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

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.

1. Бурова Л.А., Гаврилова Е.А., Пигаревский П.В., Селиверстова В.Г., Нагорнев В.А., Шален К., Тотолян Артем А. Способность стрептококков группы А типа М12 связывать иммунные комплексы и их роль в патогенезе постстрептококкового гломерулонефрита // Мед. иммунол. – 2006. – Т. 8. – № 5-6. – С. 623-630.

2. Тотолян Артем А., Бурова Л.А. Критический анализ предполагаемых механизмов патогенеза постстрептококкового гломерулонефрита // Клин. микроб. химиотерапия. – 2001. – Т. 3. – № 4. – С. 316-323.

3. Тотолян Артем А., Бурова Л.А., Нагорнев В.А., Пигаревский П.В., Шален К. Сердечнососудистые поражения при инфекционных заболеваниях // Вестник РАМН. – 2003. – 12. – С. 56-61.

4. Тотолян А.А., Бурова Л.А., Нагорнев В.А., Пигаревский П.В. Анализ механизмов иммунопатологического пострептококкового гломерулонефрита (AGN) // Тер. Архив. – 2008. – № 6. – С. 90-95.

5. Угрюмов М.В. Современные методы иммуноцитохимии и гистохимии // Итоги науки и техники. Серия «Морфология человека и животных». – М.: Наука. – 1991. – Т. 15. – 117 с.

6. Batsford S.R., Mezzano S., Mihatsch M., Schiltz E., Rodriguez-Iturbe B. Is the nephritogenic antigen in post-streptococcal glomerulonephritis pyrogenic exotoxin b (spe b) or gapdh? // Kidney Int. – 2005. – 68. – P. 1120-1129.

7. Beres S.B., Sesso R., Pinto S.W., Hoe N.P., Porcella S.F., Deleo F.R., Musser J.M. Genome sequence of a Lancefield group C Streptococcus zooepidemicus strain causing epidemic nephritis: New information about an old disease // PLoS One. – 2008. – 3: e3026.

8. Burova L.A., Christensen P., Grubb R., Schalen C., Svensson M.L., Beltukov P.P., Totolian A.A. Anti-immunoglobulins in experimental streptococcal immunization; relation to bacterial growth conditions and fc-receptors // Acta Pathol. Microbiol. Immunol. Scand. C. – 1985. – 93. – P. 19-23.

9. Burova L.A., Schalen C., Koroleva I.V., Svensson M.L. Role of group A streptococcal IgG Fcreceptor in induction of anti-IgG by immunization in the rabbit // FEMS Microbiol. Immunol. – 1989. – 1. – P. 443-448.

10. Burova L.A., Koroleva I.V., Ogurtzov R.P., Murashov S.V., Svensson M.L., Schalen C. Role of streptococcal IgG Fc-receptor in tissue deposition of IgG in rabbits immunized with Streptococcus pyogenes // APMIS. – 1992. – 100. – P. 567-574.

11. Burova L.A., Nagornev V.A., Pigarevsky P.V., Gladilina M.M., Seliverstova V.G., Schalen C., Totolian A.A. Triggering of renal tissue damage in the rabbit by IgG Fc-receptor-positive group A streptococci // APMIS. – 1998. – 106. – P. 277-287.

12. Burova L., Thern A., Pigarevsky P., Gladilina M., Seliverstova V., Gavrilova E., Nagornev V., Schalen C., Totolian A. Role of group A streptococcal IgG-binding proteins in triggering experimental glomerulonephritis in the rabbit // APMIS. – 2003. – 111. – P. 955-962.

13. Burova L., Pigarevsky P., Seliverstova V., Gupalova T., Schalen C., Totolian A.. Experimental poststreptococcal glomerulonephritis Elicited by IgG Fc-binding M family proteins and blocked by IgG Fc-fragment // APMIS. – 2012. – 120. – 3. – P. 221-230.

14. Carlsson F., Berggard K., Stalhammar-Carlemalm M., Lindahl G. Evasion of phagocytosis through cooperation between two ligand-binding regions in Streptococcus pyogenes M protein // J. Exp. Med. – 2003. – 198. – P. 1057-1068.

15. Cu G.A., Mezzano S., Bannan J.D., Zabriskie J.B. Immunohistochemical and serological evidence for the role of streptococcal proteinase in acute post-streptococcal glomerulonephritis // Kidney Int. – 1998. – 54. – P. 819-826.

16. Cunningham M.W. Pathogenesis of group A streptococcal infections // Clin. Microbiol. Rev. – 2000. – 13. – P. 470-511.

17. Eison T.M., Ault B.H., Jones D.P., Chesney R.W., Wyatt R.J. Post-streptococcal acute glomerulonephritis in children: Clinical features and pathogenesis // Pediatr. Nephrol. – 2011. – 26. – P. 165-180.

18. Fischetti V.A. Streptococcal M protein: Molecular design and biological behavior // Clin. Microbiol. Rev. – 1989. – 2. – P. 285-314.

19. Frick I.M., Akesson P., Cooney J., Sjobring U., Schmidt K.H., Gomi H., Hattori S., Tagawa C., Kishimoto F., Bjorck L. Protein H--a surface protein of Streptococcus pyogenes with separate binding sites for IgG and albumin // Mol. Microbiol. – 1994. – 12. – P. 143-151.

20. Haanes E.J., Heath D.G., Cleary P.P. Architecture of the vir regulons of group A streptococci parallels opacity factor phenotype and M protein class // J. bacterial. – 1992. – 174. – P. 4967-4976.

21. Herwald H., Cramer H., Morgelin M., Russell W., Sollenberg U., Norrby-Teglund A., Flodgaard H., Lindbom L., Bjorck L. M protein, a classical bacterial virulence determinant, forms complexes with fibrinogen that induce vascular leakage // Cell 2004; 116: 367-379.

22. Kraus W., Beachey E.H. Renal autoimmune epitope of group A streptococci specified by M protein tetrapeptide: Ile-Arg-Leu-Arg // Proc. Natl. Acad. Sci USA. – 1988. – 85. – P. 4516-4520.

23. Kronvall G. A surface component in group A, C, and G streptococci with non-immune reactivity for immunoglobulin g // J. Immunol. 1973; 111: 1401-1406.

24. Luo Y.H., Kuo C.F., Huang K.J., Wu J.J., Lei H.Y., Lin M.T., Chuang W.J., Liu C.C., Lin C.F., Lin Y.S. Streptococcal pyrogenic exotoxin B antibodies in a mouse model of glomerulonephritis // Kidney Int. 2007; 72: 716-724.

25. Martin D.R. Rheumatogenic and nephritogenic group A streptococci. Myth or reality? An opening lecture // Adv. Exp. Med. Biol. 1997; 418: 21-27.

26. Masuda M., Nakanishi K., Yoshizawa N., Iijima K., Yoshikawa N. Group A streptococcal antigen in the glomeruli of children with henoch-schonlein nephritis // Am. J. Kidney Dis. 2003; 41: 366-370.

27. Mezzano S., Olavarria F., Ardiles L., Lopez M.I. Incidence of circulating immune complexes in patients with acute poststreptococcal glomerulonephritis and in patients with streptococcal impetigo // Clin. Nephrol. 1986; 26: 61-65.

28. Nordstrand A., Norgren M., Ferretti J.J., Holm S.E. Streptokinase as a mediator of acute poststreptococcal glomerulonephritis in an experimental mouse model // Infect. Immun. 1998; 66: 315-321.

29. Nordstrand A., Norgren M., Holm S.E. Pathogenic mechanism of acute post-streptococcal glomerulonephritis // Scand. J. Infect. Dis. 1999; 31:523-537.

30. Ringdahl U., Svensson M., Wistedt A.C., Renne T., Kellner R., Muller-Esterl W., Sjobring U. Molecular coperation between protein pam and streptokinase for plasmin acquisition by Streptococcus pyogenes // J. Biol. Chem. 1998; 273: 6424-6430.

31. Rodriguez-Iturbe B., Carr R.I., Garcia R., Rabideau D., Rubio L., McIntosh R.M. Circulating immune complexes and serum immunoglobulins in acute poststreptococcal glomerulonephritis // Clin. Nephrol. 1980; 13: 1-4.

32. Rodriguez-Iturbe B. Nephritis-associated streptococcal antigens: Where are we now? // J. Am. Soc. Nephrol. 2004; 15: 1961-1962.

33. Rodriguez-Iturbe B., Batsford S. Pathogenesis of poststreptococcal glomerulonephritis a century after clemens von pirquet // Kidney Int. 2007; 71: 1094-1104.

34. Rodriguez-Iturbe B., Musser J.M. The current state of poststreptococcal glomerulonephritis // J. Am. Soc. Nephrol. 2008; 19: 1855-1864.

35. Schalen C., Kurl D., Christensen P. Independent binding of native and aggregated IgG in group A streptococci // Acta Pathol. Microbiol. Immunol. Scand. B. 1986; 94: 333-338.

36. Schroder A.K., Nardella F.A., Mannik M., Johansson P.J., Christensen P. Identification of the site on igg fc for interaction with streptococci of groups A, C and G // Immunology 1987; 62: 523-527.

37. Sesso R.C., Ramos O.L., Pereira A.B. Detection of IgG-rheumatoid factor in sera of patients with acute poststreptococcal glomerulonephritis and its relationship with circulating immunecomplexes // Clin. Nephrol. 1986; 26: 55-60.

38. Sjoholm A.G. Complement components and complement activation in acute poststreptococcal glomerulonephritis // Int. Arch. Allergy Appl. Immunol. 1979; 58: 274-284.

39. Stollerman G.H. Rheumatogenic and nephritogenic streptococci // Circulation 1971; 43:915-921.

40. Tewodros W., Nordstrand A., Kronvall G., Holm S.E., Norgren M. Streptokinase gene polymorphism in group a streptococci isolated from ethiopian children with various disease manifestations // Microb. Pathog. 1993; 15: 303-311.

41. Thern A., Wastfelt M., Lindahl G. Expression of two different antiphagocytic m proteins by Streptococcus pyogenes of the OF+ lineage // J. Immunol. 1998; 160:860-869.

42. Voltchek N., Gupalova T., Totolian A. Protein G expressed by human group C and G streptococci: Cloning of gene and binding properties // Folia Microbiol. (Praha) 1999; 44: 735-736.

43. Wyatt R.J., Forristal J., West C.D., Sugimoto S., Curd J.G. Complement profiles in acute poststreptococcal glomerulonephritis // Pediatr. Nephrol. 1988; 2: 219-223.

44. Yoshizawa N., Treser G., McClung J.A., Sagel I., Takahashi K. Circulating immune complexes in patients with uncomplicated group A streptococcal pharyngitis and patients with acute poststreptococcal glomerulonephritis // Am. J. Nephrol. 1983; 3: 23-29.

45. Yoshizawa N., Yamakami K., Fujino M., Oda T., Tamura K., Matsumoto K., Sugisaki T., Boyle M.D. Nephritis-associated plasmin receptor and acute poststreptococcal glomerulonephritis: Characterization of the antigen and associated immune response // J. Am. Soc. Nephrol. 2004; 15: 1785-1793.