FUNCTIONS OF GLUTATHIONE AND GLUTATHIONE DISULFIDE IMMUNOLOGY AND IMMUNOPATHOLOGY

Even a moderate increase in the cellular cysteine supply elevates the intracellular glutathione (GSH) and glutathione disulfide (GSSG) level s and potentiates immunological functions of lymphocytes in vitro. At low GSSG levels, T cells cannot optimally activate the immunologically important transcription factor NF kappa B, whereas high GSSG levels i nhibit the DNA binding activity of NF kappa B. The effects of GSSG are antagonized by reduced thioredoxin (TRX). As the protein tyrosine kin ase activities p56(lck) and p59(fyn) are activated in intact cells by hydrogen peroxide, they are likely targets for GSSG action. These redo x-regulated enzymes trigger signal cascades for NF kappa B activation and transduce signals from the T cell antigen receptor, from CD4 and C D8 molecules, and from the IL-2 receptor beta-chain. The effector phas e of cytotoxic T cell responses and IL-2-dependent functions are inhib ited even by a partial depletion of the intracellular GSH pool. As sig nal transduction is facilitated by prooxidant conditions, we propose t hat the well-known immunological consequences of GSH depletion ultimat ely may be results of the accompanying GSSG deficiency. As HIV-infecte d patients and SIV-infected rhesus macaques have, on the average, sign ificantly decreased plasma cyst(e)ine and intracellular GSH levels, we also hypothesize that AIDS may be the consequence of a GSSG deficienc y as well.