Hyperhomocysteinemia and Cytokine Profiles in Henoch-Schönlein Purpura: Genetic Associations and Treatment Outcomes-Scilight

Trends in Immunotherapy

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Hyperhomocysteinemia and Cytokine Profiles in Henoch-Schönlein Purpura: Genetic Associations and Treatment Outcomes

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https://doi.org/10.54963/ti.v9i2.1192
Ormonbek Dzhakypbaev, Akmatbek Saparbaev, Rysbek Sadyjev, Asel Kenzheeva, Kunduz Shuku‑ ralieva, Nurzhan Usenova, & Sagynali Mamatov. (2025). Hyperhomocysteinemia and Cytokine Profiles in Henoch-Schönlein Purpura: Genetic Associations and Treatment Outcomes. Trends in Immunotherapy, 9(2), 95–106. https://doi.org/10.54963/ti.v9i2.1192
Volume 9 Issue 2 (2025): (in progress)
Copyright (c) 2025 Ormonbek Dzhakypbaev, Akmatbek Saparbaev, Rysbek Sadyjev, Asel Kenzheeva, Kunduz Shuku‑ ralieva, Nurzhan Usenova, Sagynali Mamatov
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Authors

  • Ormonbek Dzhakypbaev

    Department of Hospital Internal Medicine with a Course of Hematology, I. K. Akhunbaev Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Akmatbek Saparbaev

    Department of Physics, Informatics and Mathematics, I. K. Akhunbaev Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Rysbek Sadyjev

    Department of Therapeutic Dentistry, I. K. Akhunbaev Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Asel Kenzheeva

    Department of Therapeutic Dentistry, I. K. Akhunbaev Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Kunduz Shuku‑ ralieva

    4Department of Therapeutic Dentistry, I. K. Akhunbaev Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Nurzhan Usenova

    Department of Therapeutic Dentistry, I. K. Akhunbaev Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan
  • Sagynali Mamatov

    Department of Hospital Internal Medicine with a Course of Hematology, I. K. Akhunbaev Kyrgyz State Medical Academy, Bishkek 720020, Kyrgyzstan

Received: 23 April 2025; Revised: 19 May 2025; Accepted: 23 May 2025; Published: 6 June 2025

Henoch-Schönlein purpura (HSP) is a systemic vasculitis characterized by purpura, joint pain, abdominal discomfort, and renal involvement in children. This study aimed to evaluate the homocysteine (Hcy) levels, polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) C677T and methionine synthase (MTR) A2756G genes, and immunological parameters in 183 patients with HSP. Hyperhomocysteinemia (HHcy) was found in 67.5% of patients, with 66.6% and 7.4% of patients with HHcy having MTHFR C677T heterozygosity and homozygosity, respectively. MTR A2756G polymorphisms were present in 44.4% of patients with HHcy. Patients with both HHcy and gene mutations experience more severe symptoms. Flow cytometry revealed reduced CD4 and CD8 antigen expressions in some patients. Serum cytokine analysis showed significantly higher IL-6 and TNF-α levels in patients with generalized HSP than in controls and those with cutaneous-articular HSP. Immunomodulatory treatments, such as cyclosporin A and rituximab, were effective in severe, treatment-resistant cases, reducing symptoms and inflammatory markers in these patients. This study highlights the importance of genetic, metabolic, and immunological assessments in guiding personalized treatment for HSP. Recommendations include measuring Hcy levels, genotyping for MTHFR C677T and MTR A2756G polymorphisms, immunophenotyping, and considering immunomodulatory treatments in cases that are severe.

Keywords:

Henoch‑Schö nlein Purpura; IgA Immune Complexes; Homocysteine; Cytokines; Cyclosporin‑A; Ritux‑ imab

References

  1. Hetland, L.E.; Susrud, K.S.; Lindahl, K.H.; et al. Henoch-Schönlein Purpura: A Literature Review. Acta Derm. Venereol. 2017, 97, 1160–1166.
  2. Trnka, P. Henoch-Schönlein Purpura in Children. J. Paediatr. Child. Health 2013, 49, 995–1003.
  3. Ben-Chetrit, E.; Yazici, H. Non-Thrombocytopenic Purpura in Familial Mediterranean Fever-Comorbidity with Henoch-Schönlein Purpura or an Additional Rare Manifestation of Familial Mediterranean Fever? Rheumatology 2016, 55, 1153–1158.
  4. Kawasaki, Y. The Pathogenesis and Treatment of Pediatric Henoch-Schönlein Purpura Nephritis. Clin. Exp. Nephrol. 2011, 15, 648–657.
  5. Roberts, P.F.; Waller, T.A.; Brinker, T.M.; et al. Henoch-Schönlein Purpura: a Review Article. South. Med. J. 2007, 100, 821–824.
  6. Al-Sheyyab, M.; El-Shanti, H.; Ajlouni, S.; et al. The Clinical Spectrum of Henoch-Schönlein Purpura in Infants and Young Children. Eur. J. Pediatr. 1995, 154, 969–972.
  7. Chan, J.C.; Li, P.K.; Lai, F.M.; et al. Fatal adult Henoch-Schönlein purpura due to Small Intestinal Infarction. J. Intern. Med. 1992, 232, 181–184.
  8. Chang, W.L.; Yang, Y.H.; Wang, L.C.; et al. Renal Manifestations in Henoch-Schönlein Purpura: A 10-Year Clinical Study. Pediatr. Nephrol. 2005, 20, 1269–1272.
  9. Salem, Y.; Alam, Z.; Shalabi, M.M.; et al. IgA Vasculitis Associated with COVID-19. Cureus 2023, 15, e38725.
  10. Nikolaishvili, M.; Pazhava, A.; Di Lernia, V. Viral Infections may be Associated with Henoch-Schönlein Purpura. J. Clin. Med. 2023, 12, 697.
  11. Van Der Helm-Van Mil, A.H.; Smith, A.C.; Pouria, S.; et al. Immunoglobulin A Multiple Myeloma Presenting with Henoch-Schönlein Purpura Associated with Reduced Sialylation of IgA1. Br. J. Haematol. 2003, 122, 915–917.
  12. Hall, R.P.; Lawley, T.J.; Heck, J.A.; et al. IgA-Containing Circulating Immune Complexes in Dermatitis Herpetiformis, Henoch-Schönlein Purpura, Systemic Lupus Erythematosus and Other Diseases. Clin. Exp. Immunol. 1980, 40, 431–437.
  13. Ballinger, S. Henoch-Schonlein Purpura. Curr. Opin. Rheumatol. 2003, 15, 591–594.
  14. Saulsbury, F.T. Henoch-Schönlein Purpura. Curr. Opin. Rheumatol. 2010, 22, 598–602.
  15. Kawakami, T.; Watabe, H.; Mizoguchi, M.; et al. Elevated Serum IgA Anticardiolipin Antibody Levels In Adult Henoch-Schönlein Purpura. Br. J. Dermatol. 2006, 155, 983–987.
  16. Yang, Y.H.; Chang, C.J.; Chuang, Y.H.; et al. Identification and Characterization of IgA Antibodies Against β2-Glycoprotein I in Childhood Henoch-Schönlein Purpura. Br. J. Dermatol. 2012, 167, 874–881.
  17. Shi, X.; Li, W.C.; Mo, L.J.; et al. Altered Mean Platelet Volume in Children with Henoch-Schonlein Purpura and its Association with Disease Activity. Ann. Clin. Biochem. 2018, 55, 368–372.
  18. Lei, W.; Yun-Yun, S.; Ai-E, X. Neutrophil-to-Lymphocyte Ratio: A Biomarker for Predicting Systemic Involvement in Henoch-Schonlein Purpura. Indian J. Dermatol. Venereol. Leprol. 2021, 88, 132.
  19. Froese, D.S.; Fowler, B.; Baumgartner, M.R. Vitamin B12 , Folate, and the Methionine Remethylation Cycle-Biochemistry, Pathways, and Regulation. J. Inherit. Metab. Dis. 2019, 42, 673–685.
  20. Carmel, R.; Green, R.; Rosenblatt, D.S.; et al. Update on Cobalamin, Folate, and Homocysteine. Hematol. Am. Soc. Hematol. Educ. Progr. 2003, 2003, 62–81.
  21. McCully, K.S. Homocysteine Metabolism, Atherosclerosis, and Diseases of Aging. Compr. Physiol. 2015, 6, 471–505.
  22. Li, W.X.; Dai, S.X.; Zheng, J.J.; et al. Homocysteine Metabolism Gene Polymorphisms (MTHFR C677T, MTHFR A1298C, MTR A2756G and MTRR A66G) Jointly Elevate the Risk of Folate Deficiency. Nutrients 2015, 7, 6670–6687.
  23. Jacques, P.F.; Bostom, A.G.; Williams, R.R.; et al. Relation Between Folate Status, a Common Mutation in Methylenetetrahydrofolate Reductase, and Plasma Homocysteine Concentrations. Circulation 1996, 93, 7–9.
  24. Dillon, M.J. Henoch-Schönlein Purpura: Recent Advances. Clin Exp Rheumatol 2007, 25, S66–S68.
  25. Someya, T.; Kaneko, K.; Fujinaga, S.; et al. Cyclosporine A for Heavy Proteinuria in a Child with Henoch-Schönlein Purpura Nephritis. Pediatr. Int. 2004, 46, 111–113.
  26. Kawasaki, Y.; Ono, A.; Ohara, S.; et al. Henoch-Schönlein Purpura Nephritis in Childhood: Pathogenesis, Prognostic Factors and Treatment. Fukushima J. Med. Sci. 2013, 59, 15–26.
  27. Georgaki-Angelaki, E.; Kostaridou, S.; Lourida, A.; et al. Abrupt and Durable Remission of Henoch-Schönlein Purpura Nephritis with Cyclosporine A. NDT Plus 2008, 1, 300–302.
  28. Torosoff, M.; Breen, T.; Balulad, S.; et al. Resolution of Sinus Bradycardia, High-Grade Heart Block, and Left Ventricular Systolic Dysfunction with Rituximab Therapy in Henoch-Schonlein Purpura. Intern. Med. J. 2018, 48, 868–871.
  29. Pillebout, E.; Rocha, F.; Fardet, L.; et al. Successful Outcome Using Rituximab as the Only Immunomodulation in Henoch-Schonlein Purpura: Case Report. Nephrol. Dial. Transpl. 2011, 26, 2044–2046.
  30. Nikibakhsh, A.A.; Mahmoodzadeh, H.; Karamyyar, M.; et al. Treatment of Severe Henoch-Schonlein Purpura Nephritis with Mycophenolate Mofetil. Saudi. J. Kidney Dis. Transpl. 2014, 25, 858–863.
  31. Sugino, H.; Sawada, Y.; Nakamura, M. IgA Vasculitis: Etiology, Treatment, Biomarkers and Epigenetic Changes. Int. J. Mol. Sci. 2021, 22, 7538.
  32. Pillebout, E.; Jamin, A.; Ayari, H.; et al. Biomarkers of IgA Vasculitis Nephritis in Children. PLoS ONE 2017, 12, e0188718.
  33. Chen, T.; Guo, Z.P.; Jiao, X.Y.; et al. CCL5, CXCL16, and CX3CL1 are Associated with Henoch-Schonlein Purpura. Arch Dermatol. Res. 2011, 303, 715–725.
  34. Yang, Y.H.; Huang, Y.H.; Lin, Y.L.; et al. Circulating IgA from Acute Stage of Childhood Henoch-Schönlein Purpura can Enhance Endothelial Interleukin (IL)-8 Production Through MEK/ERK Signalling Pathway. Clin. Exp. Immunol. 2006, 144, 247–253.
  35. Maritati, F.; Fenoglio, R.; Pillebout, E.; et al. Brief Report: Rituximab for the Treatment of Adult-Onset IgA Vasculitis (Henoch-Schönlein). Arthritis Rheumatol. 2018, 70, 109–114.
  36. Van de Perre, E.; Jones, R.B.; Jayne, D.R.W. IgA Vasculitis (Henoch-Schönlein Purpura): Refractory and Relapsing Disease Course in the Adult Population. Clin. Kidney J. 2021, 14, 1953–1960.
  37. Jaiswal, S.K.; Sukla, K.K.; Mishra, S.K.; et al. Association of Genetic Polymorphisms in Genes Involved at the Branch Point of Nucleotide Biosynthesis and Remythylation with Down Syndrome Birth Risk – A Case-Control Study. J. Mol. Genet. Med. 2016, 10, 207.
  38. James, S.J.; Pogribna, M.; Pogribny, I.P.; et al. Abnormal folate Metabolism and Mutation in the Methylenetetrahydrofolate Reductase Gene may be Maternal Risk Factors for Down Syndrome. Am. J. Clin. Nutr. 1999, 70, 495–501.
  39. He, L.; Shen, Y. MTHFR C677T Polymorphism and Breast, Ovarian Cancer Risk: A Meta-Analysis of 19,260 Patients and 26,364 Controls. Onco. Targets Ther. 2017, 10, 227–238.
  40. Ma, L.M.; Yang, H.P.; Yang, X.W.; et al. Methionine Synthase A2756G Polymorphism Influences Pediatric Acute Lymphoblastic Leukemia Risk: A Meta-Analysis. Biosci. Rep. 2019, 39, BSR20181770.
  41. Pushpakumar, S.; Kundu, S., Sen, U. Endothelial Dysfunction: The Link Between Homocysteine and Hydrogen Sulfide. Curr. Med. Chem. 2014, 21, 3662–3672.
  42. Papatheodorou, L.; Weiss, N. Vascular Oxidant Stress and Inflammation in Hyperhomocysteinemia. Antioxid Redox Signal 2007, 9, 1941–1958.
  43. Sanders, J.T.; Wyatt, R.J. IgA Nephropathy and Henoch-Schönlein Purpura Nephritis. Curr. Opin. Pediatr. 2008, 20, 163–170.
  44. Mizerska-Wasiak, M.; Gajewski, Ł.; Cichoń-Kawa, K.; et al. Serum GDIgA1 Levels in Children With IgA Nephropathy and Henoch-Schönlein Nephritis. Cent. Eur. J. Immunol. 2018, 43, 162–167.
  45. Cheung, C.K.; Barratt, J. Biomarkers to Predict Progression in IgA Nephropathy. Clin. J. Am. Soc. Nephrol. 2019, 14, 1421–1423.
  46. Wang, J.K.; Yan, B.; Zhao, J.M.; et al. Effect of Gut Microbiota From Henoch-Schönlein Purpura Patients on Acid-Sensitive Ion Channel 3 Expression and Intestinal Motility in Germ-Free Rats. BMC Pediatr. 2021, 21, 536.
  47. Li, Y.; Xue, J.; Zhang, Z.; et al. Alteration of Gut Microbiota in Henoch-Schönlein Purpura Children with Gastrointestinal Involvement. Ir. J. Med. Sci. 2024, 193, 2397–2406.