title: A pivotal role of cell-bound but not soluble CD4 molecules in full development of lupus-like manifestations in MRL-Fas(lprcg)/Fas(lprcg) mice.
abstract: The role of CD4 molecules in the autoimmune and lymphoproliferative syndrome caused by murine Fas mutations was studied using the novel systemic lupus erythematosus (SLE) model, MRL-Fas(lpr(cg))/Fas(lprcg) (MRL-lpr(cg)) mice, in combination with the novel mutant CD4 gene producing soluble CD4 (sCD4) instead of membrane-bound CD4 (mCD4). For this purpose, various autoimmune manifestations were compared among MRL-lpr(cg) mice homozygous (CD4slprcg), heterozygous (CD4s/mlpr(cg)), and wild-type (CD4mlpr(cg)) for the CD4 mutation. The mortality, glomerulonephritis, proteinuria, and lymphadenopathy were significantly ameliorated in CD4slprcg compared with CD4mlpr(cg) and CD4s/mlpr(cg) mice, both being comparable in these clinical characteristics. In parallel with the clinical improvement, the serum levels of immunoglobulin, anti-DNA antibodies, anti-nuclear antibodies and immune complexes, and the extent of glomerular immune deposition, were significantly lower in the former. The results indicate that mCD4 is important and can not be replaced by sCD4 in full development of SLE-like manifestations, and suggest that CD4+ T cells may aggravate the autoimmune disease by stimulating autoreactive B cells to produce autoantibodies through their helper activity in Fas mutant models. The sCD4 levels in the serum and spleen elevated with the increased accumulation of B220+CD4-CD8- (double-negative (DN)) T cells in CD4slpr(cg) mice. This, together with the significantly milder lymphadenopathy associated with lower DN T cell contents in CD4slpr(cg) than CD4mlpr(cg) mice, implies that some of abnormal DN T cells may be derived from cells of the CD4 lineage.
authors.affiliation: Laboratory Animal Research Centre, University of Tokyo and Intractable Disease Research Centre, Tokyo Medical University, Tokyo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Yasuda
authors.forename: C R
authors.initials: CR
authors.lastname: Wang
authors.forename: T
authors.initials: T
authors.lastname: Yoshimoto
authors.forename: H
authors.initials: H
authors.lastname: Nagase
authors.forename: M
authors.initials: M
authors.lastname: Takamoto
authors.forename: A
authors.initials: A
authors.lastname: Tsubura
authors.forename: M
authors.initials: M
authors.lastname: Kimura
authors.forename: A
authors.initials: A
authors.lastname: Matsuzawa
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015415:Biomarkers; D015704:CD4 Antigens / Q000097:blood / Q000276:immunology*; D015922:Complement C1q / Q000032:analysis; D005260:Female; D006801:Humans; D006965:Hyperplasia / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007668:Kidney / Q000276:immunology / Q000473:pathology; D007678:Kidney Glomerulus / Q000276:immunology; D008181:Lupus Nephritis / Q000097:blood / Q000276:immunology* / Q000503:physiopathology; D008198:Lymph Nodes / Q000276:immunology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011507:Proteinuria / Q000276:immunology; D012995:Solubility; D013154:Spleen / Q000276:immunology
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D015704:CD4 Antigens; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D015922:Complement C1q