Sains Malaysiana 51(4)(2022): 1155-1165

http://doi.org/10.17576/jsm-2022-5104-17

Effect of Protein A-Immunoadsorption Therapy on Serum Cytokines in AAV Patients

(Kesan Terapi A-Imunopenjerapan Protein ke atas Serum Sitokin pada Pesakit AAV)

XIEJIA LI^1,2, ZHENG LI^1,2,*, HONGMEI DENG¹, CUIFANG SUN¹, HONG LIU^1,2 & FANG YUAN^1,2

¹Department of Nephrology, the Second Xiangya Hospital, Central South University, Changsha, Hunan, P.R. China

²Hunan Key Laboratory of Kidney Disease and Blood Purification, Changsha, Hunan, P.R. China

Received: 18 May 2021/Accepted: 14 October 2021

ABSTRACT

Protein A-immunoadsorption (IA) is an extracorporeal apheresis technique used in patients with autoimmune diseases which aims to remove pathogenic autoantibodies. Apart from the adsorption of immunoglobulins (IgG), IA may influence cellular and humoral immunity. The aim of this study was to observe the effect of protein A-IA on cytokine networks in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) patients. A total of 12 newly diagnosed AAV patients received IA therapy on days 1, 3, and 5. Serum levels of inflammatory cytokines were measured before and after treatment including members of the interleukin family, PDGF-BB, TNF-α and IFN-γ. IL-1β, IL-9, IL-17A, PDGF-BB, IFN-γ, and TNF-α were elevated in AAV patients compared to healthy individuals. There were no changes in the levels of any cytokines after the first IA session but after 3 sessions, IL-9, PDGF-BB, and TNF-α dramatically decreased. Moreover, reductions in IL-9 levels were positively correlated with the changes of myeloperoxidase-ANCA (MPO-ANCA). Our observations suggest that protein A-IA therapy does not directly adsorb cytokines, but removes autoantibodies (MPO-ANCA) which indirectly leads to changes in cytokine networks linked to cellular or humoral immunity.

Keywords: Cytokines; immunoadsorption; protein-A, ANCA; vasculitis

ABSTRAK

A-imunopenjerapan protein (IA) merupakan teknik ekstrakorporeum aferesis yang digunakan pada pesakit yang mempunyai penyakit autoimun bertujuan untuk menyingkirkan autoantibodi patogen. Selain daripada penjerapan immunoglobulin (IgG), IA boleh mempengaruhi imuniti sel dan humoral. Tujuan kajian ini adalah untuk melihat kesan protein A-IA ke atas rangkaian sitokin pada pesakit vasculitis (AAV) yang berkait dengan antibodi sitoplasmik antineutrofil (ANCA). Seramai 12 pesakit AAV yang baru didiagnos telah menerima terapi IA pada hari 1, 3 dan 5. Tahap serum daripada keradangan sitokin telah diukur sebelum dan selepas rawatan termasuk anggota daripada keluarga interleukin, PDGF-BB, TNF- α dan IFN-γ. IL-1β, IL-9, IL-17A, PDGF-BB, IFN-γ dan TNF-α menaik pada pesakit AAV berbanding dengan individu yang sihat. Tiada perubahan pada tahap dalam mana-mana sitokin selepas sesi pertama IA tetapi selepas sesi ketiga, IL-9, PDGF-BB dan TNF-α menurun dengan mendadak. Selain itu, penurunan dalam paras IL-9 berkorelasi secara positif dengan perubahan mieloperoksidase-ANCA (MPO-ANCA). Berdasarkan pemerhatian kami, terapi protein A-IA tidak menjerap sitokin secara langsung, tetapi mengeluarkan autoantibodi (MPO-ANCA) yang secara tidak langsung mengakibatkan perubahan kepada rangkaian sitokin yang berpaut kepada imuniti sel atau humoral.

Kata kunci: ANCA; imunopenjerapan; protein-A; sitokin; vasculitis

REFERENCES

Aljuhani, M., Makati, D., Hoff, A., Thompson, J., Pellegrino, B., Shawwa, K., Schmidt, R. & Kannabhiran, D. 2021. Antibody subtypes and titers predict clinical outcomes in ANCA-associated vasculitis. Rheumatology International 41(5): 965-972.

Baggi, F., Ubiali, F., Nava, S., Nessi, V., Andreetta, F., Rigamonti, A., Maggi, L., Mantegazza, R. & Antozzi, C. 2008. Effect of IgG immunoadsorption on serum cytokines in MG and LEMS patients. Journal of Neuroimmunology 201: 104-110.

Braun, N. & Risler, T. 1999. Immunoadsorption as a tool for the immunomodulation of the humoral and cellular immune system in autoimmune disease. Therapeutic Apheresis 3(3): 240-245.

Bossuyt, X., Tervaert, J.W.C., Arimura, Y., Blockmans, D., Flores-Suárez, L.F., Guillevin, L., Hellmich, B., Jayne, D., Jennette, J.C., Kallenberg, C.G. & Moiseev, S. 2017. Revised 2017 International Consensus on testing of ANCAs in granulomatosis with polyangiitis and microscopic polyangiitis. Nature Reviews Rheumatology 13(11): 683-692.

Bulut, D., Creutzenberg, G. & Mügge, A. 2013. The number of regulatory T cells correlates with hemodynamic improvement in patients with inflammatory dilated cardiomyopathy after immunoadsorption therapy. Scandinavian Journal of Immunology 77(1): 54-61.

Bulut, D., Scheeler, M., Wichmann, T., Börgel, J., Miebach, T. & Mügge, A. 2010. Effect of protein A immunoadsorption on T cell activation in patients with inflammatory dilated cardiomyopathy. Clinical Research in Cardiology 99(10): 633-638.

Casian, A. & Jayne, D. 2011. Plasma exchange in the treatment of Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome and renal limited vasculitis. Current Opinion in Rheumatology 23(1): 12-17.

Cornec, D., Cornec-Le Gall, E., Fervenza, F.C. & Specks, U. 2016. ANCA-associated vasculitis - Clinical utility of using ANCA specificity to classify patients. Nature Reviews Rheumatology 12(10): 570-579.

Flossmann, O., Berden, A., de Groot, K., Hagen, C., Harper, L., Heijl, C., Höglund, P., Jayne, D., Luqmani, R., Mahr, A. & Mukhtyar, C. 2011. Long-term patient survival in ANCA-associated vasculitis. Annals of the Rheumatic Diseases 70(3): 488-494.

Gaskin, G. & Pusey, C.D. 2001. Plasmapheresis in antineutrophil cytoplasmic antibodies‐associated systemic vasculitis. Therapeutic Apheresis 5(3): 176-181.

Gioffredi, A., Maritati, F., Oliva, E. & Buzio, C. 2014. Eosinophilic granulomatosis with polyangiitis: An overview. Frontiers in Immunology 5: 549.

Goto, H., Matsuo, H., Nakane, S., Izumoto, H., Fukudome, T., Kambara, C. & Shibuya, N. 2001. Plasmapheresis affects T helper type‐1/T helper type‐2 balance of circulating peripheral lymphocytes. Therapeutic Apheresis 5(6): 494-496.

Hehmke, B., Salzsieder, E., Matic, G.B., Winkler, R.E., Tiess, M. & Ramlow, W. 2000. Immunoadsorption of immunoglobulins alters intracytoplasmic type 1 and type 2 T cell cytokine production in patients with refractory autoimmune diseases. Therapeutic Apheresis 4(4): 296-302.

Hogan, S.L., Falk, R.J., Chin, H., Cai, J., Jennette, C.E., Jennette, J.C. & Nachman, P.H. 2005. Predictors of relapse and treatment resistance in antineutrophil cytoplasmic antibody-associated small-vessel vasculitis. Annals of Internal Medicine 143(9): 621-631.

Inganäs, M. 1981. Comparison of mechanisms of interaction between protein A from Staphylococcus aureus and human monoclonal IgG, IgA and IgM in relation to the classical Fcγ and the alternative F(ab')2γ protein A interactions. Scandinavian Journal of Immunology 13(4): 343-352.

Ishizaki, J., Takemori, A., Suemori, K., Matsumoto, T., Akita, Y., Sada, K.E., Yuzawa, Y., Amano, K., Takasaki, Y., Harigai, M. & Arimura, Y. 2017. Targeted proteomics reveals promising biomarkers of disease activity and organ involvement in antineutrophil cytoplasmic antibody-associated vasculitis. Arthritis Research & Therapy 19(1): 1-17.

Jennette, J.C., Falk, R.J., Bacon, P.A., Basu, N., Cid, M.C., Ferrario, F., Flores-Suarez, L.F., Gross, W.L., Guillevin, L., Hagen, E.C. & Hoffman, G.S. 2013. Arthritis Rheum. In 2012 Revised International Chapel Hill Consensus Conference Nomenclature of Vasculitides. CHCC. pp. 1-11.

Kemna, M.J., Damoiseaux, J., Austen, J., Winkens, B., Peters, J., van Paassen, P. & Tervaert, J.W.C. 2015. ANCA as a predictor of relapse: Useful in patients with renal involvement but not in patients with nonrenal disease. Journal of the American Society of Nephrology 26(3): 537-542.

Kronbichler, A., Leierer, J., Gauckler, P. & Shin, J.I. 2020a. Comorbidities in ANCA-associated vasculitis. In Rheumatology. Oxford: Oxford University Press. pp. iii79-iii83.

Kronbichler, A., Lee, K.H., Denicolò, S., Choi, D., Lee, H., Ahn, D., Kim, K.H., Lee, J.H., Kim, H., Hwang, M. & Jung, S.W. 2020b. Immunopathogenesis of ANCA-associated vasculitis. International Journal of Molecular Sciences 21(19): 7319.

Kronbichler, A., Leierer, J., Shin, J.I., Merkel, P.A., Spiera, R., Seo, P., Langford, C.A., Hoffman, G.S., Kallenberg, C.G., St Clair, E.W. & Brunetta, P. 2019. Association of pulmonary hemorrhage, positive proteinase 3, and urinary red blood cell casts with venous thromboembolism in antineutrophil cytoplasmic antibody–associated vasculitis. Arthritis & Rheumatology 71(11): 1888-1893.

Kronbichler, A., Jayne, D.R. & Mayer, G. 2015. Frequency, risk factors and prophylaxis of infection in ANCA‐associated vasculitis. European Journal of Clinical Investigation 45(3): 346-368.

Lai, Q.Y., Ma, T.T., Li, Z.Y., Chang, D.Y., Zhao, M.H. & Chen, M. 2014. Predictors for mortality in patients with antineutrophil cytoplasmic autoantibody associated vasculitis: A study of 398 Chinese patients. J. Rheumatol. 41(9): 1849-1855.

Le Guenno, G., Mahr, A., Pagnoux, C., Dhote, R., Guillevin, L. & French Vasculitis Study Group. 2011. Incidence and predictors of urotoxic adverse events in cyclophosphamide‐treated patients with systemic necrotizing vasculitides. Arthritis & Rheumatism 63(5): 1435-1445.

Li, Z.Y., Ma, T.T., Chen, M. & Zhao, M.H. 2015. The prevalence and management of anti-neutrophil cytoplasmic antibody-associated vasculitis in China. Kidney Diseases 1(4): 216-223.

Lilliebladh, S., Johansson, Å., Pettersson, Å., Ohlsson, S. & Hellmark, T. 2018. Phenotypic characterization of circulating CD4+ T cells in ANCA-associated vasculitis. Journal of Immunology Research 2018: 6984563.

Lyons, P.A., Rayner, T.F., Trivedi, S., Holle, J.U., Watts, R.A., Jayne, D.R., Baslund, B., Brenchley, P., Bruchfeld, A., Chaudhry, A.N. & Cohen Tervaert, J.W. 2012. Genetically distinct subsets within ANCA-associated vasculitis. New England Journal of Medicine 367(3): 214-223.

Mahr, A., Heijl, C., Le Guenno, G. & Faurschou, M. 2013. ANCA-associated vasculitis and malignancy: Current evidence for cause and consequence relationships. Best Practice & Research Clinical Rheumatology 27(1): 45-56.

Maillard, N., Absi, L., Claisse, G., Masson, I., Alamartine, E. & Mariat, C. 2015. Protein A-based immunoadsorption is more efficient than conventional plasma exchange to remove circulating anti-HLA antibodies. Blood Purification 40(2): 167-172.

Martinez Valenzuela, L., Bordignon Draibe, J., Fulladosa Oliveras, X., Bestard Matamoros, O., Cruzado Garrit, J.M. & Torras Ambrós, J. 2019. T-lymphocyte in ANCA-associated vasculitis: What do we know? A pathophysiological and therapeutic approach. Clinical Kidney Journal 12(4): 503-511.

Monach, P.A., Warner, R.L., Tomasson, G., Specks, U., Stone, J.H., Ding, L., Fervenza, F.C., Fessler, B.J., Hoffman, G.S., Iklé, D. & Kallenberg, C.G. 2013. Serum proteins reflecting inflammation, injury and repair as biomarkers of disease activity in ANCA-associated vasculitis. Annals of the Rheumatic Disease 72(8): 1342-1350.

Palmer, A., Cairns, T., Dische, F., Gluck, G., Gjorstrup, P., Parsons, V., Welsh, K. & Taube, D. 1991. Treatment of rapidly progressive glomerulonephritis by extracorporeal immunoadsorption, prednisolone and cyclophosphamide. Nephrology Dialysis Transplantation 6(8): 536-542.

Philipponnet, C., Garrouste, C., Le Guenno, G., Cartery, C., Guillevin, L., Boffa, J.J. & Heng, A.E. 2017. Antineutrophilic cytoplasmic antibody-associated vasculitis and malignant hemopathies, a retrospective study of 16 cases. Joint Bone Spine 84(1): 51-57.

Rahmattulla, C., Mooyaart, A.L., van Hooven, D., Schoones, J.W., Bruijn, J.A., Dekkers, O.M., Bajema, I.M. & European Vasculitis Genetics Consortium. 2016. Genetic variants in ANCA-associated vasculitis: A meta-analysis. Annals of the Rheumatic Diseases 75(9): 1687-1692.

Rowaiye, O.O., Kusztal, M. & Klinger, M. 2015. The kidneys and ANCA-associated vasculitis: From pathogenesis to diagnosis. Clinical Kidney Journal 8(3): 343-350.

Schneidewind‐Müller, J.M., Winkler, R.E., Tiess, M., Müller, W. & Ramlow, W. 2002. Changes in lymphocytic cluster distribution during extracorporeal immunoadsorption. Artificial Organs 26(2): 140-144.

Stegmayr, B., Almroth, G., Berlin, G., Fehrman, I., Kurkus, J., Norda, R., Olander, R., Sterner, G., Thysell, H., Wikström, B. & Wiren, J.E. 1999. Plasma exchange or immunoadsorption in patients with rapidly progressive crescentic glomerulonephritis a Swedish multi-center study. The International Journal of Artificial Organs 22(2): 81-87.

Szczeklik, W., Jakieła, B., Wawrzycka‐Adamczyk, K., Sanak, M., Hubalewska‐Mazgaj, M., Padjas, A., Surmiak, M., Szczeklik, K., Sznajd, J. & Musiał, J. 2017. Skewing toward Treg and Th2 responses is a characteristic feature of sustained remission in ANCA‐positive granulomatosis with polyangiitis. European Journal of Immunology 47(4): 724-733.

Tanna, A., Guarino, L., Tam, F.W., Rodriquez-Cubillo, B., Levy, J.B., Cairns, T.D., Griffith, M., Tarzi, R.M., Caplin, B., Salama, A.D. & Cook, T. 2015. Long-term outcome of anti-neutrophil cytoplasm antibody-associated glomerulonephritis: Evaluation of the international histological classification and other prognostic factors. Nephrology Dialysis Transplantation 30(7): 1185-1192.

Tomasson, G., Grayson, P.C., Mahr, A.D., LaValley, M. & Merkel, P.A. 2012. Value of ANCA measurements during remission to predict a relapse of ANCA-associated vasculitis - A meta-analysis. Rheumatology 51(1): 100-109.

Unizony, S., Villarreal, M., Miloslavsky, E.M., Lu, N., Merkel, P.A., Spiera, R., Seo, P., Langford, C.A., Hoffman, G.S., Kallenberg, C.M. & Clair, E.W.S. 2016. Clinical outcomes of treatment of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis based on ANCA type. Annals of the Rheumatic Diseases 75(6): 1166-1169.

Wallace, Z.S., Fu, X., Harkness, T., Stone, J.H., Zhang, Y. & Choi, H. 2020. All-cause and cause-specific mortality in ANCA-associated vasculitis: Overall and according to ANCA type. Rheumatology 59(9): 2308-2315.

Watanabe, H., Sada, K.E., Matsumoto, Y., Harigai, M., Amano, K., Dobashi, H., Fujimoto, S., Usui, J., Yamagata, K., Atsumi, T. & Banno, S. 2018. Association between reappearance of myeloperoxidase - antineutrophil cytoplasmic antibody and relapse in antineutrophil cytoplasmic antibody - associated vasculitis: Subgroup analysis of nationwide prospective cohort studies. Arthritis & Rheumatology 70(10): 1626-1633.

Watts, R.A., Mahr, A., Mohammad, A.J., Gatenby, P., Basu, N. & Flores-Suárez, L.F. 2015. Classification, epidemiology and clinical subgrouping of antineutrophil cytoplasmic antibody (ANCA) - associated vasculitis. Nephrology Dialysis Transplantation 30: i14-i22.

Xiao, H., Hu, P., Falk, R.J. & Jennette, J.C. 2015. Overview of the pathogenesis of ANCA-associated vasculitis. Kidney Diseases 1(4): 205-215.

Yokoyama, H., Wada, T. & Furuichi, K. 2003. Immunomodulation effects and clinical evidence of apheresis in renal diseases. Therapeutic Apheresis and Dialysis 7(6): 513-519.

^*Corresponding author; email: lizheng2064@csu.edu.cn