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

Abstract

Circulating immunoglobulins including immunoglobulin G (IgG) and IgM play a critical role in the immune homeostasis by modulating functions of immune cells. These functions are mediated in part by natural antibodies. However, despite being second most abundant antibody in the circulation, the immunoregulatory function of IgA is relatively unexplored. As Th17 cells are the key mediators of a variety of autoimmune, inflammatory, and allergic diseases, we investigated the ability of monomeric IgA (mIgA) isolated from pooled plasma of healthy donors to modulate human Th17 cells. We show that mIgA inhibits differentiation and amplification of human Th17 cells and the production of their effector cytokine IL-17A. mIgA also suppresses IFN-γ responses under these experimental conditions. Suppressive effect of mIgA on Th17 responses is associated with reciprocal expansion of FoxP3-positive regulatory T cells. The effect of mIgA on Th17 cells is dependent on F(ab′)2 fragments and independent of FcαRI (CD89) and DC-SIGN. Mechanistically, the modulatory effect of mIgA on Th17 cells implicates suppression of phosphorylation of signal transducer and activator of transcription 3. Furthermore, mIgA binds to CD4+ T cells and recognizes in a dose-dependent manner the receptors for cytokines (IL-6Rα and IL-1RI) that mediate Th17 responses. Our findings thus reveal novel anti-inflammatory functions of IgA and suggest potential therapeutic utility of mIgA in autoimmune and inflammatory diseases that implicate Th17 cells.

IgA subclasses have different effector functions associated with distinct glycosylation profiles

“…This different behavior of IgA1 and IgA2 could be an explanation for the at first sight controversial effects of IgA observed in previous studies. Many studies describing anti-inflammatory effects of IgA worked with total serum IgA [16][17][18][19]39 , which is to 90% composed of IgA1 that did not induce inflammatory cytokine production in our hands. On the other hand, the described associations with autoimmune diseases are most likely due to specific autoantibodies that may have an increased IgA2 fraction, as we have observed for RA-specific ACPA.…”

Intravenous immunoglobulin mediates anti-inflammatory effects in peripheral blood mononuclear cells by inducing autophagy

“…This indicates that glycosylation patterns of Fc-fragments including sialylation 26,60 have no major role in IVIG-induced autophagy. Indeed, several F (ab′) 2 fragments-mediated functions of IVIG have been reported like neutralization of C3a and C5a anaphylatoxins and pathogenic autoantibodies, regulation of human DCs and granulocyte functions, inhibition of phagocytosis, expansion of human regulatory T cells and inhibition of Th17 responses [61][62][63][64][65][66][67][68] . However, we found that IVIG might not induce autophagy by signaling via cell surface receptors, as inhibition of endocytosis of IgG via cytochalasin D that inhibits phagocytosis and macropinocytosis abrogated IVIG-induced autophagy.…”

Natural Antibodies: from First-Line Defense Against Pathogens to Perpetual Immune Homeostasis

“…In line with the immune modulatory effects of IgG and IgM nAbs, other subclasses of normal Igs, particularly IgA, have been explored. Preclinical evaluation of pooled IgA (analogous to IVIG) provided evidence that normal IgA also ameliorates inflammation and hence demands further clinical evaluation [104,105].…”