Rheumatoid Factors in Health and Disease: Structure, Function, Induction and Regulation

Haberman, Ann M.; William, Jacqueline; Euler, Chad W.; Shlomchik, Mark J.

doi:10.1159/000066861

Cited by 19 publications

(13 citation statements)

References 176 publications

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“…21 In the case of RA, the presence of GC within the inflamed synovium is not the most common phenotype, but it is present in a significant minority of patients, and is accompanied by distinct patterns of cytokine and chemokine expression. 22 Rheumatoid factor is produced locally by B cells within the inflamed synovium, and sequence analysis of these immunoglobulins can show evidence of somatic mutation 23,24 4 Evidence of such somatic mutation is consistent with the T cell dependent B cell differentiation that typically occurs within GC. It is not entirely clear whether the variability of synovial pathology reflects meaningful disease subsets or different stages of disease, or both.…”

Section: Discussionmentioning

confidence: 73%

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

et al. 2004

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We have recently described the association between rheumatoid arthritis and a coding single-nucleotide polymorphism in the intracellular protein tyrosine phosphatase, PTPN22. The disease-associated polymorphism, 1858 C/T (rs2476601), encodes an amino-acid change (R620W) in one of four SH3 domain binding sites in the PTPN22 molecule. We have now extended our initial studies to address three questions: (1) Is the association with rheumatoid arthritis limited to rheumatoid factor (RF) positive disease? (2) Does homozygosity for PTPN22 R620W substantially increase disease susceptibility? (3) Is there an interaction between PTPN22 and the rheumatoid arthritis (RA)-associated HLA-DRB1 shared epitope alleles? A total of 1413 Caucasian rheumatoid arthritis patients and 1401 Caucasian controls were genotyped. The results support the view that PTPN22 was strongly and preferentially associated with RF positive disease (OR ¼ 1.75, 95% CI 1.46-2.10, P ¼ 1.3 Â 10 À9 ). The PTPN22 risk allele was not significantly associated with RF negative disease (OR ¼ 1.19, 95% CI 0.92-1.53, P ¼ 0.18), although a very weak association cannot be completely excluded. There was a strong dose effect on disease risk; two copies of the PTPN22 R620W allele more than doubles the risk for RF positive RA (OR ¼ 4.57, 95% CI 2.35-8.89). There was no evidence of a genetic association between PTPN22 and HLA susceptibility alleles.

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Section: Discussionmentioning

confidence: 73%

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

et al. 2004

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“…Extrafollicular responses are critically regulated by TLRs and involve self-antigens containing a TLR-ligand that is recognized by a B cell-intrinsic TLR, as is the case of self-IgG [21]. Somatic hypermutation and isotype switch of Ig genes, which classically characterize T cell-dependent GC responses, can also occur extrafollicularly upon TLR signaling, and some RF clones from RA patients are indeed somatically mutated compared to healthy subjects [23]. Importantly, although T cells are not required for the initiation of extrafollicular responses, they substantially amplify and sustain chronic autoantibody production via CD40L and interleukin (IL)-21 signaling [21].…”

Section: Different Roles Of B Cells In Ra Pathobiologymentioning

confidence: 99%

B Cells in Rheumatoid Arthritis: From Pathogenic Players to Disease Biomarkers

Bugatti

Vitolo

Caporali

et al. 2014

BioMed Research International

137

113

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The therapeutic benefit of depleting B cells in rheumatoid arthritis (RA) has refocused attention on B cells with increasing awareness on their role in autoimmunity and their function beyond autoantibody production. The rapid increase in our comprehension of B-cell pathobiology is progressively opening novel perspectives in the area of B cell-targeted therapies with the expectation to define more specific approaches able to preserve the homeostasis of the humoral response while disrupting the pathogenic components. In parallel, B-cell activity in RA is starting to be explored in its clinical value, in search of novel biomarkers embedded in the pathogenic process that could help classifying the disease and predicting its heterogeneous outcome beyond inflammation dynamics. In this review, we summarize current knowledge on the multiple roles that B cells play in several aspects of RA. We also analyze their distribution and potential function in different anatomic compartments with specific reference to the main sites in which the disease may be sustained and exert its detrimental effects: the systemic circulation, synovium, bone marrow, and draining lymph nodes. We also highlight novel data encouraging further research in the field of biomarkers related to B cells and their regulatory factors.

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“…It is thus important to study B cells specific for relevant autoantigens. We have focused on the regulation of rheumatoid factor (RF)-expressing B cells that bind to the constant region of Ig (19). RFs are prevalent in RA patients but are also produced by patients with a number of other systemic autoimmune diseases such as Sjogren's syndrome, mixed cryoglobulinemia, and SLE (2,20,21), and by Fas-deficient lpr mice (22).…”

mentioning

confidence: 99%

B Cell Tolerance Checkpoints That Restrict Pathways of Antigen-Driven Differentiation

William¹,

Euler

Primarolo

et al. 2006

The Journal of Immunology

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Autoreactive B cells can be regulated by deletion, receptor editing, or anergy. Rheumatoid factor (RF)-expressing B lymphocytes in normal mice are not controlled by these mechanisms, but they do not secrete autoantibody and were presumed to ignore self-Ag. Surprisingly, we now find that these B cells are not quiescent, but instead are constitutively and specifically activated by self-Ag. In BALB/c mice, RF B cells form germinal centers (GCs) but few Ab-forming cells (AFCs). In contrast, autoimmune mice that express the autoantigen readily generate RF AFCs. Most interestingly, autoantigen-specific RF GCs in BALB/c mice appear defective. B cells in such GCs neither expand nor are selected as efficiently as equivalent cells in autoimmune mice. Thus, our data establish two novel checkpoints of autoreactive B cell regulation that are engaged only after initial autoreactive B cell activation: one that allows GCs but prevents AFC formation and one that impairs selection in the GC. Both of these checkpoints fail in autoimmunity.

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Rheumatoid Factors in Health and Disease: Structure, Function, Induction and Regulation

Cited by 19 publications

References 176 publications

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

The PTPN22 R620W polymorphism associates with RF positive rheumatoid arthritis in a dose-dependent manner but not with HLA-SE status

B Cells in Rheumatoid Arthritis: From Pathogenic Players to Disease Biomarkers

B Cell Tolerance Checkpoints That Restrict Pathways of Antigen-Driven Differentiation

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