Journal
ARTHRITIS & RHEUMATOLOGY
Volume 67, Issue 7, Pages 1766-1777Publisher
WILEY
DOI: 10.1002/art.39142
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Funding
- Agence Nationale de la Recherche (ANR)
- Laboratoire d'Excellence Inflamex [ANR-11-IDEX-0005-02]
- Fondation pour la Recherche Medicale
- CSL Behring
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ObjectiveRheumatoid 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 Fc receptor type I (FcRI). FcRI targeting by anti-FcRI 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. MethodsThe effect of plasma-derived human mIgA on inhibition of multiple heterologous receptors was evaluated on FcRI+ cell transfectants, blood phagocytes from healthy individuals, and synovial cells from RA patients. FcRI-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. ResultsTreatment with mIgA impaired cell activation in an FcRI-FcR-dependent manner, involving ITAMi signaling. Human mIgA or anti-FcRI Fab were strongly effective in either preventing or attenuating CAIA or CIA in FcRI-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. ConclusionThese results demonstrate a therapeutic potential of human mIgA in experimental arthritis. The findings support future clinical exploration of mIgA for the treatment of RA.
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