, and a recent genome-wide association study (GWAS) of the risk of critical illness revealed a significant genetic component. To gain insight into how human genetic variation attenuates or exacerbates disease following SARS-CoV-2 infection, we implicated putatively functional COVID risk variants in the cis-regulatory landscapes of human immune cell types with established roles in disease severity and used high-resolution chromatin conformation capture to map these disease-associated elements to their effector genes., Results: This functional genomic approach implicates 16 genes involved in viral replication, the interferon response, and inflammation. Several of these genes (PAXBP1, IFNAR2, OAS1, OAS3, TNFAIP8L1, GART) were differentially expressed in immune cells from patients with severe versus moderate COVID-19 disease, and we demonstrate a previously unappreciated role for GART in T cell-dependent antibody-producing B cell differentiation in a human tonsillar organoid model., Conclusions: This study offers immunogenetic insight into the basis of COVID-19 disease severity and implicates new targets for therapeutics that limit SARS-CoV-2 infection and its resultant life-threatening inflammation., (© 2022. The Author(s).)
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- 2022
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24. Lymphocytes Utilize Somatic Mutations, Epigenetic Silencing, and the Proteasome to Escape Truncated WASP Expression.
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Khanna C, Le Coz C, Vaccaro C, Pillarisetti P, Knox AVC, Sy A, Behrens EM, Buchbinder D, and Romberg N
- Subjects
- Animals, Epigenesis, Genetic, Humans, Lymphocytes metabolism, Mice, Mutation genetics, Proteasome Endopeptidase Complex genetics, Proteasome Endopeptidase Complex metabolism, Wiskott-Aldrich Syndrome genetics, Wiskott-Aldrich Syndrome Protein genetics
- Abstract
Wiskott-Aldrich Syndrome Protein (WASP) deficiency causes Wiskott-Aldrich Syndrome (WAS), a sex-linked disorder characterized by combined immunodeficiency, microthrombocytopenia, and eczema. Like WASP-deficient humans, WASP-deficient mice produce normal numbers of functionally defective T cells. Here, we report a WAS patient with a novel germline frameshifting WAS mutation encoding a truncated form of WASP lacking the C-terminal cofilin homology (C) and the acidic region (A) domains (WASPΔCA). Although stably overexpressed in embryonic kidney cell lines, WASPΔCA was undetectable in circulating patient leukocytes. Deep sequencing, transcript profiling, and protein degradation analyses demonstrated patient lymphocytes employ an array of genetic, epigenetic, and proteasomal strategies to avoid expressing WASPΔCA., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
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- 2022
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25. Identification of germline monoallelic mutations in IKZF2 in patients with immune dysregulation.
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Shahin T, Mayr D, Shoeb MR, Kuehn HS, Hoeger B, Giuliani S, Gawriyski LM, Petronczki ÖY, Hadjadj J, Bal SK, Zoghi S, Haimel M, Jimenez Heredia R, Boutboul D, Triebwasser MP, Rialland-Battisti F, Costedoat Chalumeau N, Quartier P, Tangye SG, Fleisher TA, Rezaei N, Romberg N, Latour S, Varjosalo M, Halbritter F, Rieux-Laucat F, Castanon I, Rosenzweig SD, and Boztug K
- Subjects
- Germ Cells, Humans, Ikaros Transcription Factor genetics, Ikaros Transcription Factor metabolism, T-Lymphocytes, Regulatory metabolism, Germ-Line Mutation, Proteomics
- Abstract
Helios, encoded by IKZF2, is a member of the Ikaros family of transcription factors with pivotal roles in T-follicular helper, NK- and T-regulatory cell physiology. Somatic IKZF2 mutations are frequently found in lymphoid malignancies. Although germline mutations in IKZF1 and IKZF3 encoding Ikaros and Aiolos have recently been identified in patients with phenotypically similar immunodeficiency syndromes, the effect of germline mutations in IKZF2 on human hematopoiesis and immunity remains enigmatic. We identified germline IKZF2 mutations (one nonsense (p.R291X)- and 4 distinct missense variants) in six patients with systemic lupus erythematosus, immune thrombocytopenia or EBV-associated hemophagocytic lymphohistiocytosis. Patients exhibited hypogammaglobulinemia, decreased number of T-follicular helper and NK cells. Single-cell RNA sequencing of PBMCs from the patient carrying the R291X variant revealed upregulation of proinflammatory genes associated with T-cell receptor activation and T-cell exhaustion. Functional assays revealed the inability of HeliosR291X to homodimerize and bind target DNA as dimers. Moreover, proteomic analysis by proximity-dependent Biotin Identification revealed aberrant interaction of 3/5 Helios mutants with core components of the NuRD complex conveying HELIOS-mediated epigenetic and transcriptional dysregulation., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2022
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26. Kikuchi-Fujimoto disease is mediated by an aberrant type I interferon response.
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Li EY, Xu J, Nelson ND, Teachey DT, Tan K, Romberg N, Behrens E, and Pillai V
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- Antiviral Agents, Humans, Lymph Nodes pathology, Histiocytic Necrotizing Lymphadenitis diagnosis, Histiocytic Necrotizing Lymphadenitis genetics, Histiocytic Necrotizing Lymphadenitis pathology, Interferon Type I genetics, Lymphadenitis pathology
- Abstract
Kikuchi-Fujimoto disease (KFD) is a reactive lymphadenitis of unclear etiology. To understand the pathogenesis of KFD, we performed targeted RNA sequencing of a well-characterized cohort of 15 KFD specimens with 9 non-KFD lymphadenitis controls. Two thousand and three autoimmunity-related genes were evaluated from archived formalin-fixed paraffin-embedded lymph node tissue and analyzed by a bioinformatics approach. Differential expression analysis of KFD cases compared to controls revealed 44 significantly upregulated genes in KFD. Sixty-eight percent of these genes were associated with the type I interferon (IFN) response pathway. Key component of the pathway including nucleic acid sensors, IFN regulatory factors, IFN-induced antiviral proteins, IFN transcription factors, IFN-stimulated genes, and IFN-induced cytokines were significantly upregulated. Unbiased gene expression pathway analysis revealed enrichment of IFN signaling and antiviral pathways in KFD. Protein-protein interaction analysis and a molecular complex detection algorithm identified a densely interacting 15-gene module of type I IFN pathway genes. Apoptosis regulator IFI6 was identified as a key seed gene. Transcription factor target analysis identified enrichment of IFN-response elements and IFN-response factors. T-cell-associated genes were upregulated while myeloid and B-cell-associated genes were downregulated in KFD. CD123+ plasmacytoid dendritic cells (PDCs) and activated T cells were noted in KFD. In conclusion, KFD is mediated by an aberrant type I interferon response that is likely driven by PDCs and T cells., (© 2021. The Author(s), under exclusive licence to United States & Canadian Academy of Pathology.)
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- 2022
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27. BTK inhibition limits B-cell-T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy.
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Li R, Tang H, Burns JC, Hopkins BT, Le Coz C, Zhang B, de Barcelos IP, Romberg N, Goldstein AC, Banwell BL, Luning Prak ET, Mingueneau M, and Bar-Or A
- Subjects
- Cell Communication, Humans, Agammaglobulinaemia Tyrosine Kinase antagonists & inhibitors, B-Lymphocytes drug effects, B-Lymphocytes metabolism, Multiple Sclerosis drug therapy, Protein Kinase Inhibitors pharmacology, Protein Kinase Inhibitors therapeutic use
- Abstract
Inhibition of Bruton's Tyrosine Kinase (BTKi) is now viewed as a promising next-generation B-cell-targeting therapy for autoimmune diseases including multiple sclerosis (MS). Surprisingly little is known; however, about how BTKi influences MS disease-implicated functions of B cells. Here, we demonstrate that in addition to its expected impact on B-cell activation, BTKi attenuates B-cell:T-cell interactions via a novel mechanism involving modulation of B-cell metabolic pathways which, in turn, mediates an anti-inflammatory modulation of the B cells. In vitro, BTKi, as well as direct inhibition of B-cell mitochondrial respiration (but not glycolysis), limit the B-cell capacity to serve as APC to T cells. The role of metabolism in the regulation of human B-cell responses is confirmed when examining B cells of rare patients with mitochondrial respiratory chain mutations. We further demonstrate that both BTKi and metabolic modulation ex vivo can abrogate the aberrant activation and costimulatory molecule expression of B cells of untreated MS patients. Finally, as proof-of-principle in a Phase 1 study of healthy volunteers, we confirm that in vivo BTKi treatment reduces circulating B-cell mitochondrial respiration, diminishes their activation-induced expression of costimulatory molecules, and mediates an anti-inflammatory shift in the B-cell responses which is associated with an attenuation of T-cell pro-inflammatory responses. These data collectively elucidate a novel non-depleting mechanism by which BTKi mediates its effects on disease-implicated B-cell responses and reveals that modulating B-cell metabolism may be a viable therapeutic approach to target pro-inflammatory B cells., (© 2022. The Author(s).)
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- 2022
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28. Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals.
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Lederer K, Bettini E, Parvathaneni K, Painter MM, Agarwal D, Lundgreen KA, Weirick M, Muralidharan K, Castaño D, Goel RR, Xu X, Drapeau EM, Gouma S, Ort JT, Awofolaju M, Greenplate AR, Le Coz C, Romberg N, Trofe-Clark J, Malat G, Jones L, Rosen M, Weiskopf D, Sette A, Besharatian B, Kaminiski M, Hensley SE, Bates P, Wherry EJ, Naji A, Bhoj V, and Locci M
- Abstract
Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. Herein, through a fine-needle aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant recipients (KTXs). We found that, unlike healthy subjects, KTXs presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cell, SARS-CoV-2 receptor binding domain-specific memory B cell, and neutralizing antibody responses. KTXs also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals and suggest a GC origin for certain humoral and memory B cell responses following mRNA vaccination., Competing Interests: Declaration of interests E.J.W. is consulting or is an advisor for Merck, Elstar, Janssen, Related Sciences, Synthekine, and Surface Oncology. E.J.W. is a founder of Surface Oncology and Arsenal Biosciences. E.J.W. is an inventor on a patent (US Patent number 10,370,446) submitted by Emory University that covers the use of PD-1 blockade to treat infections and cancer. S.E.H. has received consultancy fee from Sanofi Pasteur, Lumen, Novavax, and Merck for work unrelated to this report. A.S. is a consultant for Gritstone, Flow Pharma, Arcturus, Immunoscape, CellCarta, Oxford Immunotech, and Avalia., (Copyright © 2022 Elsevier Inc. All rights reserved.)
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- 2022
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29. Cost Utility of Lifelong Immunoglobulin Replacement Therapy vs Hematopoietic Stem Cell Transplant to Treat Agammaglobulinemia.
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Sun D, Heimall JR, Greenhawt MJ, Bunin NJ, Shaker MS, and Romberg N
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- Humans, Markov Chains, United States, Agammaglobulinemia therapy, Cost-Benefit Analysis, Genetic Diseases, X-Linked therapy, Hematopoietic Stem Cell Transplantation economics, Immunoglobulins, Intravenous administration & dosage, Immunoglobulins, Intravenous economics
- Abstract
Importance: Lifelong immunoglobulin replacement therapy (IRT) is standard-of-care treatment for congenital agammaglobulinemia but accrues high annual costs ($30 000-$90 000 per year) and decrements to quality of life over patients' life spans. Hematopoietic stem cell transplant (HSCT) offers an alternative 1-time therapy, but has high morbidity and mortality., Objective: To evaluate the cost utility of IRT vs matched sibling donor (MSD) and matched unrelated donor (MUD) HSCT to treat patients with agammaglobulinemia in the US., Design, Setting, and Participants: This economic evaluation used Markov analysis to model the base-case scenario of a patient aged 12 months with congenital agammaglobulinemia receiving lifelong IRT vs MSD or MUD HSCT. Costs, probabilities, and quality-of-life measures were derived from the literature. Microsimulations estimated premature deaths for each strategy in a virtual cohort. One-way sensitivity and probabilistic sensitivity analyses evaluated uncertainty around parameter estimates performed from a societal perspective over a 100-year time horizon. The threshold for cost-effective care was set at $100 000 per quality-adjusted life-year (QALY). This study was conducted from 2020 across a 100-year time horizon., Exposures: Immunoglobulin replacement therapy vs MSD or MUD HSCT for treatment of congenital agammaglobulinemia., Main Outcomes and Measures: The primary outcomes were incremental cost-effectiveness ratio (ICER) expressed in 2020 US dollars per QALY gained and premature deaths associated with each strategy., Results: In this economic evaluation of patients with congenital agammaglobulinemia, lifelong IRT cost more than HSCT ($1 512 946 compared with $563 776 [MSD] and $637 036 [MUD]) and generated similar QALYs (20.61 vs 17.25 [MSD] and 17.18 [MUD]). Choosing IRT over MSD or MUD HSCT yielded ICERs of $282 166 per QALY gained over MSD and $255 633 per QALY gained over MUD HSCT, exceeding the US willingness-to-pay threshold of $100 000/QALY. However, IRT prevented at least 2488 premature deaths per 10 000 microsimulations compared with HSCT. When annual IRT price was reduced from $60 145 to below $29 469, IRT became the cost-effective strategy. Findings remained robust in sensitivity and probabilistic sensitivity analyses., Conclusions and Relevance: In the US, IRT is more expensive than HSCT for agammaglobulinemia treatment. The findings of this study suggest that IRT prevents more premature deaths but does not substantially increase quality of life relative to HSCT. Reducing US IRT cost by 51% to a value similar to IRT prices in countries implementing value-based pricing may render it the more cost-effective strategy.
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- 2022
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30. Human Adenovirus 7-Associated Hemophagocytic Lymphohistiocytosis-like Illness: Clinical and Virological Characteristics in a Cluster of Five Pediatric Cases.
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Otto WR, Behrens EM, Teachey DT, Lamson DM, Barrett DM, Bassiri H, Lambert MP, Mount S, Petrosa WL, Romberg N, Sullivan KE, Topjian AA, Fisher BT, and Kajon AE
- Subjects
- Child, Humans, Pennsylvania, Phylogeny, Adenoviruses, Human genetics, Lymphohistiocytosis, Hemophagocytic epidemiology
- Abstract
Background: Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening condition of immune dysregulation. Children often suffer from primary genetic forms of HLH, which can be triggered by infection. Others suffer from secondary HLH as a complication of infection, malignancy, or rheumatologic disease. Identifying the exact cause of HLH is crucial, as definitive treatment for primary disease is hematopoietic stem cell transplant. Adenoviruses have been associated with HLH but molecular epidemiology data are lacking., Methods: We describe the clinical and virologic characteristics of 5 children admitted with adenovirus infection during 2018-2019 who developed HLH or HLH-like illness. Detailed virologic studies, including virus isolation and comprehensive molecular typing were performed., Results: All patients recovered; clinical management varied but included immunomodulating and antiviral therapies. A genetic predisposition for HLH was not identified in any patient. Adenovirus isolates were recovered from 4/5 cases; all were identified as genomic variant 7d. Adenovirus type 7 DNA was detected in the fifth case. Phylogenetic analysis of genome sequences identified 2 clusters-1 related to strains implicated in 2016-2017 outbreaks in Pennsylvania and New Jersey, the other related to a 2009 Chinese strain., Conclusions: It can be challenging to determine whether HLH is the result of an infectious pathogen alone or genetic predisposition triggered by an infection. We describe 5 children from the same center presenting with an HLH-like illness after onset of adenovirus type 7 infection. None of the patients were found to have a genetic predisposition to HLH. These findings suggest that adenovirus 7 infection alone can result in HLH., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)
- Published
- 2021
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31. Hematopoietic Stem Cell Transplantation Successfully Treats CD40LG Duplication.
- Author
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Sun D, Le Coz C, Bunin N, and Romberg N
- Subjects
- Autoimmune Diseases genetics, Autoimmune Diseases immunology, CD4-Positive T-Lymphocytes immunology, CD40 Ligand immunology, Chromosome Duplication, Cyclosporine therapeutic use, Humans, Immunosuppressive Agents therapeutic use, Infant, Lymphopenia genetics, Lymphopenia immunology, Lymphopenia therapy, Male, Autoimmune Diseases therapy, CD40 Ligand genetics, Hematopoietic Stem Cell Transplantation
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- 2021
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32. Germinal center responses to SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals.
- Author
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Lederer K, Parvathaneni K, Painter MM, Bettini E, Agarwal D, Lundgreen KA, Weirick M, Goel RR, Xu X, Drapeau EM, Gouma S, Greenplate AR, Coz CL, Romberg N, Jones L, Rosen M, Besharatian B, Kaminiski M, Weiskopf D, Sette A, Hensley SE, Bates P, Wherry EJ, Naji A, Bhoj V, and Locci M
- Abstract
Vaccine-mediated immunity often relies on the generation of protective antibodies and memory B cells, which commonly stem from germinal center (GC) reactions. An in-depth comparison of the GC responses elicited by SARS-CoV-2 mRNA vaccines in healthy and immunocompromised individuals has not yet been performed due to the challenge of directly probing human lymph nodes. In this study, through a fine-needle-aspiration-based approach, we profiled the immune responses to SARS-CoV-2 mRNA vaccines in lymph nodes of healthy individuals and kidney transplant (KTX) recipients. We found that, unlike healthy subjects, KTX recipients presented deeply blunted SARS-CoV-2-specific GC B cell responses coupled with severely hindered T follicular helper cells, SARS-CoV-2 receptor-binding-domain-specific memory B cells and neutralizing antibodies. KTX recipients also displayed reduced SARS-CoV-2-specific CD4 and CD8 T cell frequencies. Broadly, these data indicate impaired GC-derived immunity in immunocompromised individuals, and suggest a GC-origin for certain humoral and memory B cell responses following mRNA vaccination.
- Published
- 2021
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33. Diagnostic Challenges in Pediatric Hemophagocytic Lymphohistiocytosis.
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Si SJ, Tasian SK, Bassiri H, Fisher BT, Atalla J, Patel R, Romberg N, Lambert MP, Paessler M, Behrens EJ, Teachey DT, and Sullivan KE
- Subjects
- Child, Cytokine Release Syndrome diagnosis, Female, Humans, Male, Lymphohistiocytosis, Hemophagocytic diagnosis
- Abstract
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome of severe immune dysregulation that encompasses a broad range of underlying genetic diseases and infectious triggers. Monogenic conditions, autoimmune diseases, and infections can all drive the phenotype of HLH and associated immune hyperactivation with hypercytokinemia. A diagnosis of HLH usually requires a combination of clinical and laboratory findings; there is no single sensitive and specific diagnostic test, which often leads to "diagnostic dilemmas" and delays in treatment initiation. Ferritin levels, one of the most commonly used screening tests, were collected across a large tertiary care pediatric hospital to identify the positive predictive value for HLH. Herein, we present several cases that illustrate the clinical challenges of confirming an HLH diagnosis. Additionally, we report on the utility of establishing a formal multi-disciplinary group to aid the prompt diagnosis and treatment of patients presenting with HLH-like pathophysiologies., (© 2021. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)
- Published
- 2021
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34. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients.
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Le Coz C, Nguyen DN, Su C, Nolan BE, Albrecht AV, Xhani S, Sun D, Demaree B, Pillarisetti P, Khanna C, Wright F, Chen PA, Yoon S, Stiegler AL, Maurer K, Garifallou JP, Rymaszewski A, Kroft SH, Olson TS, Seif AE, Wertheim G, Grant SFA, Vo LT, Puck JM, Sullivan KE, Routes JM, Zakharova V, Shcherbina A, Mukhina A, Rudy NL, Hurst ACE, Atkinson TP, Boggon TJ, Hakonarson H, Abate AR, Hajjar J, Nicholas SK, Lupski JR, Verbsky J, Chinn IK, Gonzalez MV, Wells AD, Marson A, Poon GMK, and Romberg N
- Subjects
- Adolescent, Adult, B-Lymphocytes physiology, Cell Differentiation genetics, Cell Line, Child, Child, Preschool, Dendritic Cells physiology, Female, Gene Expression Regulation, Developmental genetics, HEK293 Cells, Hematopoiesis genetics, Hematopoietic Stem Cells physiology, Humans, Infant, Lymphopoiesis genetics, Male, Mutation genetics, Precursor Cells, B-Lymphoid physiology, Stem Cells physiology, Young Adult, Agammaglobulinemia genetics, Chromatin genetics, Proto-Oncogene Proteins genetics, Trans-Activators genetics
- Abstract
The pioneer transcription factor (TF) PU.1 controls hematopoietic cell fate by decompacting stem cell heterochromatin and allowing nonpioneer TFs to enter otherwise inaccessible genomic sites. PU.1 deficiency fatally arrests lymphopoiesis and myelopoiesis in mice, but human congenital PU.1 disorders have not previously been described. We studied six unrelated agammaglobulinemic patients, each harboring a heterozygous mutation (four de novo, two unphased) of SPI1, the gene encoding PU.1. Affected patients lacked circulating B cells and possessed few conventional dendritic cells. Introducing disease-similar SPI1 mutations into human hematopoietic stem and progenitor cells impaired early in vitro B cell and myeloid cell differentiation. Patient SPI1 mutations encoded destabilized PU.1 proteins unable to nuclear localize or bind target DNA. In PU.1-haploinsufficient pro-B cell lines, euchromatin was less accessible to nonpioneer TFs critical for B cell development, and gene expression patterns associated with the pro- to pre-B cell transition were undermined. Our findings molecularly describe a novel form of agammaglobulinemia and underscore PU.1's critical, dose-dependent role as a hematopoietic euchromatin gatekeeper., Competing Interests: Disclosures: D. Nguyen reported a patent to PCT/US2019/066079 with royalties paid. T. Olson reported personal fees from Bluebird Bio outside of the submitted work. J. Puck reported other from Invitae (spouse's employer) and other from UpToDate (royalties) outside the submitted work. J. Hajjar reported grants from Immune Deficiency Foundation, the US immunodeficiency network, Chao-physician Scientist award, the Texas Medical Center Digestive Diseases Center, and the Jeffrey Modell Foundation, other from Horizon, Pharming, Baxalta, CSL Behring, and the National Guard and Al-Faisal University Hospital outside the submitted work. J. Lupski reported grants from NIH/NINDS (R35 NS105078), and NIH/NIGMS (R01 GM106373), personal fees from Regeneron Genetics Center and Novartis, and other from 23andMe outside the submitted work. A. Marson reported personal fees from Arsenal Biosciences, Spotlight Therapeutics, PACT Pharma, Merck, Vertex, AlphaSights, ALDA, Amgen, Trizell, Juno Therapeutics, Health Advances, Lonza, Bernstein, Abbvie, Genentech, Illumina, Arcus, Jackson Laboratories, NanoString Technologies, GLG, and Rupert Case Management, grants from Anthem, Gilead, GlaxoSmithKline, Juno Therapeutics, Epinomics, Sanofi, and Parker Institute for Cancer Immunotherapy (PICI), non-financial support from Illumina, other from Parker Institute for Cancer Immunotherapy (PICI), ThermoFisher, and Third Rock Ventures outside the submitted work. In addition, A. Marson had a patent to WO 2016/123578 licensed (The identity of the licensee has not been made public) and a patent to PCT/US19/66079 licensed (The identity of the licensee has not been made public); and is an investor in and informal advisor to Offline Ventures. No other disclosures were reported., (© 2021 Le Coz et al.)
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- 2021
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35. Combined use of emapalumab and ruxolitinib in a patient with refractory hemophagocytic lymphohistiocytosis was safe and effective.
- Author
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Triebwasser MP, Barrett DM, Bassiri H, Bunin N, Elgarten C, Freedman J, Geera AS, Monos D, Lambert MP, Olson T, Seif AE, Paessler M, Petrosa W, Reilly AF, Romberg N, Sullivan KE, Quinn GZ, Behrens E, and Teachey DT
- Subjects
- Antibodies, Monoclonal therapeutic use, Antibodies, Neutralizing therapeutic use, Drug Combinations, Humans, Nitriles therapeutic use, Pyrazoles therapeutic use, Pyrimidines therapeutic use, Lymphohistiocytosis, Hemophagocytic drug therapy
- Published
- 2021
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36. Infectious Complications Predict Premature CD8 + T-cell Senescence in CD40 Ligand-Deficient Patients.
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Shin JJ, Catanzaro J, Yonkof JR, Delmonte O, Sacco K, Shin MS, Reddy S, Whittington PJ, Soffer G, Mustillo PJ, Sullivan KE, Notarangelo LD, Abraham RS, Romberg N, and Kang I
- Subjects
- Adolescent, Adult, Age of Onset, Biomarkers, Case-Control Studies, Child, Preschool, Genes, X-Linked, Genetic Association Studies methods, Genetic Predisposition to Disease, Humans, Immunophenotyping, Pedigree, Phenotype, Prognosis, Receptors, Antigen, T-Cell, Young Adult, CD40 Ligand deficiency, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes metabolism, Cellular Senescence genetics, Immune System Diseases complications, Immune System Diseases etiology, Infections diagnosis, Infections etiology
- Abstract
Purpose: CD40 ligand (CD40L)-deficient patients display increased susceptibilities to infections that can be mitigated with effective prophylactic strategies including immunoglobulin G (IgG) replacement and prophylactic antibiotics. CD8
+ T-cell senescence has been described in CD40L deficiency, but it is unclear if this is an intrinsic feature of the disease or secondary to infectious exposures. To address this question, we assessed CD8+ T-cell senescence and its relationship to clinical histories, including prophylaxis adherence and infections, in CD40L-deficient patients., Methods: Peripheral CD8+ T-cells from seven CD40L-deficient patients and healthy controls (HCs) were assessed for senescent features using T-cell receptor excision circle (TREC) analysis, flow cytometry, cytometry by time of flight (CyTOF) and in vitro functional determinations including CMV-specific proliferation and cytokine release assays., Results: Three patients (5, 28, and 34 years old) who were poorly adherent to immunoglobulin G replacement and Pneumocystis jirovecii pneumonia (PJP) prophylaxis and/or experienced multiple childhood pneumonias (patient group 1) had an expansion of effector memory CD8+ T-cells with the senescent phenotype when compared to HCs. Such changes were not observed in the patient group 2 (four patients, 16, 22, 24, and 33 years old) who were life-long adherents to prophylaxis and experienced few infectious complications. CyTOF analysis of CD8+ T-cells from the 5-year-old patient and older adult HCs showed similar expression patterns of senescence-associated molecules., Conclusions: Our findings support that recurrent infections and non-adherence to prophylaxis promote early CD8+ T-cell senescence in CD40L deficiency. Premature senescence may increase malignant susceptibilities and further exacerbate infectious risk in CD40L-deficient patients.- Published
- 2021
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37. Mapping effector genes at lupus GWAS loci using promoter Capture-C in follicular helper T cells.
- Author
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Su C, Johnson ME, Torres A, Thomas RM, Manduchi E, Sharma P, Mehra P, Le Coz C, Leonard ME, Lu S, Hodge KM, Chesi A, Pippin J, Romberg N, Grant SFA, and Wells AD
- Subjects
- Autoantibodies immunology, Autoantibodies metabolism, Cells, Cultured, Chromosome Mapping methods, Gene Expression Profiling methods, Humans, Jurkat Cells, Lupus Erythematosus, Systemic immunology, Protein Serine-Threonine Kinases genetics, Proto-Oncogene Proteins c-bcl-6 genetics, RNA Interference, Receptors, CXCR5 genetics, T-Lymphocytes, Helper-Inducer immunology, Genetic Predisposition to Disease genetics, Genome-Wide Association Study methods, Lupus Erythematosus, Systemic genetics, Polymorphism, Single Nucleotide, Promoter Regions, Genetic genetics, T-Lymphocytes, Helper-Inducer metabolism
- Abstract
Systemic lupus erythematosus (SLE) is mediated by autoreactive antibodies that damage multiple tissues. Genome-wide association studies (GWAS) link >60 loci with SLE risk, but the causal variants and effector genes are largely unknown. We generated high-resolution spatial maps of SLE variant accessibility and gene connectivity in human follicular helper T cells (TFH), a cell type required for anti-nuclear antibodies characteristic of SLE. Of the ~400 potential regulatory variants identified, 90% exhibit spatial proximity to genes distant in the 1D genome sequence, including variants that loop to regulate the canonical TFH genes BCL6 and CXCR5 as confirmed by genome editing. SLE 'variant-to-gene' maps also implicate genes with no known role in TFH/SLE disease biology, including the kinases HIPK1 and MINK1. Targeting these kinases in TFH inhibits production of IL-21, a cytokine crucial for class-switched B cell antibodies. These studies offer mechanistic insight into the SLE-associated regulatory architecture of the human genome.
- Published
- 2020
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38. Immunodeficiency Masqueraders.
- Author
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Dutmer CM and Romberg N
- Subjects
- Diagnosis, Differential, Humans, Immunologic Deficiency Syndromes diagnosis
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- 2020
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39. Diagnostic interpretation of genetic studies in patients with primary immunodeficiency diseases: A working group report of the Primary Immunodeficiency Diseases Committee of the American Academy of Allergy, Asthma & Immunology.
- Author
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Chinn IK, Chan AY, Chen K, Chou J, Dorsey MJ, Hajjar J, Jongco AM 3rd, Keller MD, Kobrynski LJ, Kumanovics A, Lawrence MG, Leiding JW, Lugar PL, Orange JS, Patel K, Platt CD, Puck JM, Raje N, Romberg N, Slack MA, Sullivan KE, Tarrant TK, Torgerson TR, and Walter JE
- Subjects
- Asthma, Humans, United States, Genetic Testing, Primary Immunodeficiency Diseases diagnosis, Primary Immunodeficiency Diseases genetics, Primary Immunodeficiency Diseases therapy
- Abstract
Genetic testing has become an integral component of the diagnostic evaluation of patients with suspected primary immunodeficiency diseases. Results of genetic testing can have a profound effect on clinical management decisions. Therefore clinical providers must demonstrate proficiency in interpreting genetic data. Because of the need for increased knowledge regarding this practice, the American Academy of Allergy, Asthma & Immunology Primary Immunodeficiency Diseases Committee established a work group that reviewed and summarized information concerning appropriate methods, tools, and resources for evaluating variants identified by genetic testing. Strengths and limitations of tests frequently ordered by clinicians were examined. Summary statements and tables were then developed to guide the interpretation process. Finally, the need for research and collaboration was emphasized. Greater understanding of these important concepts will improve the diagnosis and management of patients with suspected primary immunodeficiency diseases., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2020
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40. Common variable immunodeficiency-associated endotoxemia promotes early commitment to the T follicular lineage.
- Author
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Le Coz C, Bengsch B, Khanna C, Trofa M, Ohtani T, Nolan BE, Henrickson SE, Lambert MP, Kim TO, Despotovic JM, Feldman S, Fadugba OO, Takach P, Ruffner M, Jyonouchi S, Heimall J, Sullivan KE, Wherry EJ, and Romberg N
- Subjects
- Adolescent, Adult, B-Lymphocytes pathology, Child, Child, Preschool, Common Variable Immunodeficiency pathology, Endotoxemia pathology, Female, Humans, IgA Deficiency pathology, Male, Middle Aged, T-Lymphocytes, Regulatory pathology, B-Lymphocytes immunology, Cell Differentiation immunology, Common Variable Immunodeficiency immunology, Endotoxemia immunology, IgA Deficiency immunology, T-Lymphocytes, Regulatory immunology
- Abstract
Background: Although chiefly a B-lymphocyte disorder, several research groups have identified common variable immunodeficiency (CVID) subjects with numeric and/or functional T
H cell alterations. The causes, interrelationships, and consequences of CVID-associated CD4+ T-cell derangements to hypogammaglobulinemia, autoantibody production, or both remain unclear., Objective: We sought to determine how circulating CD4+ T cells are altered in CVID subjects with autoimmune cytopenias (AICs; CVID+AIC) and the causes of these derangements., Methods: Using hypothesis-generating, high-dimensional single-cell analyses, we created comprehensive phenotypic maps of circulating CD4+ T cells. Differences between subject groups were confirmed in a large and genetically diverse cohort of CVID subjects (n = 69) by using flow cytometry, transcriptional profiling, multiplex cytokine/chemokine detection, and a suite of in vitro functional assays measuring naive T-cell differentiation, B-cell/T-cell cocultures, and regulatory T-cell suppression., Results: Although CD4+ TH cell profiles from healthy donors and CVID subjects without AICs were virtually indistinguishable, T cells from CVID+AIC subjects exhibited follicular features as early as thymic egress. Follicular skewing correlated with IgA deficiency-associated endotoxemia and endotoxin-induced expression of activin A and inducible T-cell costimulator ligand. The resulting enlarged circulating follicular helper T-cell population from CVID+AIC subjects provided efficient help to receptive healthy donor B cells but not unresponsive CVID B cells. Despite this, circulating follicular helper T cells from CVID+AIC subjects exhibited aberrant transcriptional profiles and altered chemokine/cytokine receptor expression patterns that interfered with regulatory T-cell suppression assays and were associated with autoantibody production., Conclusions: Endotoxemia is associated with early commitment to the follicular T-cell lineage in IgA-deficient CVID subjects, particularly those with AICs., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
41. Birds of a feather: Common variable immune deficiencies.
- Author
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Romberg N and Lawrence MG
- Subjects
- Common Variable Immunodeficiency genetics, Common Variable Immunodeficiency immunology, Humans, Common Variable Immunodeficiency diagnosis
- Abstract
Objective: To update the reader on recently proposed common variable immune deficiency (CVID) diagnostic criteria, newly uncovered CVID pathobiology, freshly identified CVID-related genes, and novel CVID therapies., Data Sources: PubMed Central., Study Selections: We selected 60 clinical and translational research articles that have shaped CVID diagnostic criteria, introduced personalized therapies, and advanced our understanding of CVID biology and genetics. We have incorporated recent articles and older published work that are foundational to the modern understanding of this protean disease., Results: CVID has proven to be a heterogenous group of antibody deficiency diseases driven by defects in diverse biologic processes, including B-cell development, activation, tolerance, class-switch recombination, somatic hypermutation, and lymphoproliferation. Recent genetic advances have enabled identification of several CVID-related gene defects that may contribute to patients' infectious and noninfectious symptoms., Conclusion: Improved understanding of the aberrant biologic processes that drive CVID and the disease's genetic basis may be useful in directing therapeutic decisions, especially in cases complicated by autoimmune, lymphoproliferative, and inflammatory features., (Copyright © 2019 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
- Full Text
- View/download PDF
42. AIRE expression controls the peripheral selection of autoreactive B cells.
- Author
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Sng J, Ayoglu B, Chen JW, Schickel JN, Ferre EMN, Glauzy S, Romberg N, Hoenig M, Cunningham-Rundles C, Utz PJ, Lionakis MS, and Meffre E
- Subjects
- Adolescent, Autoantibodies blood, Autoantibodies metabolism, Autoantigens immunology, B-Lymphocytes metabolism, CD3 Complex deficiency, CD3 Complex genetics, CD3 Complex immunology, Child, Child, Preschool, Cytokines immunology, Female, Humans, Immune Tolerance genetics, Lymphocyte Activation genetics, Male, Middle Aged, Mutation, Polyendocrinopathies, Autoimmune blood, Polyendocrinopathies, Autoimmune genetics, Protein Array Analysis, Proteomics methods, T-Lymphocytes, Regulatory immunology, Transcription Factors genetics, Transcription Factors immunology, AIRE Protein, Autoantibodies immunology, Autoimmunity genetics, B-Lymphocytes immunology, Polyendocrinopathies, Autoimmune immunology, Transcription Factors deficiency
- Abstract
Autoimmune regulator (AIRE) mutations result in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) syndrome characterized by defective central T cell tolerance and the production of many autoantibodies targeting tissue-specific antigens and cytokines. By studying CD3- and AIRE-deficient patients, we found that lack of either T cells or AIRE function resulted in the peripheral accumulation of autoreactive mature naïve B cells. Proteomic arrays and Biacore affinity measurements revealed that unmutated antibodies expressed by these autoreactive naïve B cells recognized soluble molecules and cytokines including insulin, IL-17A, and IL-17F, which are AIRE-dependent thymic peripheral tissue antigens targeted by autoimmune responses in APECED. AIRE-deficient patients also displayed decreased frequencies of regulatory T cells (T
regs ) that lacked common TCRβ clones found instead in their conventional T cell compartment, thereby suggesting holes in the Treg TCR repertoire of these patients. Hence, AIRE-mediated T cell/Treg selection normally prevents the expansion of autoreactive naïve B cells recognizing peripheral self-antigens., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)- Published
- 2019
- Full Text
- View/download PDF
43. Hypomorphic caspase activation and recruitment domain 11 (CARD11) mutations associated with diverse immunologic phenotypes with or without atopic disease.
- Author
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Dorjbal B, Stinson JR, Ma CA, Weinreich MA, Miraghazadeh B, Hartberger JM, Frey-Jakobs S, Weidinger S, Moebus L, Franke A, Schäffer AA, Bulashevska A, Fuchs S, Ehl S, Limaye S, Arkwright PD, Briggs TA, Langley C, Bethune C, Whyte AF, Alachkar H, Nejentsev S, DiMaggio T, Nelson CG, Stone KD, Nason M, Brittain EH, Oler AJ, Veltri DP, Leahy TR, Conlon N, Poli MC, Borzutzky A, Cohen JI, Davis J, Lambert MP, Romberg N, Sullivan KE, Paris K, Freeman AF, Lucas L, Chandrakasan S, Savic S, Hambleton S, Patel SY, Jordan MB, Theos A, Lebensburger J, Atkinson TP, Torgerson TR, Chinn IK, Milner JD, Grimbacher B, Cook MC, and Snow AL
- Subjects
- Adult, Female, Humans, Male, Mutation, Phenotype, CARD Signaling Adaptor Proteins genetics, CARD Signaling Adaptor Proteins immunology, Guanylate Cyclase genetics, Guanylate Cyclase immunology, Immune System Diseases genetics, Immune System Diseases immunology
- Abstract
Background: Caspase activation and recruitment domain 11 (CARD11) encodes a scaffold protein in lymphocytes that links antigen receptor engagement with downstream signaling to nuclear factor κB, c-Jun N-terminal kinase, and mechanistic target of rapamycin complex 1. Germline CARD11 mutations cause several distinct primary immune disorders in human subjects, including severe combined immune deficiency (biallelic null mutations), B-cell expansion with nuclear factor κB and T-cell anergy (heterozygous, gain-of-function mutations), and severe atopic disease (loss-of-function, heterozygous, dominant interfering mutations), which has focused attention on CARD11 mutations discovered by using whole-exome sequencing., Objectives: We sought to determine the molecular actions of an extended allelic series of CARD11 and to characterize the expanding range of clinical phenotypes associated with heterozygous CARD11 loss-of-function alleles., Methods: Cell transfections and primary T-cell assays were used to evaluate signaling and function of CARD11 variants., Results: Here we report on an expanded cohort of patients harboring novel heterozygous CARD11 mutations that extend beyond atopy to include other immunologic phenotypes not previously associated with CARD11 mutations. In addition to (and sometimes excluding) severe atopy, heterozygous missense and indel mutations in CARD11 presented with immunologic phenotypes similar to those observed in signal transducer and activator of transcription 3 loss of function, dedicator of cytokinesis 8 deficiency, common variable immunodeficiency, neutropenia, and immune dysregulation, polyendocrinopathy, enteropathy, X-linked-like syndrome. Pathogenic variants exhibited dominant negative activity and were largely confined to the CARD or coiled-coil domains of the CARD11 protein., Conclusion: These results illuminate a broader phenotypic spectrum associated with CARD11 mutations in human subjects and underscore the need for functional studies to demonstrate that rare gene variants encountered in expected and unexpected phenotypes must nonetheless be validated for pathogenic activity., (Published by Elsevier Inc.)
- Published
- 2019
- Full Text
- View/download PDF
44. Reply.
- Author
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Le Coz C and Romberg N
- Subjects
- Chromosomes, Humans, Autoimmune Diseases
- Published
- 2019
- Full Text
- View/download PDF
45. BCL6 Inhibitor-Mediated Downregulation of Phosphorylated SAMHD1 and T Cell Activation Are Associated with Decreased HIV Infection and Reactivation.
- Author
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Cai Y, Abdel-Mohsen M, Tomescu C, Xue F, Wu G, Howell BJ, Ai Y, Sun J, Azzoni L, Le Coz C, Romberg N, and Montaner LJ
- Subjects
- Adult, Down-Regulation, HIV Infections drug therapy, HIV-1 drug effects, HIV-1 physiology, HIV-2 drug effects, HIV-2 physiology, Humans, Lymphocyte Activation drug effects, Middle Aged, Phosphorylation, Virus Replication drug effects, Young Adult, CD4-Positive T-Lymphocytes immunology, HIV Infections metabolism, Indoles pharmacology, Proto-Oncogene Proteins c-bcl-6 metabolism, SAM Domain and HD Domain-Containing Protein 1 metabolism, Thiazolidinediones pharmacology
- Abstract
Clearance of HIV-infected germinal center (GC) CD4
+ follicular helper T cells (Tfh) after combination antiretroviral therapy (ART) is essential to an HIV cure. Blocking B cell lymphoma 6 (BCL6; the master transcription factor for Tfh cells) represses HIV infection of tonsillar CD4+ Tfh ex vivo , reduces GC formation, and limits immune activation in vivo We assessed the anti-HIV activity of a novel BCL6 inhibitor, FX1, in Tfh/non-Tfh CD4+ T cells and its impact on T cell activation and SAMHD1 phosphorylation (Thr592). FX1 repressed HIV-1 infection of peripheral CD4+ T cells and tonsillar Tfh/non-Tfh CD4+ T cells ( P < 0.05) and total elongated and multispliced HIV-1 RNA production during the first round of viral life cycle ( P < 0.01). Using purified circulating CD4+ T cells from uninfected donors, we demonstrate that FX1 treatment resulted in downregulation pSAMHD1 expression ( P < 0.05) and T cell activation (HLA-DR, CD25, and Ki67; P < 0.01) ex vivo corresponding with inhibition of HIV-1 and HIV-2 replication. Ex vivo HIV-1 reactivation using purified peripheral CD4+ T cells from HIV-infected ART-suppressed donors was also blocked by FX1 treatment ( P < 0.01). Our results indicate that BCL6 function contributes to Tfh/non-Tfh CD4+ T cell activation and cellular susceptibility to HIV infection. BCL6 inhibition represents a novel therapeutic strategy to potentiate HIV suppression in Tfh/non-Tfh CD4+ T cells without reactivation of latent virus. IMPORTANCE The expansion and accumulation of HIV-infected BCL6+ Tfh CD4+ T cells are thought to contribute to the persistence of viral reservoirs in infected subjects undergoing ART. Two mechanisms have been raised for the preferential retention of HIV within Tfh CD4+ T cells: (i) antiretroviral drugs have limited tissue distribution, resulting in insufficient tissue concentration and lower efficacy in controlling HIV replication in lymphoid tissues, and (ii) cytotoxic CD8+ T cells within lymphoid tissues express low levels of chemokine receptor (CXCR5), thus limiting their ability to enter the GCs to control/eliminate HIV-infected Tfh cells. Our results indicate that the BCL6 inhibitor FX1 can not only repress HIV infection of tonsillar Tfh ex vivo but also suppress HIV infection and reactivation in primary, non-Tfh CD4+ T cells. Our study provides a rationale for targeting BCL6 protein to extend ART-mediated reduction of persistent HIV and/or support strategies toward HIV remission beyond ART cessation., (Copyright © 2019 American Society for Microbiology.)- Published
- 2019
- Full Text
- View/download PDF
46. Patients with common variable immunodeficiency with autoimmune cytopenias exhibit hyperplastic yet inefficient germinal center responses.
- Author
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Romberg N, Le Coz C, Glauzy S, Schickel JN, Trofa M, Nolan BE, Paessler M, Xu ML, Lambert MP, Lakhani SA, Khokha MK, Jyonouchi S, Heimall J, Takach P, Maglione PJ, Catanzaro J, Hsu FI, Sullivan KE, Cunningham-Rundles C, and Meffre E
- Subjects
- Adolescent, Adult, Aged, B-Lymphocytes pathology, Biopsy, Child, Common Variable Immunodeficiency pathology, Female, Germinal Center pathology, Humans, Hyperplasia, Male, Middle Aged, T-Lymphocytes pathology, Autoantibodies immunology, B-Lymphocytes immunology, Common Variable Immunodeficiency immunology, Germinal Center immunology, Immunoglobulin G immunology, T-Lymphocytes immunology
- Abstract
Background: The lack of pathogen-protective, isotype-switched antibodies in patients with common variable immunodeficiency (CVID) suggests germinal center (GC) hypoplasia, yet a subset of patients with CVID is paradoxically affected by autoantibody-mediated autoimmune cytopenias (AICs) and lymphadenopathy., Objective: We sought to compare the physical characteristics and immunologic output of GC responses in patients with CVID with AIC (CVID+AIC) and without AIC (CVID-AIC)., Methods: We analyzed GC size and shape in excisional lymph node biopsy specimens from 14 patients with CVID+AIC and 4 patients with CVID-AIC. Using paired peripheral blood samples, we determined how AICs specifically affected B-and T-cell compartments and antibody responses in patients with CVID., Results: We found that patients with CVID+AIC displayed irregularly shaped hyperplastic GCs, whereas GCs were scarce and small in patients with CVID-AIC. GC hyperplasia was also evidenced by an increase in numbers of circulating follicular helper T cells, which correlated with decreased regulatory T-cell frequencies and function. In addition, patients with CVID+AIC had serum endotoxemia associated with a dearth of isotype-switched memory B cells that displayed significantly lower somatic hypermutation frequencies than their counterparts with CVID-AIC. Moreover, IgG
+ B cells from patients with CVID+AIC expressed VH4-34-encoded antibodies with unmutated Ala-Val-Tyr and Asn-His-Ser motifs, which recognize both erythrocyte I/i self-antigens and commensal bacteria., Conclusions: Patients with CVID+AIC do not contain mucosal microbiota and exhibit hyperplastic yet inefficient GC responses that favor the production of untolerized IgG+ B-cell clones that recognize both commensal bacteria and hematopoietic I/i self-antigens., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2019
- Full Text
- View/download PDF
47. Cytotoxic T-Lymphocyte-Associated Protein 4 Haploinsufficiency-Associated Inflammation Can Occur Independently of T-Cell Hyperproliferation.
- Author
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Le Coz C, Nolan BE, Trofa M, Kamsheh AM, Khokha MK, Lakhani SA, Novelli A, Zackai EH, Sullivan KE, Briuglia S, Bhatti TR, and Romberg N
- Abstract
Located contiguously on the long arm of the second chromosome are gene paralogs encoding the immunoglobulin-family co-activation receptors CD28 and cytotoxic T-lymphocyte-associated protein 4 (CTLA4). CD28 and CTLA4 share the same B7 ligands yet each provides opposing proliferative signals to T cells. Herein, we describe for the first time two unrelated subjects with coexisting CD28 and CTLA4 haploinsufficiency due to heterozygous microdeletions of chromosome 2q. Although their clinical phenotype, multi-organ inflammatory disease, is superficially similar to that of CTLA4 haploinsufficient autoimmune lymphoproliferative syndrome type V (ALPS5) patients, we demonstrate our subjects' underlying immunopathology to be distinct. Unlike ALPS5 T cells which hyperproliferate to T-cell receptor-mediated activation and infiltrate organs, T cells from our subjects are hypoproliferative and do not. Instead of T cell infiltrates, biopsies of affected subject tissues demonstrated infiltrates of lineage negative lymphoid cells. This histologic feature correlated with significant increases in circulating type 3 innate lymphoid cells (ILC3s) and ILC3 cytokines, interleukin 22, and interleukin-17A. CTLA4-Ig monotherapy, which we trialed in one subject, was remarkably effective in controlling inflammatory diseases, normalizing ILC3 frequencies, and reducing ILC3 cytokine concentrations.
- Published
- 2018
- Full Text
- View/download PDF
48. Reprogramming human T cell function and specificity with non-viral genome targeting.
- Author
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Roth TL, Puig-Saus C, Yu R, Shifrut E, Carnevale J, Li PJ, Hiatt J, Saco J, Krystofinski P, Li H, Tobin V, Nguyen DN, Lee MR, Putnam AL, Ferris AL, Chen JW, Schickel JN, Pellerin L, Carmody D, Alkorta-Aranburu G, Del Gaudio D, Matsumoto H, Morell M, Mao Y, Cho M, Quadros RM, Gurumurthy CB, Smith B, Haugwitz M, Hughes SH, Weissman JS, Schumann K, Esensten JH, May AP, Ashworth A, Kupfer GM, Greeley SAW, Bacchetta R, Meffre E, Roncarolo MG, Romberg N, Herold KC, Ribas A, Leonetti MD, and Marson A
- Subjects
- Animals, Autoimmunity genetics, CRISPR-Cas Systems genetics, Cells, Cultured, Humans, Interleukin-2 Receptor alpha Subunit genetics, Male, Mice, Neoplasm Transplantation, Protein Engineering, Receptors, Antigen, T-Cell genetics, T-Lymphocytes cytology, Cellular Reprogramming genetics, Gene Editing, Genome, Human genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism
- Abstract
Decades of work have aimed to genetically reprogram T cells for therapeutic purposes
1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4 . The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6 . Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells.- Published
- 2018
- Full Text
- View/download PDF
49. CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation.
- Author
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Le Coz C, Trofa M, Syrett CM, Martin A, Jyonouchi H, Jyonouchi S, Anguera MC, and Romberg N
- Subjects
- Adult, Female, Humans, Infant, Male, Pedigree, Autoimmune Diseases genetics, CD40 Ligand genetics, Chromosome Duplication genetics, X Chromosome Inactivation genetics
- Published
- 2018
- Full Text
- View/download PDF
50. NLRC4 inflammasomopathies.
- Author
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Romberg N, Vogel TP, and Canna SW
- Subjects
- Animals, Autoimmune Diseases immunology, Biomarkers, Tumor genetics, CARD Signaling Adaptor Proteins metabolism, Calcium-Binding Proteins metabolism, Humans, Inflammation, Interleukin-18 metabolism, Urticaria immunology, Autoimmune Diseases genetics, CARD Signaling Adaptor Proteins genetics, Calcium-Binding Proteins genetics, Inflammasomes metabolism, Mutation genetics, Urticaria genetics
- Abstract
Purpose of Review: The purpose of the review is to highlight developments in autoinflammatory diseases associated with gain-of-function mutations in the gene encoding NLR-family CARD-containing protein 4 (NLRC4), the NLRC4-inflammasomopathies., Recent Findings: Three years since the identification of the first autoinflammation with infantile enterocolitis (AIFEC) patients, there is an improved understanding of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and also intestinal epithelial cells. This information has opened new therapeutic avenues to treat AIFEC patients with targeted agents like recombinant IL-18 binding protein and antiinterferon-γ antibodies. Additional phenotypes traditionally associated with NLRP3 mutations like familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), have now also been associated with gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has now been identified in a NOMID and an AIFEC patient, a finding emphasizing nontraditional modes of inheritance in autoinflammatory diseases., Summary: The NLRC4 inflammasomopathies constitute a growing autoinflammatory disease category that spans a broad clinical spectrum from cold urticaria to NOMID and the often fatal disease AIFEC. Rapid case identification with biomarkers like elevated serum IL-18 concentrations and early intervention with targeted immunomodulatory therapies are key strategies to improving outcomes for AIFEC patients.
- Published
- 2017
- Full Text
- View/download PDF
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