The isolation and functional characterization of autoimmune clones expressing inappropriate Ia.
The MRL/lpr mouse is an inbred strain widely accepted as a model for autoimmune disease both in murine and human systems. Developed from a series of crosses involving four strains of mice, the MRL/lpr (H-2k) genome is a composite estimated to contain approximately 75% of its parental LG/J (H-2d) genome. To explore the cellular mechanism underlying lymphoproliferation in the MRL/lpr mouse, we have isolated a series of clones from the lymph nodes of MRL/lpr mice with autoimmune disease. Extensive immunofluorescent analyses of these clones, designated the PAC series, reveal expression of IAk and IEk (beta-chain) cell surface antigens, as well as inappropriate expression of IAd, IEd (beta-chain), and H-2d. PAC cells also express MAC-1, MAC-2, RA3-2C2, and RA3-6B2 and contain esterase-positive cytoplasmic granules. The capacity of PAC cells to present antigen was investigated by co-culturing PAC with IA-restricted, antigen-specific T cell hybridomas +/- antigen. These assays demonstrated the PAC inability to present antigen to IAk-restricted T cell hybridomas, as well as their capacity to present antigen to IAd-restricted T cell hybridomas. In addition, activation of MRL/lpr peritoneal macrophages using gamma-interferon resulted in increased fluorescent staining for IAd and IEd concomitant with decreased fluorescent staining for IAk. Based on these findings, we propose a model of lymphoproliferation in which Ly-1+, H-2K+ T cells proliferate to inappropriate d haplotype antigens expressed by a small subset of monocytes in the MRL/lpr lymph node. The major genomic contribution of the LG/J (H-2d) mouse may be in part responsible for inappropriate antigen expression either by age-dependent expansion of d haplotype cells or by age-regulated expression of Iad and H-2d genes.
D000818:Animals; D000954:Antigens, Surface / Q000032:analysis / Q000276:immunology; D001327:Autoimmune Diseases / Q000276:immunology*; D002469:Cell Separation; D002999:Clone Cells / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis* / Q000276:immunology; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation; D008211:Lymphocyte Cooperation; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains / Q000276:immunology*; D009000:Monocytes / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology
D000954:Antigens, Surface; D000949:Histocompatibility Antigens Class II