Glutathione inhibits antibody and complement-mediated immunologic cell injury via multiple mechanisms

Abstract

Antioxidant glutathione (GSH) plays an important role in the regulation of immunity. However, little is known about its effects on humoral immunity, especially its action on effector molecules like antibody and complement. Given that these molecules contain abundant disulfide bonds, we speculated that GSH might influence the action of these proteins via its thiol function. Using a model of a glomerular mesangial cell (MC) lysis induced by antibodies plus complement, we addressed this hypothesis. Exposure of rat MCs to anti-Thy-1 antibody plus complement or anti-MC rabbit serum caused a complement-dependent cell lysis, which was completely blocked by GSH. Moreover, GSH potently prevented the antibody-mediated agglutination of red blood cells and aggregation of antibody-sensitized microspheres. Further analysis revealed that GSH inhibited antibody binding to antigens and promoted the conversion of the antibodies to its reduced forms. GSH also potently inhibited the formation and deposition of C5b-9 in MCs and suppressed both the classic and alternative complement activation pathway. Lastly, GSH attenuated P38 activation, an oxidative sensitive kinase that partially mediated the antibody- and complement-dependent MC lysis. Depletion of GSH via inhibiting gamma-glutamylcysteine synthetase or xCT transporter augmented P38 activation and sensitized MCs to the cell lysis. Collectively, our results indicate that GSH protects cells from immunological cell damage via mechanisms involving inhibition of antibody binding to the antigens, suppression of complement activation and augmentation of cellular defense mechanism. Our study provides novel mechanistic insights into the actions of GSH in the regulation of immune responses and suggests that GSH might be used to treat certain immune disorders.

Precision Medicine: The Role of the MSIDS Model in Defining, Diagnosing, and Treating Chronic Lyme Disease/Post Treatment Lyme Disease Syndrome and Other Chronic Illness: Part 2

“…Our study and chart review showed that evaluating patients for associated environmental toxicity and using detoxification with glutathione (GSH) is clinically useful, especially during Herxheimer reactions. Glutathione modulates inflammation [172,173]. A 2018 PNAS report found that intracellular GSH production was increased up to 10-fold during an infection with Borrelia burgdorferi , and infection was a key factor in inflammation/cytokine production [174].…”

Immunomodulatory Effects of Glutathione, Garlic Derivatives, and Hydrogen Sulfide

“…Likewise, when GSH levels were restored with N-acetycysteine (NAC), a precursor of L-cysteine, supplementation, T cell proliferation and IL-2 levels were increased. More recently, it has been suggested that GSH supplementation may protect cells from immunological cell damage by inhibiting the complement activation cascade and the binding of antibodies to antigens in isolated glomerular mesangial cells from rats, suggesting the possible use of GSH in the treatment of certain immune disorders [ 99 ].…”

N‐acetylcysteine prevents glutathione decrease and does not interfere with paracetamol antinociceptive effect at therapeutic dosage: a randomized double‐blind controlled trial in healthy subjects

“…However, GSH is the main antioxidant in the body and studies have underlined that GSH depletion is involved in a number of pathologies . GSH decrease is certainly involved in oxidative damage and risk factors for cardiovascular disease , inflammatory reactions , cognitive processes , and immunity . The observation that NAC at therapeutic doses counteracts the deleterious effect of APAP on whole blood GSH concentration in healthy volunteers suggests that this depletion could be prevented by adequate sulfur amino acids intake such as methionine, cysteine , or NAC for the biosynthesis of GSH, especially in vulnerable persons.…”