Mechanisms that potentially contribute to the development of post-streptococcal glomerulonephritis

Abstract

Post-streptococcal glomerulonephritis (PSGN) is primarily associated with preceding group A streptococcal skin or throat infections, now mainly observed in economically disadvantaged communities. This condition significantly predisposes individuals to later-life chronic kidney disease and concurrent renal complications, with the elderly experiencing increased severity and less favourable outcomes. Streptococcal pyrogenic exotoxin B and nephritis-associated plasmin receptor are identified nephritogenic antigens (nephritogens). Pathogenesis of PSGN is multifactorial. It can involve the formation of antigen-antibody immune complexes, causing inflammatory damage to renal glomeruli. Deposition of circulating immune complexes or in situ formation of immune complexes in glomeruli, or both, results in glomerulonephritis. Additionally, molecular mimicry is hypothesized as a mechanism, wherein cross-reactivity between anti-streptococcal antibodies and glomerular intrinsic matrix proteins leads to glomerulonephritis. Besides, as observed in clinical studies, streptococcal inhibitor of complement, a streptococcal-secreted protein, can also be associated with PSGN. However, the interplay between these streptococcal antigens in the pathogenesis of PSGN necessitates further investigation. Despite the clinical significance of PSGN, the lack of credible animal models poses challenges in understanding the association between streptococcal antigens and the disease process. This review outlines the postulated mechanisms implicated in the development of PSGN with possible therapeutic approaches.

Keywords: animal model; chronic kidney disease; nephritis-associated plasmin receptor; post-streptococcal glomerulonephritis; streptococcal inhibitor of complement; streptococcal pyrogenic exotoxin B.

Figure 1.

Postulated mechanisms implicated in the development of PSGN. GAS initially causes pharyngitis and pyoderma. In a proportion of individuals, untreated or repeated streptococcal infections lead to post-streptococcal complications of the kidney. Three distinct pathways, or a combination of these, may be associated with the pathogenesis. (a) Plasmin-mediated injury: Streptococcal nephritogenic antigens (e.g. SpeB/NAPlr) can convert plasminogen to plasmin that can activate glomerular MMPs and modify extracellular matrix composition, including chemotaxis of inflammatory cells, leading to degradation of GBM. (b) Immune complex-mediated injury: This involves glomerular subepithelial immune complex deposition via three different mechanisms; (b₁) streptococcal antigens (e.g. SpeB/NAPlr/SIC) could interact with antibodies in circulation to form complexes that deposit in the GBM, (b₂) streptococcal antigens (e.g. SpeB/NAPlr/SIC) could deposit in the GBM, and circulatory antibodies specific to these antigens can cross the glomerular capillary endothelial lining and bind these exogenous antigens already embedded in GBM, (b₃) anti-streptococcal antibodies might transverse the capillary endothelium and cross-react with glomerular intrinsic matrix proteins (i.e. endogenous/native antigens). Immune complexes formed through any of these mechanisms can activate complement cascade (C5b-9), monocyte/macrophage and neutrophil recruitment, activation, and cytokine release resulting in inflammation and injury to glomerular capillary tufts and podocytes. (c) SIC-mediated injury: Circulatory SIC may penetrate the podocyte, bind, and co-localize with Ezrin intracellularly. This may cause cytoskeletal defects leading to podocytopathy. GBM: glomerular basement membrane, ICs: immune complexes, MMPs: matrix metalloproteinases, NAPlr: nephritis-associated plasmin receptor, PSGN: post-streptococcal glomerulonephritis, SIC: streptococcal inhibitor of complement, SpeB: streptococcal pyrogenic exotoxin B.

Figure 2.

Histological features of kidney pathology. (a) Light microscopy demonstrating normal renal cortex (Haematoxylin and Eosin stain, 200 × magnification); (b) Light microscopy demonstrating abnormal glomerulus in PSGN with diffuse hypercellularity including numerous neutrophils and mesangial cell increase (Haematoxylin and Eosin stain, 200 × magnification); (c) In PSGN, a cellular crescent (black star) is observed in the glomerulus (Periodic acid-Schiff/diastase stain, 100 × magnification); (d) Immunofluorescence demonstrating granular staining of C3 along the glomerular capillary loops in PSGN (400 × magnification); (e) Electron microscopy demonstrating characteristic subepithelial deposit/hump (white star) and several smaller subendothelial deposits (arrows) in PSGN.