CD74 mediates MHC class-II antigenic peptide loading and presentation and plays an important role in the pathogenesis of autoimmune diseases, including systemic lupus erythematosus. C57BL/6 Faslpr mice that develop spontaneous lupus-like autoimmunity and pathology showed elevated CD74 expression in the inflammatory cell infiltrates and the adjacent tubular epithelial cells (TECs) in kidneys affected by lupus nephritis but negligible levels in kidneys from age-matched wild-type mice. The inflammatory cytokine IFN-γ or IL-6 induced CD74 expression in kidney TECs in vitro. The presence of kidney TECs from Faslpr mice, rather than from wild-type mice, produced significantly stronger histones, dsDNA, and ribonucleoprotein-Smith Ag complex–induced CD4+ T cell activation. Splenocytes from CD74-deficient FaslprCd74−/− mice had muted responses in a MLR and to the autoantigen histones. Compared with FaslprCd74+/+ mice, FaslprCd74−/− mice had reduced kidney and spleen sizes, splenic activated T cells and B cells, serum IgG and autoantibodies, urine albumin/creatinine ratio, kidney Periodic acid–Schiff score, IgG and C3 deposition, and serum IL-6 and IL-17A levels, but serum IL-2 and TGF-β levels were increased. Study of chronic graft-versus-host C57BL/6 mice that received donor splenocytes from B6.C-H2bm12/KhEg mice and those that received syngeneic donor splenocytes yielded similar observations. CD74 deficiency reduced lupus-like autoimmunity and kidney pathology in chronic graft-versus-host mice. This investigation establishes the direct participation of CD74 in autoimmunity and highlights a potential role for CD74 in kidney TECs, together with professional APCs in systemic lupus erythematosus.
This work was supported by National Institutes of Health Grants HL81090, HL60942, and HL123568 (to G.-P.S.) and HL34636 and HL80472 (to P.L.).
Abbreviations used in this article:
- chronic graft-versus-host
- chronic lymphocytic leukemia
- graft-versus-host disease
- 4,5-dihydro-3-(4-hydroxyphenyl)-5-isoxazoleacetic acid
- mantle cell lymphoma
- MHC class II
- macrophage migration inhibitory factor
- CD74 10-kDa fragment
- CD74 41-kDa fragment
- periodic acid–Schiff
- ribonucleoprotein–Smith Ag complex
- systemic lupus erythematosus
- tubular epithelial cell
- regulatory T cell
- Received January 7, 2016.
- Accepted January 22, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.