Autoantibodies: Focus on anti-DNA antibodies

Almqvist, Nina; Winkler, Thomas; Mårtensson, Inga‐Lill

doi:10.4161/self.2.1.15087

Cited by 18 publications

(16 citation statements)

References 98 publications

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“…Relevant to these observations, telomere length measurements 21 have shown that proliferation of leukemic cells with unmutated IGHV is more intense compared to that of cells with mutated IGHV. Furthermore, it is worth men-tioning that longer VH CDR3 are a frequent feature of auto-and multi-reactive cells, 40,41 which is also in line with the reactivity profile of IGHV-unmutated CLL clones. This indicates that antigen drive may underline clonal drift leading to selection for more aggressive clones with distinctive molecular features.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 54%

“…Multiple IGH rearrangements in CLL haematologica | 2014; 99(2) 337 tioning that longer VH CDR3 are a frequent feature of auto-and multi-reactive cells, 40,41 which is also in line with the reactivity profile of IGHV-unmutated CLL clones. This indicates that antigen drive may underline clonal drift leading to selection for more aggressive clones with distinctive molecular features.…”

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 73%

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Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

et al. 2013

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In chronic lymphocytic leukemia, usually a monoclonal disease, multiple productive immunoglobulin heavy chain gene rearrangements are identified sporadically. Prognostication of such cases based on immunoglobulin heavy variable gene mutational status can be problematic, especially if the different rearrangements have discordant mutational status. To gain insight into the possible biological mechanisms underlying the origin of the multiple rearrangements, we performed a comprehensive immunogenetic and immunophenotypic characterization of 31 cases with the multiple rearrangements identified in a cohort of 1147 patients with chronic lymphocytic leukemia. For the majority of cases (25/31), we provide evidence of the co-existence of at least two B lymphocyte clones with a chronic lymphocytic leukemia phenotype. We also identified clonal drifts in serial samples, likely driven by selection forces. More specifically, higher immunoglobulin variable gene identity to germline and longer complementarity determining region 3 were preferred in persistent or newly appearing clones, a phenomenon more pronounced in patients with stereotyped B-cell receptors. Finally, we report that other factors, such as TP53 gene defects and therapy administration, influence clonal selection. Our findings are relevant to clonal evolution in the context of antigen stimulation and transition of monoclonal B-cell lymphocytosis to chronic lymphocytic leukemia. Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones ABSTRACT © F e r r a t a S t o r t i F o u n d a t i o nalso represent co-existence of CLL with another B lymphoproliferative disorder. 12Clonal drift is a phenomenon in lymphoid malignancies with multiple productive antigen receptor gene rearrangements, in particular T-cell large granular lymphocyte leukemia, referring to a dynamic process of alterations in the proportion of the malignant clones. 20 Clonal drift has never been examined in CLL, though potentially relevant given evidence that the proliferation and overall biological behavior of CLL cells may differ between clones with mutated or unmutated IGHV. 21,22 Previous studies analyzing CLL cases with MP-IGH rearrangements lack a detailed genomic analysis of IG light chains and partial IGHD-IGHJ rearrangements that can be extremely informative about the molecular status of the IG loci, thus contributing to clarification of the mechanisms involved. In the present study, we performed a comprehensive analysis of IG heavy and light chain gene rearrangements in MP-IGH CLL patients with the aim of obtaining molecular insight into the biological causes of this phenomenon. Also, for the first time, we attempted a systematic study of clonal drift in MP-IGH CLL by tracing each rearrangement at different time-points in the natural history of the disease. Methods Study groupMP-IGH cases were sought among 1147 CLL patients tested for IGHV gene mutational status at the University Hospital Brno, Czech Republic...

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Section: © F E R R a T A S T O R T I F O U N D A T I O Nsupporting

confidence: 54%

Section: © F E R R a T A S T O R T I F O U N D A T I O Nmentioning

confidence: 73%

Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

et al. 2013

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“…We found that the antibodies predominantly recognized nuclear antigens staining with a homogeneous, speckled, and diffuse grainy pattern (31). This pattern is typically found with antibodies from patients with autoimmune diseases, such as systemic lupus erythematosus and rheumatoid arthritis (RA), indicating that the antibodies may be specific for DNA (3).…”

Section: Expansion Of the Igm Memory B Cell Subset In Chronic Hcvmentioning

confidence: 96%

Chronic Hepatitis C Virus Infection Breaks Tolerance and Drives Polyclonal Expansion of Autoreactive B Cells

Roughan¹,

Reardon²,

Cogburn³

et al. 2012

Clin. Vaccine Immunol.

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b Chronic Hepatitis C virus (HCV) infection has been linked with B cell lymphoproliferative disorders and several autoimmune-related diseases. The mechanisms of how chronic viral infection affects B cell development and predisposes the patients to autoimmune manifestations are poorly understood. In this study, we established an experimental system to probe the B cell responses and characterize the antibodies from chronic-HCV-infected individuals. We identified an unusual polyclonal expansion of the IgM memory B cell subset in some patients. This B cell subset is known to be tightly regulated, and autoreactive cells are eliminated by tolerance mechanisms. Genetic analysis of the immunoglobulin (Ig) heavy chain variable gene (V H ) sequences of the expanded cell population showed that the levels of somatic hypermutation (SHM) correlate with the extent of cell expansion in the patients and that the V H genes exhibit signs of antigen-mediated selection. Functional analysis of the cloned B cell receptors demonstrated autoreactivity in some of the expanded IgM memory B cells in the patients which is not found in healthy donors. In summary, this study demonstrated that, in some patients, chronic HCV infection disrupts the tolerance mechanism that normally deletes autoreactive B cells, therefore increasing the risk of developing autoimmune antibodies. Long-term follow-up of this expanded B cell subset within the infected individuals will help determine whether these cells are predictors of more-serious clinical manifestations. Hepatitis C virus (HCV) is a single-stranded RNA virus that is transmitted predominantly through direct blood contact, such as accidental needle sticks in the health care workplace, blood transfusions, and needle sharing among intravenous drug users (reviewed in reference 33). About 70% of those infected cannot clear the virus and succumb to persistent infection (reviewed in reference 22). Of those, more than half will develop some form of liver disease and ϳ2 to 3% will develop liver cancer over a course of 20 to 40 years (4, 17). HCV has also been associated with B cell and antibody abnormalities (non-Hodgkin's lymphoma [NHL] [40]) and a number of autoimmune diseases (mixed cryoglobulinemia [MC] [2], celiac disease [56], Sjögren's syndrome [68], and systemic autoimmune diseases [53]). The contribution of the virus to these diseases is unclear. One hypothesis is that E2, a glycoprotein found on the surface of HCV, binds to CD81 instead of B cell receptors (BCRs) on B cells, stimulating cell proliferation (55) and hypermutation of immunoglobulin (Ig) genes (38). Prolonged stimulation by E2 during chronic infection can eventually lead to some form of B cell lymphoproliferative disorder. It is also thought that HCV itself may provide a chronic antigen stimulus that drives clonal expansion of B cells. In support of this, it was shown that Ig cloned from NHL biopsy specimens bound E2 (50). In addition, Charles et al. demonstrated an antigen-driven expansion of peripheral blood (PB) IgM ϩ CD27 ϩ B c...

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“…Even though this in itself is not sufficient to tip the balance to overt autoimmunity, it could potentially result in the production of pathogenic autoantibodies. In current models of B-cell development, some degree of autoreactivity displayed by the pre-BCR appears to be critical for downstream signalling events at the pre-B-cell stage [24][25][26][27]51 . This is provided by the l5-tail that interacts with molecules on stromal cells and with neighbouring mH chains 24,26,52,53 .…”

Section: Discussionmentioning

confidence: 99%

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

et al. 2015

Self Cite

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Random recombination of antibody heavy-and light-chain genes results in a diverse B-cell receptor (BCR) repertoire including self-reactive BCRs. However, tolerance mechanisms that prevent the development of self-reactive B cells remain incompletely understood. The absence of the surrogate light chain, which assembles with antibody heavy chain forming a pre-BCR, leads to production of antinuclear antibodies (ANAs). Here we show that the naive follicular B-cell pool is enriched for cells expressing prototypic ANA heavy chains in these mice in a non-autoimmune background with a broad antibody repertoire. This results in the spontaneous formation of T-cell-dependent germinal centres that are enriched with B cells expressing prototypic ANA heavy chains. However, peripheral tolerance appears maintained by selection thresholds on cells entering the memory B-cell and plasma cell pools, as exemplified by the exclusion of cells expressing the intrinsically self-reactive V H 81X from both pools.

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Autoantibodies: Focus on anti-DNA antibodies

Cited by 18 publications

References 98 publications

Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

Multiple productive immunoglobulin heavy chain gene rearrangements in chronic lymphocytic leukemia are mostly derived from independent clones

Chronic Hepatitis C Virus Infection Breaks Tolerance and Drives Polyclonal Expansion of Autoreactive B Cells

Absence of surrogate light chain results in spontaneous autoreactive germinal centres expanding VH81X-expressing B cells

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