title: Natural IgM anti-leukocyte autoantibodies attenuate excess inflammation mediated by innate and adaptive immune mechanisms involving Th-17.
abstract: 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.
authors.affiliation: Division of Nephrology, Center for Immunity, Inflammation and Regenerative Medicine, University of Virginia, Charlottesville, VA 22908, USA. pil@virginia.edu
authors.forename: Peter I
authors.initials: PI
authors.lastname: Lobo
authors.forename: Amandeep
authors.initials: A
authors.lastname: Bajwa
authors.forename: Kailo H
authors.initials: KH
authors.lastname: Schlegel
authors.forename: John
authors.initials: J
authors.lastname: Vengal
authors.forename: Sang J
authors.initials: SJ
authors.lastname: Lee
authors.forename: Liping
authors.initials: L
authors.lastname: Huang
authors.forename: Hong
authors.initials: H
authors.lastname: Ye
authors.forename: Umesh
authors.initials: U
authors.lastname: Deshmukh
authors.forename: Tong
authors.initials: T
authors.lastname: Wang
authors.forename: Hong
authors.initials: H
authors.lastname: Pei
authors.forename: Mark D
authors.initials: MD
authors.lastname: Okusa
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D017252:CD3 Complex / Q000276:immunology; D002454:Cell Differentiation; D005699:Galactosylceramides / Q000276:immunology; D007113:Immunity, Innate; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D020381:Interleukin-17 / Q000096:biosynthesis / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D007962:Leukocytes / Q000276:immunology*; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology*; D051197:Toll-Like Receptor 4 / Q000037:antagonists & inhibitors
chemical_list: D001323:Autoantibodies; D017252:CD3 Complex; D005699:Galactosylceramides; D007075:Immunoglobulin M; D020381:Interleukin-17; D007519:Isoantigens; D016328:NF-kappa B; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C493154:alpha-galactosylceramide; D007371:Interferon-gamma