Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17.

Little is known about the function of natural IgM autoantibodies, especially that of IgM anti-leukocyte autoantibodies (IgM-ALA). Natural IgM-ALA are present at birth and characteristically increase during inflammatory and infective conditions. Our prior clinical observations and those of other investigators showing fewer rejections in renal and cardiac allografts transplanted into recipients with high levels of IgM-ALA led us to investigate whether IgM-ALA regulate the inflammatory response. In this article, we show that IgM, in physiologic doses, inhibit proinflammatory cells from proliferating and producing IFN-γ and IL-17 in response to alloantigens (MLR), anti-CD3, and the glycolipid α-galactosyl ceramide. We showed in an IgM knockout murine model, with intact B cells and regulatory T cells, that there was more severe inflammation and loss of function in the absence of IgM after renal ischemia reperfusion injury and cardiac allograft rejection. Replenishing IgM in IgM knockout mice or increasing the levels of IgM-ALA in wild-type B6 mice significantly attenuated the inflammation in both of these inflammatory models that involve IFN-γ and IL-17. The protective effect on renal ischemia reperfusion injury was not observed using IgM preadsorbed with leukocytes to remove IgM-ALA. We provide data to show that the anti-inflammatory effect of IgM is mediated, in part, by inhibiting TLR-4-induced NF-κB translocation into the nucleus and inhibiting differentiation of activated T cells into Th-1 and Th-17 cells. These observations highlight the importance of IgM-ALA in regulating excess inflammation mediated by both innate and adaptive immune mechanisms and where the inflammatory response involves Th-17 cells that are not effectively regulated by regulatory T cells.

Naturally occurring IgM anti-leukocyte autoantibodies inhibit T-cell activation and chemotaxis.

INTRODUCTION: Naturally occurring IgM antileukocyte autoantibodies (IgM-ALA) are present from birth and increase during inflammatory processes of diverse etiologies. The clinical observation demonstrating a significant correlation (P < 01) between lack of acute rejections and presence of high levels of IgM-ALA in recipients of kidney allografts prompted us to study if IgM-ALA alters T-cell function and leukocyte chemotaxis. METHODS: In-vitro functional assays were performed using leucocytes isolated from human peripheral blood. In-vivo studies were performed in C57BL6 mice. RESULT: Human studies revealed that IgM-ALA consist of several different IgM, each with specificities for a different leukocyte receptor, e.g., CD3, CD4, CCR5, and CXCR4. We show that IgM inhibits T-cell activation, proliferation, and chemotaxis. Data on in vivo murine models of ischemia-reperfusion injury and cardiac transplantation support our hypothesis. CONCLUSION: The innate anti-inflammatory mechanism of IgM-ALA can be exploited by using purified normal IgM to inhibit inflammatory states or by a vaccine approach to increase in vivo production of IgM-ALA (e.g., prior to a transplant).