Effects of the lpr mutation on elimination and inactivation of self-reactive B cells.
Mice homozygous for the lymphoproliferation (lpr) mutation, which disrupts expression of the Fas cell surface molecule, develop an autoimmune syndrome with a spectrum of autoantibodies resembling human SLE. It is not known how the loss of Fas leads to autoantibody production. To study the fate of autoreactive B cells in lpr/lpr mice, C57BL/6 (B6) strain transgenic mice expressing hen egg lysozyme (HEL) as a model autoantigen in soluble or membrane-bound forms and carrying HEL-specific Ig (Ig) transgenes were mated onto the congenic B6-lpr/lpr background. Despite the absence of Fas, elimination of self-reactive lpr/lpr B cells recognizing membrane-bound autoantigen occurred as efficiently as in autoreactive B cells bearing the wild-type (+/+) Fas gene. Functional inactivation of autoreactive B cells binding soluble HEL also occurred normally in most young lpr/lpr animals. Nevertheless, breakdown of B cell tolerance to soluble lysozyme occurred in one of eight young lpr/lpr animals and in four of seven old animals with lymphadenopathy. Interestingly, the presence of the rearranged Ig transgenes markedly delayed the onset of lymphadenopathy. These results demonstrate that Fas is not an essential molecule in the biochemical pathways mediating autoreactive B cell elimination or inactivation. The breakdown of tolerance observed in a considerable fraction of older animals nevertheless confirms that autoantibody production in this model of SLE involves a defect in active censoring of autoreactive B cells. The possible basis for that defect is discussed.
Rathmell
J C
JC
Program in Immunology, Stanford University School of Medicine, CA 94305.
Goodnow
C C
CC
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D015139:Blotting, Southern; D001854:Bone Marrow Cells; D004527:Egg Proteins / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains / Q000276:immunology; D008822:Mice, Transgenic; D009113:Muramidase / Q000276:immunology; D011828:Radiation Chimera / Q000276:immunology; D017634:Self Tolerance / Q000235:genetics*
D004527:Egg Proteins; D009113:Muramidase