PURIFIED IGG F C-BINDING PROTEINS FROM M22 GROUP A STREPTOCOCCUS ARE ABLE TO INDUCE EXPERIMENTAL GLOMERULONEPHRITIS

Abstract

Abstract. Pathogenesis of acute post-streptococcal glomerulonephritis (APSGN), a major complication of group A streptococcal (GAS) throat or skin disease, remains unclear. Over years, various theories were based on distinct streptococcal extracellular factors, as well as immunological mimicry of streptococci for renal tissue antigens was considered. Previously we reported that a lot of clinical GAS isolates with proven nephritogenic ability show a non-immune binding of monomeric or aggregated IgG. Moreover, using a rabbit model of APSGN, we obtained evidence for important causative role of streptococcal IgG Fc-binding proteins (IgG FcBPs) belonging to the M family surface proteins. I.e., rabbits injected by whole IgG FcBP-positive streptococci showed induction of renal glomerular changes, with deposition of IgG and complement C3, resembling the picture recorded in human APSGN. These typical renal changes were always preceded by development of circulating anti-IgG antibodies. Present study was performed in the same rabbit model. Both purified IgG FcBPs isolated from type M22 GAS were found to elicit glomerular degenerative damage of renal glomeruli comparable to those caused by whole bacteria, as well as induce anti-IgG antibodies, deposition of IgG and C3 complement and production of proinflammatory cytokines (IL-1β, TNFα, IL-6) by glomerular mesangial and endothelial cells. By contrast, rabbits injected with proteins A or G, IgG FcBPs of S. aureus and group G streptococci, respectively, exhibited only low levels of circulating anti-IgG and reversible glomerular changes. In these settings, we have not observed any features of membranousproliferative glomerulonephritis (GN) resembling morphological traits of acute post-streptococcal GN in humans. These data correlated with results obtained after injection of intact Staphylococcus aureus (Cowan 1 strain) or group G streptococci (G148 strain). Both microbial types are known to harbor IgG Fc-binding proteins (А and G, respectively). These results support the idea that GAS IgG FcBPs are unique in their ability to initiate strong post-streptococcal glomerular changes and could be considered as important factors in pathogenesis of APSGN similar to acute post-streptococcal GN in humans.