Potential role of autoantibodies in the regulation of cytokine responses during bacterial infections

Abstract

An immunoregulatory mechanism involving release of neutralizing autoantibodies (Aabs) to self cytokines during bacterial infections is presented herein. Intraperitoneal inoculation of Haemophilus influenzae type b into Sprague-Dawley rats resulted in a self-limiting meningitis. High levels of cells expressing mRNA for gamma interferon (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) were detected 12 to 48 h postinoculation (p.i.) in splenocytes, and large numbers of IFN-gamma-secreting cells were present in the spleen on day 3 p.i. These levels were undetectable at days 9 and 14 p.i. Increased titers of Aabs of immunoglobulin G (IgG) isotypes to both cytokines were observed, with a peak at day 7 p.i. and with very low levels at day 30. Upon reinoculation with H. influenzae type b at day 30, regeneration of Aabs was recorded 7 days later (i.e., at day 37). To elucidate their regulatory importance, Aabs dose-dependently inhibited IFN-gamma production by splenocytes, 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. Furthermore, preincubation of the sera with a cytokine inhibited the binding and neutralization effects of that particular cytokine, but not those of any other cytokine. Aab-producing B cells were cloned, and their supernatants had similar effects. Our data suggest a role for autoimmunity in cytokine regulation and suggest that a maintained balance of this mechanism may protect from sequelae.