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

The role of CD4 molecules in the autoimmune and lymphoproliferative syndrom e caused by murine Fas mutations was studied using the novel systemic lupus erythematosus (SLE) model, MRL-Fas(lprcg)/ 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 (CD4(s)-lpr( cg)), heterozygous (CD4(s/m)-lpr(cg)), and wild-type (CD4(m)-lpr(cg)) for t he CD4 mutation. The mortality, glomerulonephritis, proteinuria, and lympha denopathy were significantly ameliorated in CD4(s)-lpr(cg) compared with CD 4(m)-lpr(cg) and CD4(s/m)- lpr(cg) mice, both being comparable in these cli nical 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 sig nificantly lower in the former. The results indicate that mCD4 is important and can not he replaced by sCD4 in full development of SLE-like manifestat ions, 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 spl een elevated with the increased accumulation of B210(+)CD4(-)CD8(-) (double -negative (DN)) T cells in CD4(s)-lpr(cg) mice. This, together with the sig nificantly milder lymphadenopathy associated with lower DN T cell contents in CDC-lpr''* than CD4(m)-lpr(cg) mice, implies that some of abnormal DN T cells may be derived from cells of the CD4 lineage.