The Fas/Fas ligand (FasL) system has been shown to participate in activation induced apoptotic cell death (AICD) of mature B cells. To determine whether any abnormalities in this system are involved in the autoreactive B cells, we examined levels of Fas expression and sensitivity to apoptosis of and-DNA antibody-producing B cells from autoimmune disease-prone NZB×NZW (NZB/W) F1 mice. Unstimulated B cells from the spleen and the peritoneal cavity of 2-month-old NZB/W Fl and normal healthy Balb/c mice expressed no, if any, Fas and were not prone to apoptosis when stimulated with anti-Fas mAb. When stimulated in vitro with agonistic anti-CD40mAb, but not LPS or anti-μ, these B cells from Balb/c and NZB/WF1 mice expressed Fas. However, the patterns of Fas expression differed between CD5
+B (B1) cells and conventional B2 cells, in which all B2 cells expressed a high level of Fas, but the Bl cell population was divided into two levels of big and low Fas expression. Although all B cells with high levels of Fas were highly sensitive to Fasmediated apoptosis, Bi cells with low Fas expressior were virtually apoptosis-resistant. Because low Fas expression and apoptosis insensitivity remained unchanged in vitro, even in the presence of larger amounts of and-CD40 or following restimulation with anti-CD40, these properties of low Fas B1 cells seemed to be intrinsic and restricted to the low Fas Bl cell subpopulation. An intriguing finding was that such anti-CD40-induced low Fas B1 cell subpopulation from 2-month-old NZB/W Fl spleens was almost totally responsible for the in vitro IgM and-DNA antibody production. The spleen, but not the peritoneal cavity, from aged NZB/W F1 mice with overt autoimmune disease contained B cells with a spontaneous low Fas expression. These B cells were also apoptosis-resistant and were almost totally responsible for in vitro IgG and-DNA antibody synthesis. Thus, although such B cells lacked a CD5 phenotype, they were thought to be derived from low Fas Bl cells in young mice. Possibilities that autoantibody-producing B cells in autoimmune disease originate from a restricted subpopulation of apoptosis-resistant B1 cells, and that the selection and affinity maturation of certain clones from such a subpopulation may lead to the development of pathogenic autoantibodies are discussed.
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