Impact of IgG Fc-fragments on experimental glomerulonephritis induced by Streptococcus pyogenes strain binding various immunoglobulin classes

Cover Page


Cite item

Full Text

Abstract

The pathogenesis of poststreptococcal glomerulonephritis (PSGN), a major complication of acute infections caused by group A streptococci (GAS) remains unclear. Several theories, based on the role of certain streptococcal virulence factors, as well as immunological mimicry between GAS and renal tissue, have been proposed. Earlier, we reported that many virulent clinical GAS isolates showing confirmed nephritogenic activity were capable of nonimmune Fc binding of monomeric or aggregated IgG. Moreover, a rabbit model of PSGN allowed to obtain findings regarding a crucial role of streptococcal IgG Fc binding proteins belonging to the M family surface proteins, in the onset of PSGN. Rabbits injected with inactivated IgGFcBP-positive streptococci, acquired changes in the renal tissue with deposited IgG and complement C3, as well as signs of immune inflammation characteristic for human PSGN. Also, it was shown that the induction of experimental glomerulonephritis could be inhibited after normal IgG or its purified Fc fragments were inoculated at early stages of the process. The data obtained in rabbits injected with group A streptococcal type M60 also showed pathogenic functions of the IgA Fc-binding proteins of GAS. The aim of the study was to examine inhibiting activity of the purified rabbit IgG Fc fragments on the manifestations of glomerulonephritis induced by S. pyogenes strains capable of binding diverse forms of immunoglobulins such native IgG, immune complexes, and IgA.

Materials and methods. GAS strains of emml, emml2 and emm60 genotypes were used to induce PSGN or IgA-nephropa-thy in rabbits. Fc fragments derived from rabbit IgG were obtained by enzymatic digestion and purified by affinity chromatography on a protein G-sepharose FF column. Immunomorphological changes of renal tissue were estimated by morphometric analysis.

Results. In the present study, using the rabbit model, we revealed pathological changes of different intensity and localization in the renal tissue. For streptococci of the emm1 and emm12 genotypes, PSGN was characterized by deposition of IgG or IgG-anti-IgG immune complexes within the basal glomerular membrane. Morphological changes were evaluated as a membranous-proliferative glomerulonephritis. Meanwhile, IgA-glomerulonephritis is characterized by deposition of IgA in mesangial cells of glomeruli, leading to the mesangial-proliferative glomerulonephritis or IgA-nephropathy. Intravenously administered purified Fc fragments derived from normal rabbit IgG varied in effects on pathological processes: (i) IgG Fc fragments of fully inhibited development of the PSGN induced by IgG Fc binding strain of emml genotype, (ii) IgG Fc fragments of partially reverted changes caused by the emm12 genotype strain, which was binding only to immune complexes, and (iii) had no effects on pathological changes caused by the emm60 genotype GAS strain, which was binding only IgA.

Conclusion. The data obtained point and emergence of differences in mechanisms of renal lesions development at glomerulonephritis, depending on the emm genotype of GAS strain. In addition, it also confirmed GAS-derived involvement for various IgFc-receptor proteins in the pathology. Further studies on potential prophylactic or curative effects of IgG Fc fragments in PSGN should therefore be of interest. The findings might suggest a new therapeutic approach for non-suppurative poststreptococcal diseases.

About the authors

L. A. Burova

Institute of Experimental Medicine

Email: lburova@yandex.ru

PhD, MD (Medicine), Leading Researcher, Department of Molecular Microbiology.

St. Petersburg

Russian Federation

P. V. Pigarevsky

Institute of Experimental Medicine

Email: pigarevsky@mail.ru

PhD, MD (Biology), Head of the Department of General Morphology.

St. Petersburg

Russian Federation

V. A. Snegova

Institute of Experimental Medicine

Email: biolaber@inbox.ru

Researcher, Department of General Morphology.

St. Petersburg

Russian Federation

A. A. Totolian

Institute of Experimental Medicine

Author for correspondence.
Email: totolyan@hotmail.com

Totolian Artem A. - PhD, MD (Medicine), RAS Full Member, Head Researcher, Department of Molecular Microbiology.

St. Petersburg

Russian Federation

References

  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 // Медицинская иммунология. 2006. Т. 8, № 5—6. С. 623—630.
  2. БуроваЛ.А., Пигаревский П.В., Снегова В.А., Кулешевич Е.В.,Жарков Д.А., Шален К., Тотолян Артем А. Нефритогенная активность Streptococcus pyogenes генотипов emm1 и emm12, различающихся по источнику выделения // Инфекция и иммунитет. 2015. Т. 5, № 3. С. 233-242.
  3. Бурова Л.А., Пигаревский П.В., Снегова В.А., Дуплик Н.В., Шален К., Тотолян Артем А. Нефритогенность IgA-связывающих Streptococcus pyogenes. Моделирование IgA гломерулонефрита // Медицинская иммунология. 2016. Т. 18, № 3. С. 221-230.
  4. Тотолян Артем А., Бурова Л.А. Fc-рецепторные белки Streptococcus pyogenes и патогенез постинфекционных осложнений // Журнал микробиологии, эпидемиологии и иммунобиологии. 2014. № 3. С. 78-90
  5. Allhorn M., Collin M. Sugar-free antibodies — the bacterial solution to autoimmunity. Ann. NY Acad. Sci., 2009, vol. 1173, pp. 664-669. doi: 10.1111/j.1749-6632.2009.04739.x
  6. Akilesh Sh., Huber T.B., Wu H., Wang G., Hartleben B., Kopp J.B., Miner J.J.H., Roopenian D.C., Unanue E.R., Shaw A.S. Podocytes use fcR to clear IgG from the glomerular basement membrane. PNAS, 2008, vol. 105, no. 3, pp. 967-972. doi: 10.1073/pnas.0711515105
  7. Anthony R.M., Wermeling F., Ravetch J.V. Novel roles for IgG Fc glycan. Ann. NY Acad. Sci, 2012, vol. 1253, pp. 170-180. doi: 10.1111/j.1749-6632.2011.06305.x170
  8. Barabas A.Z., Cole C.D., Lafreniere R., Weir D.M. Immunopathological events initiated and maintained by pathogenic IgG autoantibodies in an experimental autoimmune kidney disease. Autoimmunity, 2012, vol. 45, no. 7, pp. 495-509. doi: 10.3.109/089.934.2012.70281216
  9. Burova L.A., Nagornev V.A., Pigarevsky P.V., Gladilina M.M., Seliverstova V.G., Schalen C. Triggering of renal damage in the rabbit by IgGFc-receptor-positive group A streptococci. APMIS, 1998, vol. 106, pp. 277-287.
  10. Burova L., Pigarevsky P., Duplik N., Snegova V., Suvorov A., Schalen C., Totolian A. Immune complex binding Streptococcus pyogenes type M12/emm12 in experimental glomerulonephritis. J. Med. Microbiol., 2013, vol. 62, pt 9, pp. 1272-1280. doi: 10.1099/jmm.0.059196-0
  11. Collan Y. Morphometry in pathology: another look at diagnostic histopathology. Pathol. Res. Pract., 1984, no. 1, pp. 189-192.
  12. Collin M., Shannon O., Bjorck L. IgG glycan hydrolysis by a bacterial enzyme as a therapy against autoimmune conditions. Natl Acad. Sci. USA, 2008, vol. 105, no. 11, pp. 4265-4270. doi: 10.1073/pnas.0711271105
  13. Danilova T.A. Fc receptors of endothelial cells of cardiac valves: comparison of IgG Fc binding activity of these receptors and of Fc receptors of group A streptococci. Zh. Mikrobiol. Epidemiol. Immunobiol., 2003, no. 2, pp. 46-51.
  14. Gomez-Guerrero C., Duque N., Casado M.T., Pastor C., Blanco J., Mampaso F., Vivanco F., Egido J. Administration of IgG Fc-fragments prevents glomerular injury in experimental immune complex nephritis. J. Immunol., 2000, vol., 164, pp. 2092-2101. doi: 10.4049/jimmunol.164/4.2092
  15. Hayes J.M., Frostell H.A., Cosgrave E., Strume W., Potter O., Davey G., Karisson R., Anneren C., Rudd P. Fc gamma receptor glycosylation modulates the binding of IgG glycoforms: a requirement for stable antibody interactions. J. Proteome Res., 2014, vol. 13, no. 12, pp. 5471-5485. doi: 10.1021/pr500414q
  16. Hayes J.M., Cosgrave E.F., Struwe W.B., Wormald M., Davey G.P., Jefferis R., Rudd P.M. Glycosylation and Fc receptors. Cur. Top. Microbiol. Immunol, 2014, vol. 382, pp. 165-199. doi: 10.1007/978-3-319-07911-08
  17. Haymann J.P., Delarue F., Baud L., Sraer J.D. Aggregated IgG bind to glomerular epithelial cells to stimulate urokinase release through an endocytosis independent process. Nephron Exp. Nephrol, 2004, vol. 98, no. 1, pp. 13-21. doi: 10.1159/000079928
  18. Homma H., Tozawa K., Yasui T., ItohY, Hayashi Y., Kohri K. Abnormal glycosylation of serum IgG in patients with IgA nephropathy. Clin. Exp. Nephrol., 2006, vol. 10, no. 3,pp. 180-185. doi: 10.1007/s10157-006-0422-y
  19. Monteiro R.C., Leroy V., Launay P., Moura I.C., Arcos-Fajardo M., Benhamou M., Haddad E. Pathogenesis of Berger’s disease: recent advances on the involvement of immunoglobulin A and their receptors. Med. Sci. (Paris), 2003, vol. 19, no. 12, pp. 12331241. doi: 10.1051/medsci/200319121233
  20. Monteiro R.C., Moura I.C., Launay P., Tsuge T., Haddad E., Benhamou M., Cooper M.D., Arcos-Fajardo M. Pathogenic significance of IgA receptor interactions in IgA nephropathy. Trends Mol. Med., 2002, vol. 8, no. 10, pp. 464- 468.
  21. Nordenfelt P., Waldemarson S., Linder A., Morgelin M., Karlsson C., Malmstrom J., Bjorck L. Antibody orientation at bacterial surfaces is related to invasive infection. Exp. Med., 2012, vol. 209, no. 13, pp. 2367-2381. doi: 10.1084/jem.20120325
  22. Okazaki K., Suzuki Y., Otsuji M., Suzuki H., Kihara M., Kajiyama T., Hashimoto A., Nishimura H., Brown R., Hall S., Novak J., Izui S., Hirose S., Tomino Y. Development of a model of early-onset IgA nephropathy. J. Am. Soc. Nephrol., 2012, vol. 23, no. 8, pp. 1364-1374. doi: 10.1681/ASN.2011121160
  23. Qu Z., Cui Z., Liu G., Zhao M.H. The distribution of IgG subclass deposition on renal tissues from patients with anti-glomerular basement membrane disease. BMC Immunol., 2013, vol. 14, pp. 19-26. doi: 10.1186/1471-2172-14-19
  24. Schmitt R., StAhl A.L., Olin A.I., Kristoffersson A.C., Rebetz J., Novak J., Lindahl G., Karpman D. 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. J. Immunol., 2014, vol. 93, no. 1, pp. 317-326. doi: 10.4049/jimmunol.1302249.
  25. Siberil S., Dutertre C.A., Boix C., Bonnin E., Menez R., Stura E., Jorieux S., Fridman W.H., Teillaud J.L.. Molecular aspects of human Fc gamma R interactions with IgG: functional and therapeutic consequences. Immunol Lett., 2006, vol. 106, no. 2, pp. 111-118. doi: 10.1016/j.imlet.2006.05.009
  26. Soderberg J.J., Pawel-Rammingen U. The streptococcal protease IdeS modulates bacterial IgGFc binding and generates 1/2Fc fragments with the ability to prime polymorphonuclear leucocytes. Mol. Immunol., 2008, vol. 45, no. 12, pp. 3347-3353. doi: 10.1016/j.molimm. 2008.04.013
  27. Su Y.F., Chuang W.J., Wang S.M., Chen W.Y., Chiang-Ni C., Lin Y.S., Wu J.J., Liu C.C. The deficient cleavage of M protein-bound IgG by IdeS: insight into the escape of Streptococcus pyogenes from antibody-mediated immunity. Mol. Immunol., 2011, vol. 49, no. 1-2, pp. 134-142. doi: 10.1016/j.molimm.2011.08.002
  28. Van Timmeren M.M., van der Veen B.S., Stegeman C.A., Petersen A.H., Hellmark T., Collin M., Heeringa P. IgG glycan hydrolysis attenuates ANCA-mediated glomerulonephritis. J. Am. Soc. Nephrol., 2010, vol. 21, no. 7, pp. 1103—1114. doi: 10.1681/ ASN.2009090984
  29. Xue J., Zhu L.P., Wei Q. IgG-Fc N-glycosylation at Asn297 and IgA O-glycosylation in the hinge region in health and disease. Glycoconj. J, 2013, vol. 30, no. 8,pp. 735-745. doi: 10.1007/s10719-013-9481-y
  30. Yang R., Otten M.A., Hellmark T., Collin M., Bjorck L., Zhao M.H., Daha M.R., Segelmark M. Successful treatment of experimental glomerulonephritis with IdeS and EndoS, IgG-degrading streptococcal enzymes. Nephrol. Dial. Transplant., 2010, vol. 25, no. 8, pp. 2479-2786. doi: 10.1093/ndt/gfq115

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2020 Burova L.A., Pigarevsky P.V., Snegova V.A., Totolian A.A.

Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 64788 от 02.02.2016.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies