Antibodies to DNA: infection or genetics?

Lupus ◽  
2009 ◽  
Vol 18 (13) ◽  
pp. 1176-1180 ◽  
Author(s):  
DS Pisetsky ◽  
IA Vrabie
Keyword(s):  
Innate Immunity ◽  
Lupus Erythematosus ◽  
Cell Repertoire ◽  
Bacterial Dna ◽  
B Cell Repertoire ◽  
Antibody Induction ◽  
Unique Markers ◽  
Pathogenic Autoantibody ◽  
Genetically Determined ◽  
Antibodies To Dna

Antibodies to DNA (anti-DNA) are the serological hallmark of systemic lupus erythematosus (SLE) and unique markers of the immunological disturbances critical to disease pathogenesis. In the form of immune complexes, anti-DNA autoantibodies can deposit in the tissue to incite inflammation and damage; in addition, these complexes can induce cytokine production, most prominently, type 1 interferon. Studies in both patients and animal models have implicated genetic as well as environmental factors in the aetiology of the anti-DNA response. Because bacterial DNA is a potent stimulant of innate immunity by both toll-like receptor (TLR) and non-TLR signalling pathways, foreign DNA introduced during the course of bacterial or viral infection could have a dual role in antibody induction. This DNA could serve as an adjuvant to activate innate immunity as well as an immunogen to drive an antigen-specific antibody response. In this scenario, the generation of cross-reactive autoantibodies, in contrast to highly specific antibodies to bacterial DNA, most likely depends on genetically determined abnormalities in the B-cell repertoire in patients with SLE. Given the universal expression of DNA, this model suggests that many different kinds of infections could trigger pathogenic autoantibody responses in SLE, as well as induce flare.

scholarly journals Regulation of Anti–double-stranded DNA B Cells in Nonautoimmune Mice: Localization to the T–B Interface of the Splenic Follicle

1997 ◽  
Vol 186 (8) ◽  
pp. 1257-1267 ◽  
Author(s):  
Laura Mandik-Nayak ◽  
Anh Bui ◽  
Hooman Noorchashm ◽  
Ashlyn Eaton ◽  
Jan Erikson
Keyword(s):  
B Cells ◽  
Lupus Erythematosus ◽  
Turnover Rate ◽  
Cell Repertoire ◽  
Developmental Arrest ◽  
Double Stranded Dna ◽  
B Cell Repertoire ◽  
Dna Antibodies ◽  
Unique Surface

Systemic lupus erythematosus (SLE) and the MRL-lpr/lpr murine model for SLE are characterized by the presence of serum anti–double-stranded (ds)DNA antibodies (Abs), whereas nonautoimmune individuals have negligible levels of these Abs. To increase the frequency of anti-DNA B cells and identify the mechanisms involved in their regulation in nonautoimmune mice, we have used Ig transgenes (tgs). In the present study, we used the VH3H9 heavy (H) chain tg which expresses an H chain that was repeatedly isolated from anti-dsDNA Abs from MRL-lpr/lpr mice. Because the VH3H9 H chain can pair with endogenous L chains to generate anti–single-stranded DNA, anti-dsDNA, and non-DNA B cells, this allowed us to study the regulation of anti-dsDNA B cells in the context of a diverse B cell repertoire. We have identified anti-dsDNA B cells that are located at the T–B interface in the splenic follicle where they have an increased in vivo turnover rate. These anti-dsDNA B cells exhibit a unique surface phenotype suggesting developmental arrest due to antigen exposure.

scholarly journals Balancing diversity and tolerance

2005 ◽  
Vol 202 (3) ◽  
pp. 341-344 ◽  
Author(s):  
Annett M. Jacobi ◽  
Betty Diamond
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Tolerance ◽  
Systemic Lupus ◽  
Cell Repertoire ◽  
B Cell Tolerance ◽  
Repertoire Selection ◽  
B Cell Repertoire ◽  
Disease Systemic Lupus Erythematosus

The autoimmune disease systemic lupus erythematosus (SLE) is caused by a failure of B cell tolerance. Recent studies in mouse models of SLE have identified several distinct tolerance checkpoints that must each function appropriately to protect against disease. However, studies of B cell repertoire selection in humans are essential to understand which checkpoints are defective in human autoimmune diseases.

scholarly journals Defective B cell tolerance checkpoints in systemic lupus erythematosus

2005 ◽  
Vol 201 (5) ◽  
pp. 703-711 ◽  
Author(s):  
Sergey Yurasov ◽  
Hedda Wardemann ◽  
Johanna Hammersen ◽  
Makoto Tsuiji ◽  
Eric Meffre ◽  
...  
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Tolerance ◽  
Systemic Lupus ◽  
Cell Repertoire ◽  
B Cell Tolerance ◽  
Subsequent Work ◽  
Healthy Humans ◽  
B Cell Repertoire

A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.

scholarly journals A role for gut-associated lymphoid tissue in shaping the human B cell repertoire

2013 ◽  
Vol 210 (9) ◽  
pp. 1665-1674 ◽  
Author(s):  
Anna Vossenkämper ◽  
Paul A. Blair ◽  
Niloufar Safinia ◽  
Louise D. Fraser ◽  
Lisa Das ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Lymphoid Tissue ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cell Repertoire ◽  
Human B Cells ◽  
B Cell Repertoire ◽  
Immature B Cells

We have tracked the fate of immature human B cells at a critical stage in their development when the mature B cell repertoire is shaped. We show that a major subset of bone marrow emigrant immature human B cells, the transitional 2 (T2) B cells, homes to gut-associated lymphoid tissue (GALT) and that most T2 B cells isolated from human GALT are activated. Activation in GALT is a previously unknown potential fate for immature human B cells. The process of maturation from immature transitional B cell through to mature naive B cell includes the removal of autoreactive cells from the developing repertoire, a process which is known to fail in systemic lupus erythematosus (SLE). We observe that immature B cells in SLE are poorly equipped to access the gut and that gut immune compartments are depleted in SLE. Thus, activation of immature B cells in GALT may function as a checkpoint that protects against autoimmunity. In healthy individuals, this pathway may be involved in generating the vast population of IgA plasma cells and also the enigmatic marginal zone B cell subset that is poorly understood in humans.

scholarly journals The Naive B Cell Repertoire Predisposes to Antigen-Induced Systemic Lupus Erythematosus

2003 ◽  
Vol 170 (9) ◽  
pp. 4826-4832 ◽  
Author(s):  
Chuansheng Wang ◽  
Magi Khalil ◽  
Jeffrey Ravetch ◽  
Betty Diamond
Keyword(s):  
Systemic Lupus Erythematosus ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Systemic Lupus ◽  
Cell Repertoire ◽  
B Cell Repertoire

scholarly journals B Cell Abnormalities in Systemic Lupus Erythematosus and Lupus Nephritis—Role in Pathogenesis and Effect of Immunosuppressive Treatments

2019 ◽  
Vol 20 (24) ◽  
pp. 6231 ◽  
Author(s):  
Desmond Y. H. Yap ◽  
Tak Mao Chan
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cell ◽  
B Cells ◽  
Lupus Nephritis ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Interaction ◽  
Systemic Lupus ◽  
Cell Repertoire ◽  
B Cell Repertoire

Abnormalities in B cells play pivotal roles in the pathogenesis of systemic lupus erythematosus (SLE) and lupus nephritis (LN). Breach in central and peripheral tolerance mechanisms generates autoreactive B cells which contribute to the pathogenesis of SLE and LN. Dysregulation of B cell transcription factors, cytokines and B cell–T cell interaction can result in aberrant B cell maturation and autoantibody production. These immunological abnormalities also lead to perturbations in circulating and infiltrating B cells in SLE and LN patients. Conventional and novel immunosuppressive medications confer differential effects on B cells which have important clinical implications. While cyclophosphamide and mycophenolate mofetil (MMF) showed comparable clinical efficacy in active LN, MMF induction was associated with earlier reduction in circulating plasmablasts and plasma cells. Accumulating evidence suggests that MMF maintenance is associated with lower risk of disease relapse than azathioprine, which may be explained by its more potent and selective suppression of B cell proliferation. Novel therapeutic approaches targeting the B cell repertoire include B cell depletion with monoclonal antibodies binding to cell surface markers, inhibition of B cell cytokines, and modulation of costimulatory signals in B cell–T cell interaction. These biologics, despite showing improvements in serological parameters and proteinuria, did not achieve primary endpoints when used as add-on therapy to standard treatments in active LN patients. Other emerging treatments such as calcineurin inhibitors, mammalian target of rapamycin inhibitors and proteasome inhibitors also show distinct inhibitory effects on the B cell repertoire. Advancement in the knowledge on B cell biology has fueled the development of new therapeutic strategies in SLE and LN. Modification in background treatments, study endpoints and selective recruitment of subjects showing aberrant B cells or its signaling pathways when designing future clinical trials may better elucidate the roles of these novel therapies for SLE and LN patients.

scholarly journals AB0146 DRUG DEPENDENT ALTERATIONS IN B-CELL REPERTOIRE IN SYSTEMIC LUPUS ERYTHEMATOSUS PATIENTS WITH LOW DISEASE ACTIVITY

2020 ◽  
Vol 79 (Suppl 1) ◽  
pp. 1373.2-1373
Author(s):  
S. Zenz ◽  
B. Dreo ◽  
B. Prietl ◽  
S. Kofler ◽  
H. Sourij ◽  
...  
Keyword(s):  
B Cells ◽  
Disease Activity ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Cell Repertoire ◽  
Low Disease Activity ◽  
B Cell Repertoire ◽  
Drug Dependent ◽  
B Cell Subsets

Background:B-cells play a major role in the pathogenesis and perpetuation of the immune response in systemic lupus erythematosus (SLE). So far, B-cell subtypes have been studied well, but the precise mechanisms of the B-cell alterations during disease activity and during remission, depending on different medication, are still unclear.Objectives:The aim of our study was to investigate the drug dependent alterations in the B-cell repertoire of SLE patients with low disease activity (SLEDAI – 2K ≤4).Methods:Peripheral blood samples from 39 patients suffering from SLE (mean±SD; age 43±13 years, 87.2% females, disease duration 11.1±7 years) were drawn over 2 years. All SLE patients were in remission or low disease activity (median±SE, SLEDAI of 2.0±1.5). B-cells were characterized using CD19, CD20, CD5, CD27 antibodies and were grouped in naïve (IgD+27-), non-switched memory (IgD+, CD27+), memory (IgD-,CD27+), B1 (CD5+27-) and MBL-like (CD5++) B-cells. A quantitative flow cytometric bead-based assay (QuantiBRITE PE kit from Becton Dickinson) was used for the estimation of CD19 antibodies bound per cell. Further, CD38 and CD86 antibodies were used to characterize the B-cell subsets. All cytometric measurements were performed using a standardized BD LSR Fortessa platform. After 3 years of follow-up, patients’ data about disease activity and current medication were obtained.Results:22 SLE patients were treated with hydroxychloroquine (85.8%) and 19 patients received mycophenolate mofetil (MMF; n=14; 54.6%) or azathioprine (AZA; n= 5; 19.5 %). 5 patients were treated with other DMARDs. Independently of hydroxychloroquine and/or MMF, no significant differences were seen in naïve, non-switched memory, post-switched memory, plasma blasts, B1- or MBL-like B-cells. Patients treated with AZA had significantly lower naïve B-cells (mean±SD, 39.3±6.7vs. 73.1±19.3 %; p = 0.028), but had significantly higher IgD-post switched B-cells (31.2±9.1 vs.12.5 ±9.2 %; p = 0.028, respectively) compared with no AZA-treatment. Interestingly, activated B-cells (5.5±1.5 vs. 1.8±1.1%; p = 0.009) were significantly higher in AZA-treated. After 3 years of follow-up, almost all patients were in remission (median±SE, SLEDAI of 2.0±2.0), except of 3 patients with a SLEDAI of ≥ 6. Interestingly, those patients had at baseline, statistically higher naïve B-cells (p = 0.041) and lower B1-like B-cells (p =0.020) compared with patients with low disease activity.Conclusion:Our results suggest that independently of hydroxychloroquine and/or MMF treatment, all patients with low disease activity had similar normal B-cell subsets. Interestingly, in the small group of patients who were treated with AZA, a reduced regeneration of B-cells was shown. Patients with higher disease and high naïve B-cells showed an increased disease activity after three years.Acknowledgments:The research was performed in “CBmed” and funded by the Austrian Federal Government within the COMET K1 Centre Program, Land Steiermark and Land Wien.Disclosure of Interests:None declared

Selection of the expressed B cell repertoire by infusion of normal immunoglobulin G in a patient with autoimmune thyroiditis

1993 ◽  
Vol 23 (11) ◽  
pp. 2945-2950 ◽  
Author(s):  
Gilles Dietrich ◽  
Francisco J. Varela ◽  
Vincent Hurez ◽  
Majida Bouanani ◽  
Michel D. Kazatchkine
Keyword(s):  
B Cell ◽  
Immunoglobulin G ◽  
Autoimmune Thyroiditis ◽  
Cell Repertoire ◽  
B Cell Repertoire ◽  
Selection Of
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