The B cell repertoire of patients with rheumatoid arthritis. II. Increased frequencies of IgG+ and IgA+ B cells specific for mycobacterial heat‐shock protein 60 or human type II collagen in synovial fluid and tissue

Rudolphi, U.; Rzepka, Rita; Batsford, Stephen; Kaufmann, Stefan H. E.; Mark, Klaus von der; Peter, Hans; Melchers, Inga

doi:10.1002/art.1780400808

Cited by 48 publications

(33 citation statements)

References 44 publications

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“…Switching occurred primarily to IgG and IgA 114. Evidence for class‐switched autoreactive B‐cells in RA is also supported by other studies,105, 109 where ~25% of synovial IgG+ B‐cells were reactive to citrullinated autoantigens in ACPA‐positive RA patients,109 and production of ACPAs by RA peripheral blood IgG+ plasmablasts was found in ACPA+ RA patients, but not ACPA− RA or psoriatic arthritis patients 94.…”

Section: Rasupporting

confidence: 69%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

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SummaryHigh‐throughput sequencing of the DNA/RNA encoding antibody heavy‐ and light‐chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B‐cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B‐cell development at which this occurs. The advent of technologies, such as whole‐genome sequencing, offers the chance to link abnormalities in the B‐cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B‐cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B‐cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B‐cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4‐34 gene usage. B‐cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B‐cell tolerance; however, the mechanisms and implications of these defects are not clear.

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Section: Rasupporting

confidence: 69%

Antibody repertoire analysis in polygenic autoimmune diseases

2018

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“…During cartilage destruction the liberation of COMP and further cartilage specific antigens such as CII [11,22,37,83,91], large aggregating chondroitin sulfate proteoglycan (aggreacan) [9], human chondrocyte glycoprotein 39 [101] and the cartilage-specific 65-kDa chondrocyte antigen [3] from the injured cartilage could fuel the vicious circle leading to perpetuation and amplification of joint destruction in RA.…”

Section: Organ Specific Autoantigensmentioning

confidence: 99%

Morphological and molecular pathology of the B cell response in synovitis of rheumatoid arthritis

et al. 2002

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The synovitis of rheumatoid arthritis (RA) was long regarded merely as an unspecific chronic inflammatory process of minor diagnostic value and therefore did not play a major role in the understanding of the pathogenesis of RA. It is only in recent years, along with the observation that T and B cells are expanded oligoclonally in synovial tissue and that B cells are able to undergo a local germinal center (GC) reaction, that the synovial tissue has come to be regarded as a site of specific immune processes. The analysis of the immunoglobulin (Ig) gene repertoire had great impact on the understanding of B cell response in lymphatic organs and was subsequently applied to B cells from RA patients. The analyses of the variable (V) regions of the Ig heavy (H) and light (lambda) chains suggested that an antigen specific activation and differentiation of B cells into plasma cells (Plc) takes place in the chronically inflamed synovial tissue of patients with RA. It seems that in a subset of RA patients the synovial tissue develops into an ectopic lymphoid tissue that supports a local GC reaction. Ectopic GC are characteristic of RA; however, they are in general absent from synovitis of osteoarthritis (OA). Here the accumulation of Plc follows a different mechanism. Highly mutated VH genes suggest that in OA memory B cells migrate into the synovial tissue with subsequent differentiation into Plc but without further V gene diversification. Therefore in synovitis two patterns of B cell activation can be differentiated: the maturative and the accumulative type. These two patterns are not definitely disease linked. The maturative type is only found in RA whereas the accumulative type occurs in both diseases. Clinically RA is defined via serum antibodies to the constant region of Ig, so-called rheumatoid factor. However, the spectrum of autoreactive B cells in RA patients is wide and is based on the study of antibody specificities in serum, in synovial fluid and B cell lines derived from peripheral blood, bone marrow, synovial fluid and synovial tissue. These analyses defined non-organ-specific and organ-specific antigens. One can reasonably assume that the disease is far too complex to be explained by only a single antigen. There is a whole combination of antigens acting in a multistep manner that is responsible for RA pathogenesis. It can be hypothesized that chronic synovitis, which is the underlying mechanism of joint destruction, follows a three-step process: (a) initiation, (b) destruction, and (c) perpetuation. The characterization of antigens driving the local synovial B cell maturation and accumulation could lead to an understanding of the process perpetuating the disease. Identification of arthritogenic antigens may yield new avenues for diagnostics and immunotherapy but also a new approach for prevention by vaccines with antigens probably defined by synovial B cell reactivity.

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“…B-1a B cells are elevated in patients with SS and RA [37]. The frequency of IgM-RF-expressing B cells in normal individuals is 0.9% (of total B cells) compared to 1.48% in RA patients [38]. In patients who are seropositive for RF, the RF B-cell frequency is 10-fold higher than in normal individuals [39].…”

Section: Rf B Cellsmentioning

confidence: 99%

Rheumatoid Factors: Good or Bad for You?

Nowak

Newkirk

2005

Int Arch Allergy Immunol

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Background: Rheumatoid factors (RFs) are autoantibodies associated with rheumatoid arthritis. They can be detected in normal individuals, although transiently. This dichotomy has led to questions about the origins and types of RFs. Recently it has been shown that B cells that produce RFs only do so when activated by two signals, one from engagement of the B-cell receptor and the other from recognition of a pathogen-associated molecular pattern through a Toll-like receptor (TLR). These autoantibodies thus link the innate and acquired immune responses. Objective: Through a review of the literature, an examination of the current knowledge of RF induction is presented. The focus is on a discussion of a beneficial or detrimental role for RFs in normal individuals and in those with chronic disease. Results: What makes RF ‘good’ in some cases and ‘bad’ in others may reflect the type of RF produced. Low-affinity polyreactive IgM RFs are probably beneficial as they aid in the clearance of immune complexes that are more efficiently cleared, and the RF B cell can act as an antigen-presenting cell and stimulate host defense. However, large amounts of high-affinity RFs found in patients with chronic disease may be harmful by participation in a vicious cycle of autoantibody production by stimulation of self lymphocytes, and/or deposition in blood vessels thus causing vasculitis. Conclusions: Whether RFs are beneficial or detrimental depends on the context in which they are expressed, the type and amount of RF produced, whether the response is perpetuated by TLR ligation and whether other cells are stimulated either directly or indirectly by RF-positive B cells.

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The B cell repertoire of patients with rheumatoid arthritis. II. Increased frequencies of IgG+ and IgA+ B cells specific for mycobacterial heat‐shock protein 60 or human type II collagen in synovial fluid and tissue

Cited by 48 publications

References 44 publications

Antibody repertoire analysis in polygenic autoimmune diseases

Antibody repertoire analysis in polygenic autoimmune diseases

Morphological and molecular pathology of the B cell response in synovitis of rheumatoid arthritis

Rheumatoid Factors: Good or Bad for You?

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