Tissue Deposits of IgA-Binding Streptococcal M Proteins in IgA Nephropathy and Henoch-Schönlein Purpura

Abstract

IgA nephropathy (IgAN) and Henoch-Schönlein purpura (HSP) are diseases characterized by IgA deposits in the kidney and/or skin. Both may arise after upper respiratory tract infections, but the pathogenic mechanisms governing these diseases remain unclear. Patients with IgAN (n = 16) and HSP (n = 17) were included in this study aimed at examining whether IgA-binding M proteins of group A streptococci could be involved. As M proteins vary in sequence, the study focused on the IgA-binding-region (IgA-BR) of three different M proteins: M4, M22, and M60. Renal tissue from IgAN and HSP patients and skin from HSP patients were examined for deposits of streptococcal IgA-BR by immunohistochemistry and electron microscopy using specific antibodies, and a skin sample from a HSP patient was examined by mass spectrometry. IgA-BR deposits were detected in 10/16 IgAN kidneys and 7/13 HSP kidneys. Electron microscopy demonstrated deposits of IgA-BRs in the mesangial matrix and glomerular basement membrane, which colocalized with IgA. Skin samples exhibited IgA-BR deposits in 4/5 biopsies, a result confirmed by mass spectrometry in one patient. IgA-BR deposits were not detected in normal kidney and skin samples. Taken together, these results demonstrate IgA-BR from streptococcal M proteins in patient tissues. IgA-BR, would on gaining access to the circulation, encounter circulatory IgA and form a complex with IgA-Fc that could deposit in tissues and contribute to the pathogenesis of IgAN and HSP.

Comparative Analyses of Subgingival Microbiome in Chronic Periodontitis Patients with and Without IgA Nephropathy by High Throughput 16S rRNA Sequencing

“…and IgAN was hypothesized. Besides, streptococcal proteins were recognized by sera of IgAN patients [48,49]. In the present study, Streptococcus was also upregulated in Disease, implying that Streptococcus spp.…”

The Combined Role of Galactose-Deficient IgA1 and Streptococcal IgA–Binding M Protein in Inducing IL-6 and C3 Secretion from Human Mesangial Cells: Implications for IgA Nephropathy

“…Synthetic peptides corresponding to various regions of the M protein were also used. These peptides have been fully characterized and included the N-terminal hypervariable region of the M4 protein (M4N), the IgA-binding region of M4 (Sap4) and part of the C-repeat domain in the conserved region of the M22 protein (16, 34-36). The latter peptide has a 92.3% amino acid homology with the C-repeat domain of the conserved region of M4 (Figure 1B).…”

“…We have previously shown that children with IgAN are more likely than controls to have been infected with GAS expressing an IgA-binding M protein (22). Furthermore, we detected M protein-derived IgA-binding regions co-localizing with IgA in kidney samples of children with IgAN (16). These findings suggest a possible role of GAS strains expressing IgA-binding M proteins in the etiology and pathogenesis of IgAN.…”

Complement activation associated with ADAMTS13 deficiency in human and murine thrombotic microangiopathy

“…Immunohistochemistry was performed to detect C5b-9 in human renal tissues according to a described method (25) with some modifications. Briefly, after peroxidase blocking, antigen retrieval was achieved by incubating the tissues with 0.1% protease type X1V (Sigma) for 20 min at 37 °C followed by blocking with 5% BSA in tris-buffered saline (TBS, Medicago) for 2 hr at room temperature.…”