POTENTIAL ROLE OF AUTOANTIBODIES IN THE REGULATION OF CYTOKINE RESPONSES DURING BACTERIAL-INFECTIONS

An immunoregulatory mechanism involving release of neutralizing autoan tibodies (Aabs) to self cytokines during bacterial infections is prese nted herein, Intraperitoneal inoculation of Haemophilus influenzae typ e b into Sprague-Dawley rats resulted in a self-limiting meningitis, H igh levels of cells expressing mRNA for gamma interferon (IFN-gamma) a nd tumor necrosis factor alpha (TNF-alpha) were detected 12 to 48 h po stinoculation (p.i.) in splenocytes, and large numbers of IFN-gamma-se creting cells were present in the spleen on day 3 p.i. These levels we re undetectable at days 9 and 14 p.i. Increased titers of Aabs of immu noglobulin G (IgG) isotypes to both cytokines were observed, with a pe ak at day 7 p.i. and with very low levels at day 30. Upon reinoculatio n with H. influenzae type b at day 30, regeneration of Aabs was record ed 7 days later (i.e., at day 37), To elucidate their regulatory impor tance, Aabs dose-dependently inhibited IFN-gamma production by splenoc ytes, IFN-gamma-induced major histocompatibility complex expression by peritoneal macrophages, and TNF-alpha-induced thymocyte proliferation , To control the specificity of these Aabs, Fab fragments of purified serum Igs from day p.i. exhibited binding and neutralizing effects. Fu rthermore, preincubation of the sera,vith a cytokine inhibited the bin ding and neutralization effects of that particular cytokine, but not t hose of any other cytokine, Aab-producing B cells were cloned, and the ir supernatants had similar effects, Our data suggest a role for autoi mmunity in cytokine regulation and suggest that a maintained balance o f this mechanism may protect from sequelae.