Skip to main content

Advertisement

SpringerLink
Log in

The influences of α-hemolytic Streptococcus on class switching and complement activation of human tonsillar cells in IgA nephropathy

  • Original Article
  • Published:
Immunologic Research Aims and scope Submit manuscript

Abstract

While β-hemolytic streptococcus (β-HS) infections are known to predispose patients to acute poststreptococcal glomerulonephritis, there is evidence that implicates α-hemolytic streptococcus (α-HS) in IgA nephropathy (IgAN). The alternative pathway of the complement system has also been implicated in IgAN. We aimed to explore the association between α-HS and complement activation in human tonsillar mononuclear cells (TMCs) in IgAN. In our study, α-HS induced higher IgA levels than IgG levels, while β-HS increased higher IgG levels than IgA levels with more activation-induced cytidine deaminase, in TMCs in the IgAN group. Aberrant IgA1 O-glycosylation levels were higher in IgAN patients with α-HS. C3 and C3b expression was decreased in IgAN patients, but in chronic tonsillitis control patients, the expression decreased only after stimulation with β-HS. Complement factor B and H (CFH) mRNA increased, but the CFH concentration in culture supernatants decreased with α-HS. The percentage of CD19 + CD35 + cells/complement receptor 1 (CR1) decreased with α-HS more than with β-HS, while CD19 + CD21 + cells/complement receptor 2 (CR2) increased more with β-HS than with α-HS. The component nephritis-associated plasmin receptor (NAPlr) of α-HS was not detected on tonsillar or kidney tissues in IgAN patients and was positive on cultured TMCs and mesangial cells. We concluded that α-HS induced the secretion of aberrantly O-glycosylated IgA while decreasing the levels of the inhibitory factor CFH in culture supernatants and CR1 + B cells. These findings provide testable mechanisms that relate α-HS infection to abnormal mucosal responses involving the alternative complement pathway in IgAN.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Abbreviations

TMCs:

Tonsillar mononuclear cells

α-HS:

α-Hemolytic streptococcus

β-HS:

β-Hemolytic streptococcus

IgAN:

IgA nephropathy

CT:

Chronic tonsillitis

AID:

Activation-induced cytidine deaminase

CFH:

Complement factor H

CR1:

Complement receptor 1

CR2:

Complement receptor 2

NAPlr:

Nephritis-associated plasmin receptor

APSGN:

Acute poststreptococcal glomerulonephritis

GAPDH:

Glyceraldehyde-3-phosphate dehydrogenase

SEM:

Standard error of the mean

References

  1. Maillard N, et al. Current understanding of the role of complement in IgA nephropathy. J Am Soc Nephrol. 2015;26(7):1503–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Wu J, et al. Severe glomerular C3 deposition indicated severe renal lesions and poor prognosis in patients with immunoglobulin A nephropathy. Histopathology. 2021;78(6):882–95.

  3. Ghosh S, et al. Enumerating the role of properdin in the pathogenesis of IgA nephropathy and its possible therapies. Int Immunopharmacol. 2021;93:107429.

    Article  CAS  PubMed  Google Scholar 

  4. Onda K, et al. Excretion of complement proteins and its activation marker C5b–9 in IgA nephropathy in relation to renal function. BMC Nephrol. 2011;12:64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wyatt RJ. The complement system in IgA nephropathy and Henoch-Schönlein purpura: functional and genetic aspects. Contribut Nephrol. 1993;104:82–91.

    Article  CAS  Google Scholar 

  6. Akagi H, et al. Long-term results of tonsillectomy as a treatment for IgA nephropathy. Acta Otolaryngol Suppl. 2004;555:38–42.

    Article  Google Scholar 

  7. Chen X, et al. Expression and correlation analysis of IL-4, IFN-γ and FcαRI in tonsillar mononuclear cells in patients with IgA nephropathy. Cellul Immunol. 2014;289:70–5.

    Article  CAS  Google Scholar 

  8. Huang H, et al. Decreased CD4+CD25+ cells and increased dimeric IgA-producing cells in tonsils in IgA nephropathy. J Nephrol. 2010;23(2):202–9.

    CAS  PubMed  Google Scholar 

  9. Plum AW, Mortelliti AJ, Walsh RE. Microbial flora and antibiotic resistance in peritonsillar abscesses in upstate New York. Ann Otol Rhinol Laryngol. 2015;124(11):875–80.

    Article  PubMed  Google Scholar 

  10. Shishegar M, Ashraf MJ. Posttonsillectomy bacteremia and comparison of tonsillar surface and deep culture. Adv Prev Med. 2014;2014:161878.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Brown SP, Cornforth DM, Mideo N. Evolution of virulence in opportunistic pathogens: generalism, plasticity, and control. Trends Microbiol. 2012;20(7):336–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Liu H, et al. Expression of IgA class switching gene in tonsillar mononuclear cells in patients with IgA nephropathy. Inflamm Res. 2011;60(9):869–78.

    Article  CAS  PubMed  Google Scholar 

  13. Nasr SH, Radhakrishnan J, Dagati VD. Bacterial infection-related glomerulonephritis in adults. Kidney Int. 2013;83(5):792–803.

    Article  CAS  PubMed  Google Scholar 

  14. Yoshizawa N, et al. Nephritis-associated plasmin receptor and acute poststreptococcal glomerulonephritis: characterization of the antigen and associated immune response. J Am Soc Nephrol. 2004;15(7):1785–93.

    Article  CAS  PubMed  Google Scholar 

  15. Mandache E, Penescu MN. The association of polymorphonuclears with humps in acute postinfectious glomerulonephritis. Rom J Morphol Embryol. 2012;53(3):629–33.

    CAS  PubMed  Google Scholar 

  16. Odaka J, et al. A case of post-pneumococcal acute glomerulonephritis with glomerular depositions of nephritis-associated plasmin receptor. CEN Case Rep. 2015;4(1):112–6.

    Article  PubMed  Google Scholar 

  17. Athanasiou Y, et al. Familial C3 glomerulopathy associated with CFHR5 mutations: clinical characteristics of 91 patients in 16 pedigrees. Clin J Am Soc Nephrol. 2011;6(6):1436–46.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen Y, et al. Long-term efficacy of tonsillectomy in Chinese patients with IgA nephropathy. Am J Nephrol. 2007;27(2):170–5.

    Article  PubMed  Google Scholar 

  19. Ye M, et al. Vibration induces BAFF overexpression and aberrant O-glycosylation of IgA1 in cultured human tonsillar mononuclear cells in IgA nephropathy. BioMed Res Int. 2016;2016:9125960.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Frasca D, et al. Aging down-regulates the transcription factor E2A, activation-induced cytidine deaminase, and Ig class switch in human B cells. J Immunol. 2008;180(8):5283–90.

    Article  CAS  PubMed  Google Scholar 

  21. Seidl T, et al. B-cell agonists up-regulate AID and APOBEC3G deaminases, which induce IgA and IgG class antibodies and anti-viral function. Immunology. 2012;135(3):207–15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Meng H, et al. IgA production and tonsillar focal infection in IgA nephropathy. J Clin Exp Hematop. 2012;52(3):161–70.

    Article  PubMed  Google Scholar 

  23. Shen PC, He LQ. Effect of “Gubentongluo Formula” on the IgA class switch recombination of B lymohocytes in Peyer’s patches in mice with IgA nephropathy. Sichuan da Xue Xue Bao Yi Xue Ban. 2016;47(3):337–41.

    PubMed  Google Scholar 

  24. Yang L, et al. MicroRNA-155-induced T lymphocyte subgroup drifting in IgA nephropathy. Int Urol Nephrol. 2017;49(2):353–61.

    Article  CAS  PubMed  Google Scholar 

  25. Zhang Z, et al. Serum levels of soluble ST2 and IL-10 are associated with disease severity in patients with IgA nephropathy. J Immunol Res. 2016;2016:6540937.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Ricklin D, et al. Complement: a key system for immune surveillance and homeostasis. Nat Immunol. 2010;11(9):785–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kemper C, Pangburn MK, Fishelson Z. Complement nomenclature 2014. Mol Immunol. 2014;61(2):56–8.

    Article  CAS  PubMed  Google Scholar 

  28. Gorgi Y, et al. Role of genetic polymorphisms in factor H and MBL genes in Tunisian patients with immunoglobulin A nephropathy. Int J Nephrol Renovasc dis. 2010;3:27–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Delanghe JR, Speeckaert R, Speeckaert MM. Complement C3 and its polymorphism: biological and clinical consequences. Pathology. 2014;46(1):1–10.

    Article  CAS  PubMed  Google Scholar 

  30. Tomino Y. Immunopathological predictors of prognosis in IgA nephropathy. Contrib Nephrol. 2013;181:65–74.

    Article  PubMed  Google Scholar 

  31. Schmitt R, Lindahl G, Karpman D. Antibody response to IgA-binding streptococcal M proteins in children with IgA nephropathy. Nephrol Dial Transplant. 2010;25(10):3434–6.

    Article  CAS  PubMed  Google Scholar 

  32. Fearn A, Sheerin NS. Complement activation in progressive renal disease. World J Nephrol. 2015;4(1):31–40.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Suzuki H, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011;22(10):1795–803.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Lai KN. Pathogenesis of IgA nephropathy. Nat Rev Nephrol. 2012;8(5):275–83.

    Article  CAS  PubMed  Google Scholar 

  35. Naughton MA, et al. Extrahepatic secreted complement C3 contributes to circulating C3 levels in humans. J Immunol. 1996;156(8):3051–6.

    Article  CAS  PubMed  Google Scholar 

  36. Sorman A, et al. How antibodies use complement to regulate antibody responses. Mol Immunol. 2014;61(2):79–88.

    Article  PubMed  Google Scholar 

  37. Morgan HP, et al. Structural basis for engagement by complement factor H of C3b on a self surface. Nat Struct Mol Biol. 2011;18(4):463–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Java A, et al. Role of complement receptor 1 (CR1; CD35) on epithelial cells: a model for understanding complement-mediated damage in the kidney. Molecular Immunol. 2015;67:584–95.

    Article  CAS  Google Scholar 

  39. Kiryluk K, Novak J. The genetics and immunobiology of IgA nephropathy. J Clin Investig. 2014;124(6):2325–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Gharavi AG, et al. Genome-wide association study identifies susceptibility loci for IgA nephropathy. Nat Genet. 2011;43(4):321–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Uchida T, Oda T. Glomerular deposition of nephritis-associated plasmin receptor (NAPlr) and related plasmin activity: key diagnostic biomarkers of bacterial infection-related glomerulonephritis. Int J Mol Sci. 2020;21(7):2595.

    Article  CAS  PubMed Central  Google Scholar 

  42. Fujino M, et al. Sequence and expression of NAPlr is conserved among group A streptococci isolated from patients with acute poststreptococcal glomerulonephritis (APSGN) and non-APSGN. J Nephrol. 2007;20(3):364–9.

    CAS  PubMed  Google Scholar 

  43. Kikuchi Y, et al. Streptococcal origin of a case of Henoch-Schoenlein purpura nephritis. Clin Nephrol. 2006;65(2):124–8.

    Article  CAS  PubMed  Google Scholar 

  44. Oda T, et al. Localization of nephritis-associated plasmin receptor in acute poststreptococcal glomerulonephritis. Human pathology. 2010;41(9):1276–85.

    Article  CAS  PubMed  Google Scholar 

  45. Oda T, et al. The role of nephritis-associated plasmin receptor (NAPlr) in glomerulonephritis associated with streptococcal infection. J Biomed Biotechnol. 2012;2012:417675.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by the National Natural Science Foundation of China (NSFC): 81770714, 81470947, and 81373227.

Author information

Authors and Affiliations

  1. Department of Nephrology, The Second Xiangya Hospital/Central South University, No. 139 Renmin Middle Rd, Changsha, 410011, Hunan, China

    Muyao Ye, Chang Wang, Ling Li, Qiulan Zhao, Youming Peng & Hong Liu

Authors
  1. Muyao Ye
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Chang Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ling Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Qiulan Zhao
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Youming Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HL, YP, and MY contributed to the design and conception of the study. MY, ChW, LL, and QZh performed the experiments. MY and ChW analyzed the data. MY wrote the paper. HL and YP provided financial support. All authors have read and approved the manuscript.

Corresponding author

Correspondence to Hong Liu.

Ethics declarations

Ethics approval and consent to participate

The procedures were performed in accordance with the Clinical Ethics Committee at the Second Xiangya Hospital of Central South University and with the Declaration of Helsinki. Written informed consent was obtained from all participants. Ethics approval number: 2015 S061.

Consent for publication

Not applicable.

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ye, M., Wang, C., Li, L. et al. The influences of α-hemolytic Streptococcus on class switching and complement activation of human tonsillar cells in IgA nephropathy. Immunol Res 70, 86–96 (2022). https://doi.org/10.1007/s12026-021-09223-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12026-021-09223-2

Keywords

Search

Navigation