NDT Advance Access originally published online on November 25, 2005
Nephrology Dialysis Transplantation 2006 21(5):1448-1449; doi:10.1093/ndt/gfi292
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Polyclonal activation of an IgA subclass against Staphylococcus aureus cell membrane antigen in post-methicillin-resistant S.aureus infection glomerulonephritis
Email: kidney{at}md.tsukuba.ac.jpSir,
We have previously reported cases of glomerulonephritis (GN) following methicillin-resistant Staphylococcus aureus (MRSA) infection (post-MRSA infection GN). Renal histological findings based on immunofluorescence examination showed IgA, IgG and C3 deposits in both the mesangium and peripheral capillary walls, and laboratory findings included polyclonal increases in serum IgA and IgG, with high levels of circulating immune complexes (IC) and specific T-cell receptor (TCR) Vß+ subsets [1,2], which had many similarities with IgA nephropathy (IgAN) [3]. We hypothesized that S. aureus plays an important role in post-MRSA infection GN and IgAN, and also proposed S. aureus as one of the key pathogens of IgAN [4]. It is well known that the IgA1 isotype is predominant in the serum; however, the relationship between IgA-subclass antibodies and these pathogens has not been investigated.
In this study, we examined the titres of anti-S. aureus IgA antibody subclasses in the serum of patients with post-MRSA infection GN and IgAN, and compared the results with those in other forms of renal disease. All patients were diagnosed by renal biopsy and clinical and laboratory findings. We studied 224 patients: 25 with post-MRSA infection GN, 67 with IgAN, 116 with other types of renal disease and 16 healthy controls (with normal renal function and neither urinary nor serum abnormalities). Staphylococcus aureus crude membrane antigens were prepared for enzyme-linked immunosorbent assay (ELISA) by the absorption of protein A with human IgG-coated Sepharose 4B, as reported previously [4]. Titres of IgA subclass (IgA1 and IgA2) antibodies against S. aureus in serum from patients with post-MRSA infection GN, IgAN, other forms of renal diseases and normal individuals were measured by ELISA using mouse anti-human IgA1 (Nordic Immunological Laboratories, Tilburg, the Netherlands) or mouse anti-human IgA2 (Nordic Immunological Laboratories) as the primary antibody and horseradish peroxidase-conjugated rabbit anti-mouse IgG (Invitrogen Co. Ltd, Carlsbad, CA, USA) as the secondary antibody. Statistical analysis of the serum titres of IgA subclasses against S. aureus was performed by analysis of variance (ANOVA) with Fisher's protected least significant difference (PLSD) test. P-values of <0.05 were considered significant.
The major finding of this study is that the serum titres of both IgA1 and IgA2 isotypes against S. aureus cell membrane antigen were significantly higher in patients with post-MRSA infection GN (IgA1 titre: 1.339±0.135 O.D.; IgA2: 0.094±0.025 O.D.) in comparison with those in serum from normal individuals and from patients with other types of renal diseases, including IgAN (P<0.05). Furthermore, in patients with IgAN, only the serum titre of IgA1 against S. aureus (1.023±0.062 O.D.) was significantly higher than that in patients with other renal diseases and in healthy controls (P<0.05) (Figures 1A and 1B).
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Staphylococcus aureus cell membrane antigen itself has high immunogenic activity and the host response against this antigen is much influenced by staphylococcal enterotoxin, as illustrated in toxic shock syndrome (TSS) toxic-1 in vitro [5]. Patients with MRSA infection frequently develop septicaemia or TSS caused by enterotoxins. These enterotoxins bind to major histocompatibility complex class-II molecules of the antigen-presenting cells and to the Vß region of the TCR, leading to massive T-cell activation and release of various kinds of cytokines, which in turn promote polyclonal B-cell activation, resulting in increases in immunoglobulin and IC formation. Hence, we suggest that it is likely that MRSA will influence polyclonal IgA subclass activation. Since we have shown polyclonal activation of serum antibodies of IgA subclasses against S. aureus in patients with post-MRSA infection GN, this may be induced by cytokine release by hosts through a reaction against MRSA enterotoxins. Although there are many similarities between post-MRSA infection GN and IgAN, this phenomenon may allow these conditions to be distinguished.
Pathophysiology of Renal Diseases Graduate School of Comprehensive Human Sciences University of Tsukuba Tsukuba City Ibaraki Japan
Acknowledgments
We would like to thank the members of the Tsukuba Renal Disease Research Group for providing us with renal biopsy samples, serum samples and clinical data. This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to A.K.) and from the Diseases Control Division of the Ministry of Health, Labour and Welfare, Japan, and by a research grant from Tsukuba University.
Conflict of interest statement. None declared.
References
- Koyama A, Kobayashi M, Yamaguchi N et al. Glomerulonephritis associated with MRSA infection: a possible role of bacterial superantigen. Kidney Int 1995; 47: 207–216[Medline]
- Yoh K, Kobayashi M, Yamaguchi N et al. Cytokines and T-cell responses in superantigen-related glomerulonephritis following methicillin-resistant Staphylococcus aureus infection. Nephrol Dial Transplant 2000; 15: 1170–1174
[Abstract/Free Full Text] - Muro K, Yamagata K, Kobayashi M, Hirayama K, Koyama A. The usage of T cell receptor variable segment of the ß chain in IgA nephropathy. Nephron 2002; 92: 56–63[Medline]
- Koyama A, Sharmin S, Sakurai H et al. Staphylococcus aureus cell envelope antigen is a new candidate for the induction of IgA nephropathy. Kidney Int 2004; 66: 121–132[Medline]
- Shimuzu Y, Sakurai H, Hirayama K et al. Staphylococcal cell membrane antigen, a possible antigen in post-methicillin resistant Staphylococcus aureus (MRSA) infection nephritis and IgA nephropathy, exhibits high immunogenic activity that is enhanced by superantigen. J Nephrol 2005; 18: 249–256[Medline]
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