Hydrogen sulfide donor NaHS alters antibody structure and function via sulfhydration

Hydrogen sulfide (H₂S) has emerged as an important biological mediator with numerous pathophysiological roles. One of the well-documented actions of H₂S is to inhibit immunity, especially cellular immunity. Currently, limited information is available regarding its effects on humoral immunity. Given that H₂S has reducing activity and that the effector molecules in humoral immunity, such as antibody and complement, contain abundant disulfide bonds that are indispensable for their functions, we speculated that H₂S might regulate antibody activity via modification of disulfide bonds. Here we addressed this possibility. Exposure of antibodies to H₂S donors resulted in cleavage of the disulfide bonds between the heavy and light chains of antibodies, which was associated with antibody sulfhydration. Further analysis revealed that H₂S-treated antibodies exhibited a marked reduction in antigen binding ability. It potently prevented the antibody-mediated agglutination of red blood cells and interrupted aggregation of antibody-coated microspheres. H₂S also greatly inhibited antibody-induced and complement-mediated cell lysis in glomerular mesangial cells, as well as anti-CD95 IgM antibody-initiated cell apoptosis in Jurkat cells. Moreover, it significantly suppressed the alternative complement activation pathway. Collectively, our results revealed, for the first time, that pharmacologic levels of H₂S inhibit humoral immune responses via direct sulfhydration of the effector molecules. Our study thus provides novel mechanistic insights into the immunoregulatory actions of H₂S and suggests that H₂S may have potential to treat certain humoral immune diseases.