title: Absence of CD59 exacerbates systemic autoimmunity in MRL/lpr mice.
abstract: CD59 is a GPI-anchored membrane regulator of complement expressed on blood cells as well as peripheral tissues. It protects host cells from complement injury by inhibiting formation of the membrane attack complex. Recent studies in mice have suggested also a role of CD59 in T cell immune response that was mechanistically independent of complement. In the present study, we investigated the function of CD59 in the MRL/lpr model of murine lupus. We backcrossed the Cd59a knockout (Cd59a(-/-)) mouse onto the MRL/lpr background and compared Cd59a(+/+)-MRL/lpr and Cd59a(-/-)-MRL/lpr littermates for the development of systemic autoimmunity. We found that CD59a deficiency significantly exacerbated the skin disease and lymphoproliferation characteristic of MRL/lpr mice. It also increased autoantibody titers and caused a higher level of proteinuria in male MRL/lpr mice. Bone marrow transfer experiments indicated that CD59a expression on both bone marrow-derived cells and peripheral tissues played a role in lymphoproliferation, whereas the skin disease phenotype is determined mainly by local CD59a expression. Importantly, C3 gene deletion or C5 neutralization with a blocking mAb in Cd59a(-/-)-MRL/lpr mice did not rescue the proautoimmune phenotype associated with CD59a deficiency. These results together suggest that CD59a inhibits systemic autoimmunity in MRL/lpr mice through a complement-independent mechanism.
authors.affiliation: Department of Pharmacology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Takashi
authors.initials: T
authors.lastname: Miwa
authors.forename: Lin
authors.initials: L
authors.lastname: Zhou
authors.forename: Michael A
authors.initials: MA
authors.lastname: Maldonado
authors.forename: Michael P
authors.initials: MP
authors.lastname: Madaio
authors.forename: Robert A
authors.initials: RA
authors.lastname: Eisenberg
authors.forename: Wen-Chao
authors.initials: WC
authors.lastname: Song
mesh_terms: D000743:Anemia, Hemolytic / Q000235:genetics / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001323:Autoantibodies / Q000096:biosynthesis*; D015551:Autoimmunity; D018957:CD59 Antigens / Q000235:genetics / Q000276:immunology*; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000276:immunology; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D003872:Dermatitis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006456:Hemoglobinuria / Q000235:genetics / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D011507:Proteinuria / Q000235:genetics / Q000276:immunology / Q000473:pathology; D012737:Sex Factors; D012867:Skin / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology
chemical_list: D000906:Antibodies; D001323:Autoantibodies; D018957:CD59 Antigens; C539311:CD59a protein, mouse; D003176:Complement C3; D003182:Complement C5