Reversal of Arthritis by Human Monomeric IgA Through the Receptor‐Mediated SH2 Domain–Containing Phosphatase 1 Inhibitory Pathway

Abstract

Objective Rheumatoid arthritis (RA), one of the most frequent chronic inflammatory rheumatic disorders, is characterized by the presence of autoantibodies and joint infiltration by activated immune cells, leading to cartilage and bone destruction. IgA occurs predominantly as monomers (mIgA) in plasma and regulates many cell responses through interaction with the Fcα receptor type I (FcαRI). FcαRI targeting by anti‐FcαRI Fab inhibits activating receptors by inducing an inhibitory immunoreceptor tyrosine–based activation motif (ITAMi) configuration through SH2 domain–containing phosphatase 1 (SHP‐1) recruitment. The aim of this study was to investigate the potential utility of mIgA for the treatment of arthritis by acting as an inducer of ITAMi signaling. Methods The effect of plasma‐derived human mIgA on inhibition of multiple heterologous receptors was evaluated on FcαRI+ cell transfectants, blood phagocytes from healthy individuals, and synovial cells from RA patients. FcαRI‐transgenic mice and wild‐type mice treated with mIgA were studied in models of collagen antibody–induced arthritis (CAIA) and collagen‐induced arthritis (CIA). The mice were assessed for development of arthritis using an arthritis score, and joint tissue samples were evaluated for the extent of leukocyte infiltration and expression of phosphatase. Results Treatment with mIgA impaired cell activation in an FcαRI–FcRγ‐dependent manner, involving ITAMi signaling. Human mIgA or anti‐FcαRI Fab were strongly effective in either preventing or attenuating CAIA or CIA in FcαRI‐transgenic mice. Administration of mIgA markedly inhibited the recruitment of leukocytes to the inflamed joints of mice, which was associated with induction of SHP‐1 phosphorylation in joint tissue cells. Moreover, mIgA reversed the state of inflammation in the synovial fluid of RA patients by inducing an ITAMi configuration. Conclusion These results demonstrate a therapeutic potential of human mIgA in experimental arthritis. The findings support future clinical exploration of mIgA for the treatment of RA.

Human IgA binds a diverse array of commensal bacteria

“…The finding that both Neu5Ac, a self-antigen, and Neu5Gc, a xenoantigen, showed similar binding profiles for IgA could possibly be explained by the structural similarity of the two sugars. It also supports the notion that terminal carbohydrate moieties influence the balance between immune response and tolerance, IgA being considered more tolerogenic than proinflammatory (Pasquier et al, 2005;Rossato et al, 2015). These results obtained by comparing serum IgA1 and IgA2 remain to be confirmed at the gut secretory IgA level.…”

Monomeric Immunoglobulin A from Plasma Inhibits Human Th17 Responses In Vitro Independent of FcαRI and DC-SIGN

“…The data from current report show that in addition to IgG, mIgA also exerts modulatory effects on Th17 responses. In fact, mIgA was recently demonstrated to attenuate experimental arthritis in human CD89 transgenic mice (11), a disease where Th17 cells have a key role in the pathogenesis. It should be noted that the serum levels of IgA ranges from 2 to 3 mg/ml, but we observed consistent inhibitory effect of mIgA both on differentiation and amplification of Th17 cells at higher doses (25 mg) and was analogous to what is observed with IVIG (24).…”

Immunoglobulin A: magic bullet or Trojan horse?

“…Alternatively, it would be interesting to interfere specifically with IgA-induced signalling pathways to prevent neutrophil effector functions. Furthermore, monovalent targeting of FcaRI was shown to prevent or reduce disease in murine models of asthma, rheumatoid arthritis, lupus nephritis and IgA nephritis [6,[62][63][64]. Monovalent IgA could thus potentially be used to inhibit activated Fc c or Fc e receptors and thereby reduce IgG-or IgE (auto) antibody-mediated diseases.…”