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IL-23/IL-17 in a Paradoxical Association with Primary Membranous Nephropathy

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Abstract

Primary membranous nephropathy (PMN), an autoimmune disease, is the most common cause of nephrotic syndrome in middle-aged non-diabetic adults. PMN pathophysiology includes Th1/Th2 paradigm. The IL-23/IL-17 pathway is implicated in autoimmune kidney disorders, but no study has examined its relationship with PMN. In several unrelated studies, PMN patients reported to have paradoxical IL-17 levels. This manuscript describes the best possible association of IL-23/IL-17 axis with PMN. Biopsy-proven PMN patients and age, gender-matched healthy controls were enrolled. Serum-PLA2R (Euroimmune, Germany), IL-23 and IL-17 (R&D; USA), was measured using ELISA along with biochemical parameters. Appropriate statistical tools were used for analysis. One hundred eighty-nine PMN patients (mean age 41.70 ± 12.53 years) and 100 controls (mean age 43.92 ± 10.93 years) were identified. One hundred forty were PLA2R-related. PMN patients had median proteinuria, serum albumin, and creatinine of 6.12 (3.875, 9.23) g/day, 2.32 (1.96, 2.9) g/dl, and 0.89 (0.7, 1.1) mg/dl, respectively. IL-17, but not IL-23, was significantly increased in PMN patients compared to controls (IL-17, median: 12.07 pg/ml (9.75, 24.56) vs median: 9.75 pg/ml (8.23, 17.03) p = 0.0002); (IL23, median: 6.04 pg/ml (4.22, 10.82) vs median: 5.46 pg/ml (3.34, 9.96) p = 0.142). IL-17 and IL-23 correlated significantly (p 0.05) in PMN patients, and similar trend was seen when grouped into PLA2R-related and -unrelated groups. The levels of IL-23 (p = 0.057) and IL-17 (p = 0.004) were high in MN patients that did not respond to the treatment. The current finding may indicate or suggest the involvement of IL-23/IL-17 PMN pathogenesis. A comprehensive investigation is needed to evaluate IL-23/IL-17 axis with renal infiltrating immune cells, and external stimuli.

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Data Availability

Data will be available on reasonable request.

Abbreviations

PMN:

Primary membranous nephropathy

Th1:

T helper type 1

Th2:

T helper type 2

IL-17:

Interleukin-17

IL-23:

Interleukin-23

MN:

Membranous nephropathy

PLA2R1:

Phospholipase A2 receptor 1

ELISA:

Enzyme-linked immunosorbent assay

RU/ml:

Relative units per milliliter

IEC:

Institutional Ethics Committee

OPD:

Outpatient Department

TNF-α:

Tumor necrosis factor-alpha

CGN:

Chronic glomerulonephritis

vs:

Versus

References

  1. Alok, A., and A. Yadav. 2022. Membranous nephropathy. In StatPearls. Treasure Island (FL): StatPearls Publishing.

  2. Fogo, A.B., et al. 2015. AJKD Atlas of renal pathology: membranous nephropathy. American Journal of Kidney Diseases 66: e15-7.

    Article  PubMed  Google Scholar 

  3. Liu, W., et al. 2019. Immunological pathogenesis of membranous nephropathy: Focus on PLA2R1 and its role. Frontiers in Immunology 10: 1809.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Kuroki, A., et al. 2005. Th2 cytokines increase and stimulate B cells to produce IgG4 in idiopathic membranous nephropathy. Kidney International 68: 302–10.

    Article  CAS  PubMed  Google Scholar 

  5. Masutani, K., et al. 2004. Up-regulated interleukin-4 production by peripheral T-helper cells in idiopathic membranous nephropathy. Nephrology Dialysis Transplantation 19: 580–6.

    Article  CAS  Google Scholar 

  6. Hirayama, K., et al. 2002. Predominance of type-2 immune response in idiopathic membranous nephropathy. Cytoplasmic cytokine analysis. Nephron 91: 255–261.

    Article  CAS  Google Scholar 

  7. Li, H., et al. 2020. Myeloid-derived suppressor cells promote the progression of primary membranous nephropathy by enhancing Th17 response. Frontiers in Immunology 11: 1777.

    Article  CAS  PubMed Central  Google Scholar 

  8. Zhang, Z., et al. 2017. Higher frequencies of circulating ICOS(+), IL-21(+) T follicular helper cells and plasma cells in patients with new-onset membranous nephropathy. Autoimmunity 50: 458–467.

    Article  CAS  PubMed  Google Scholar 

  9. Dolff, S., O. Witzke, and B. Wilde. 2019. Th17 cells in renal inflammation and autoimmunity. Autoimmunity reviews 18: 129–136.

    Article  CAS  PubMed  Google Scholar 

  10. Iwakura, Y., and H. Ishigame. 2006. The IL-23/IL-17 axis in inflammation. The Journal of Clinical Investigation 116: 1218–1222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Krebs, C.F., et al. 2017. T helper type 17 cells in immune-mediated glomerular disease. Nature Reviews Nephrology 13: 647–659.

    Article  CAS  PubMed  Google Scholar 

  12. Navarro-Compan, V., et al. 2023. The paradigm of IL-23-independent production of IL-17F and IL-17A and their role in chronic inflammatory diseases. Frontiers in Immunology 14: 1191782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rosine, N., and C. Miceli-Richard. 2020. Innate cells: The alternative source of IL-17 in axial and peripheral spondyloarthritis? Frontiers in Immunology 11: 553742.

    Article  CAS  PubMed  Google Scholar 

  14. Ge, Y., M. Huang, and Y.M. Yao. 2020. Biology of interleukin-17 and its pathophysiological significance in sepsis. Frontiers in Immunology 11: 1558.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Motavalli, R., et al. 2021. Altered Th17/Treg ratio as a possible mechanism in pathogenesis of idiopathic membranous nephropathy. Cytokine 141: 155452.

    Article  CAS  PubMed  Google Scholar 

  16. Rosenzwajg, M., et al. 2017. B- and T-cell subpopulations in patients with severe idiopathic membranous nephropathy may predict an early response to rituximab. Kidney International 92: 227–237.

    Article  CAS  PubMed  Google Scholar 

  17. Tang, D., J. Guo, and J. Zhang. 2018. Variation of peripheral Th17/Treg imbalance in patients with idiopathic membranous nephropathy after cyclosporin a treatment: a prognostic marker of idiopathic membranous nephropathy. Biomedical Journal of Scientific & Technical Research 7: 6.

    Google Scholar 

  18. Ramachandran, R., et al. 2016. Tacrolimus combined with corticosteroids versus Modified Ponticelli regimen in treatment of idiopathic membranous nephropathy: Randomized control trial. Nephrology (Carlton, Vic.) 21: 139–146.

    Article  CAS  PubMed  Google Scholar 

  19. Zickert, A., et al. 2015. IL-17 and IL-23 in lupus nephritis - association to histopathology and response to treatment. BMC Immunolgy 16: 7.

    Article  Google Scholar 

  20. Krishna, A., et al. 2018. Analysis of native kidney biopsy: Data from a single center from Bihar, India. Saudi Journal of Kidney Diseases and Transplantation 29: 1174–1180.

    Article  PubMed  Google Scholar 

  21. Ramani, K., and P.S. Biswas. 2016. Emerging roles of the Th17/IL-17-axis in glomerulonephritis. Cytokine 77: 238–244.

    Article  PubMed  Google Scholar 

  22. Gately, M.K., et al. 1998. The interleukin-12/interleukin-12-receptor system: Role in normal and pathologic immune responses. Annual Review of Immunology 16: 495–521.

    Article  CAS  PubMed  Google Scholar 

  23. Cremoni, M., et al. 2020. Th17-immune response in patients with membranous nephropathy is associated with thrombosis and relapses. Frontiers in Immunology 11: 574997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Chebotareva, V.N., et al. 2020. The balance of proinflammatory cytokines and Treg cells in chronic glomerulonephritis. Terapevticheskii Arkhiv 92: 46–52.

    Article  CAS  PubMed  Google Scholar 

  25. Suranyi, M.G., et al. 1993. Elevated levels of tumor necrosis factor-alpha in the nephrotic syndrome in humans. American Journal of Kidney Diseases 21: 251–259.

    Article  CAS  PubMed  Google Scholar 

  26. Bustos, C., et al. 1994. Increase of tumour necrosis factor alpha synthesis and gene expression in peripheral blood mononuclear cells of children with idiopathic nephrotic syndrome. European Journal of Clinical Investigation 24: 799–805.

    Article  CAS  PubMed  Google Scholar 

  27. Ihm, C.G., et al. 1997. Circulating factors in sera or peripheral blood mononuclear cells in patients with membranous nephropathy or diabetic nephropathy. Journal of Korean Medical Science 12: 539–544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Timoteo, R.P., et al. 2017. Th1/Th17-related cytokines and chemokines and their implications in the pathogenesis of Pemphigus vulgaris. Mediators of inflammation 2017: 7151285.

    Article  PubMed Central  Google Scholar 

  29. Gholibeigian, Z., et al. 2020. Decreased serum levels of interleukin-17, interleukin-23, TGF-beta in pemphigus vulgaris patients, and their association with disease phase. Dermatologic Therapy 33: e14071.

    Article  CAS  PubMed  Google Scholar 

  30. Takahashi, H., et al. 2010. Serum cytokines and growth factor levels in Japanese patients with psoriasis. Clinical and Experimental Dermatology 35: 645–649.

    Article  CAS  PubMed  Google Scholar 

  31. Krebs, C.F., et al. 2021.Tissue-specific therapy in immune-mediated kidney diseases: new ARGuments for targeting the IL-23/IL-17 axis. Journal of Clinical Investigation 131: e150588.

  32. Sherlock, J.P., et al. 2012. IL-23 induces spondyloarthropathy by acting on ROR-gammat+ CD3+CD4-CD8- entheseal resident T cells. Nature medicine 18: 1069–76.

    Article  CAS  PubMed  Google Scholar 

  33. Cuthbert, R.J., et al. 2019. Evidence that tissue resident human enthesis gammadeltaT-cells can produce IL-17A independently of IL-23R transcript expression. Annals of the Rheumatic Diseases 78: 1559–1565.

    Article  CAS  PubMed  Google Scholar 

  34. Yu, H.C., et al. 2015. Sulfasalazine treatment suppresses the formation of HLA-B27 heavy chain homodimer in patients with ankylosing spondylitis. International Journal of Molecular Sciences 17: 46.

  35. Hassane, M., et al. 2020. Interleukin-7 protects against bacterial respiratory infection by promoting IL-17A-producing innate T-cell response. Mucosal Immunology 13: 128–139.

    Article  CAS  PubMed  Google Scholar 

  36. Zhang, X., et al. 2011. Structure and function of interleukin-17 family cytokines. Protein & Cell 2: 26–40.

    Article  Google Scholar 

  37. Kolbinger, F., et al. 2017. Beta-Defensin 2 is a responsive biomarker of IL-17A-driven skin pathology in patients with psoriasis. The Journal of Allergy and Clinical Immunology 139: 923–932.

    Article  CAS  PubMed  Google Scholar 

  38. Gracey, E., et al. 2016. IL-7 primes IL-17 in mucosal-associated invariant T (MAIT) cells, which contribute to the Th17-axis in ankylosing spondylitis. Annals of the Rheumatic Diseases 75: 2124–2132.

    Article  CAS  PubMed  Google Scholar 

  39. Dusseaux, M., et al. 2011. Human MAIT cells are xenobiotic-resistant, tissue-targeted, CD161hi IL-17-secreting T cells. Blood 117: 1250–1259.

    Article  CAS  PubMed  Google Scholar 

  40. Raychaudhuri, S.K., et al. 2020. Functional significance of MAIT cells in psoriatic arthritis. Cytokine 125: 154855.

    Article  CAS  PubMed  Google Scholar 

  41. Konduri, V., et al. 2020. CD8(+)CD161(+) T-cells: cytotoxic memory cells with high therapeutic potential. Frontiers in Immunology 11: 613204.

    Article  CAS  PubMed  Google Scholar 

  42. Vivier, E., et al. 2012. Targeting natural killer cells and natural killer T cells in cancer. Nature Reviews Immunology 12: 239–252.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The study was supported by the Indian Council of Medical Research (ICMR).

Funding

ICMR funding 5/4/7–2/Nephro/2021/NIC-II.

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Author notes

  1. Vinod Kumar and Raja Ramachandran have equal correspondence.

Authors and Affiliations

  1. Department of Nephrology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    Prabhjot Kaur, Arun Prabhahar, Deeksha Pal, Harbir Singh Kohli & Raja Ramachandran

  2. Department of Histopathology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, India

    Ritambhra Nada

  3. Department of Dermatology, Post Graduate Institute of Medical Education and Research (PGIMER), Chandigarh, 160012, India

    Vinod Kumar

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Contributions

PK and VK perform the experimental part and data analysis, AP and DP help in data analysis, RN, HK, and RR help in patients’ identification and recruitment, and VK and RR conceptualize the work and write the manuscript with PK.

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Correspondence to Vinod Kumar or Raja Ramachandran.

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Kaur, P., Prabhahar, A., Pal, D. et al. IL-23/IL-17 in a Paradoxical Association with Primary Membranous Nephropathy. Inflammation (2024). https://doi.org/10.1007/s10753-024-01992-w

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  • DOI: https://doi.org/10.1007/s10753-024-01992-w

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