Autoantibody-mediated regulation of B cell responses by functional anti-CD22 autoantibodies in patients with systemic sclerosis

Abstract

SummaryStudies have demonstrated that B cells play important roles in systemic sclerosis (SSc), especially through the CD19/CD22 autoimmune loop. CD22 is a B cell-specific inhibitory receptor that dampens B cell antigen receptor (BCR) signalling via tyrosine phosphorylation-dependent mechanism. In this study, we examined the presence and functional property of circulating autoantibodies reacting with CD22 in systemic sclerosis. Serum samples from 10 tight skin (TSK/+) mice and 50 SSc patients were assessed for anti-CD22 autoantibodies by enzyme-linked immunosorbent assays using recombinant mouse or human CD22. The association between anti-CD22 antibodies and clinical features was also investigated in SSc patients. Furthermore, the influence of SSc serum including anti-CD22 autoantibodies for CD22 tyrosine phosphorylation was examined by Western blotting using phosphotyrosinespecific antibodies reacting with four major tyrosine motifs of CD22 cytoplasmic domain. Anti-CD22 autoantibodies were positive in 80% of TSK/+ mice and in 22% of SSc patients. Patients positive for anti-CD22 antibodies showed significantly higher modified Rodnan skin thickness score compared with patients negative for anti-CD22 antibodies. Furthermore, anti-CD22 antibodies from patients' sera were capable of reducing phosphorylation of all four CD22 tyrosine motifs, while sera negative for anti-CD22 antibodies did not affect CD22 phosphorylation. Thus, a subset of SSc patients possessed autoantibodies reacting with a major inhibitory B cell response regulator, CD22. Because these antibodies can interfere CD22-mediated suppression onto B cell activation in vitro, SSc B cells produce functional autoantibodies that can enhance their own activation. This unique regulation may contribute to the autoimmune aspect of SSc.

Breg Cells Are Numerically Decreased and Functionally Impaired in Patients With Systemic Sclerosis

“…Memory Breg cells suppress the monocyte innate immune response by suppressing tumor necrosis factor production (15,20). This finding, along with the increased expression of stimulatory CD19 receptor in B cells and the presence of functional anti-CD22 autoantibodies in patients with SSc (11), all support the notion of B cell autoaggression acting as an immunopathogenic mediator in this disease. In recent years, treatment with rituximab, an mAb that depletes B cells, decreased fibrosis in tight skin mice and in human SSc (4,52).…”

“…Anti–topoisomerase I antibodies bind to fibroblasts and promote inflammation , and autoantibodies to platelet‐derived growth factor receptor and matrix metalloproteinase 1 promote fibrosis. Antibodies to CD22, an inhibitory BCR, are functional and associated with reduced activation of CD22 . Finally, coculture of B cells with SSc dermal fibroblasts induces collagen secretion in a cell interaction–dependent manner .…”

New insights into the pathogenesis and management of juvenile systemic sclerosis

“…We were able to detect an increased expression of ubiquiten B, GRAP, CCR7 and CD22 in our jSSc population which was partly consistent with previous reports in adult SSc patients that found an increased expression of CD22 on B-lymphocytes [47], but the increased expression of ubiquiten B, GRAP, CCR7 has never been reported in children or adults with SSc before.…”

CD22: A Regulator of Innate and Adaptive B Cell Responses and Autoimmunity

“…SSc patients may also have decreases in CD22 expression and reduced CD22 phosphorylation ( 92 ). Interestingly, anti-CD22 Abs capable of inhibiting tyrosine phosphorylation of CD22 have been found in both SSc and SLE patients, which might be another, yet-to-be-explored, mechanism for regulation of CD22 function ( 93 ).…”