SUMMARYThe development of autoimmunity was investigated in BALB/c and C58 mice infected with lactate dehydrogenase-elevating virus (LDV). Autoantibodies reactive by ELISA with syngeneic central nervous system antigens appeared early during LDV infection of both strains of mice, and were maintained for many months. Western blot analysis indicated that the LDV-induced autoantibodies reacted with a variety of different brain antigens, and mouse strain differences in the pattern of autoreactivity were observed. LDV infection of C58 and BALB/c mice also stimulated antibodies reactive with syngeneic liver-, kidney-and spleen-derived antigens, and in Swiss outbred mice heart-reactive antibodies were observed following LDV infection. These results show that autoimmunity is a feature of the deregulation of the immune system which occurs during LDV infection.
B-lymphocyte activation was studied in mice infected with lactate dehydrogenase-elevating virus (LDV). ELISA determinations of blood total immunoglobulin levels demonstrated that, at 10 days post-infection (p.i.) with LDV, only the IgG2a isotype was elevated. DNA-excess dot-blot hybridization showed that RNA specific for IgG2a and IgA immunoglobulin isotypes was increased in the spleens of mice at 10 days p.i. with LDV. Immunoglobulin surface phenotype analysis of spleen cells at 8-10 days p.i. with LDV revealed that there was no alteration in immunoglobulin isotype-bearing cell proportions, although total spleen mass and number of cells increased during LDV infection. When blood immunoglobulins from LDV-infected mice were analyzed by two-dimensional isoelectric focusing gels, followed by specific immunoblotting for immunoglobulin isotype, the presence of new IgG2a species was observed at 10 days p.i.
In Th1 clones, TCR occupancy together with a costimulatory signal from APC results in IL-2 production. TCR occupancy alone results in unresponsiveness (anergy) to antigenic stimulation, a phenomenon that may be important for self-tolerance in vivo. Inasmuch as inositol phosphate production occurs during the induction of anergy other biochemical signals must be necessary for IL-2 production. Here we assess the role of tyrosine-specific protein kinases using the specific inhibitor, genistein. IL-2 secretion and responsiveness were very dependent on tyrosine-specific protein kinase activation and could be completely blocked under conditions where inositol phosphate generation occurred normally. Although anergy induction could also be blocked by inhibition of tyrosine-specific protein kinase activation this probably occurred indirectly via inhibition of inositol phospholipid hydrolysis. The differential susceptibility of IL-2 secretion and anergy induction to inhibition by genistein indicates that positive and negative outcomes of TCR occupancy may be mediated by distinct biochemical pathways.
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