Abstract
IgG4-related disease (IgG4-RD) is a systemic disease characterized by elevated serum IgG4 levels and a strong infiltration of IgG4-positive plasma cells in various organs. IgG4-RD patients also frequently suffer from allergic diseases, including asthma and atopic dermatitis. It is well known that T helper type 2 (Th2) cells have an important role in the initiation of allergic diseases, and Th2 cytokines such as interleukin (IL)-4 and IL-13 promote class switching to IgG4. Therefore, IgG4-RD is considered to be a Th2-predominant disease. However, other Th subsets, including regulatory T cells and T follicular helper cells, have recently received increasing attention with regard to the pathogenesis of IgG4-RD. Exploring the interconnected network of Th subsets in IgG4-RD is a highly promising field of investigation. In this review, we focus on the localization and functions of individual Th subsets to clarify the involvement of these cells in the pathogenesis of IgG4-RD.
Competing interests: The authors declare no competing interests.
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References
Akiyama M, Suzuki K, Yamaoka K et al (2015) Number of circulating follicular helper 2 T Cells correlates with IgG4 and Interleukin-4 levels and plasmablast numbers in IgG4-related disease. Arthritis Rheumatol 67(9):2476–2481
Dahlgren M, Khosroshahi A, Nielsen GP et al (2010) Riedel’s thyroiditis and multifocal fibrosclerosis are part of the IgG4-related systemic disease spectrum. Arthritis Care Res 62(9):1312–1318
Fukui Y, Uchida K, Sakaguchi Y et al (2015) Possible involvement of Toll-like receptor 7 in the development of type 1 autoimmune pancreatitis. J Gastroenterol 50(4):435–444
Furukawa S, Moriyama M, Tanaka A et al (2015) Preferential M2 macrophages contribute to fibrosis in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease. Clin Immunol 156(1):9–18
Hamano H, Kawa S, Horiuchi A et al (2001) High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med 344(10):732–738
Hamano H, Kawa S, Ochi Y et al (2002) Hydronephrosis associated with retroperitoneal fibrosis and sclerosing pancreatitis. Lancet 359(9315):1403–1404
Infante-Duarte C, Horton HF, Byrne MC et al (2000) Microbial lipopeptides induce the production of IL-17 in Th cells. J Immunol 165(11):6107–6115
Kennedy MK, Torrance DS, Picha KS et al (1992) Analysis of cytokine mRNA expression in the central nervous system of mice with experimental autoimmune encephalomyelitis reveals that IL-10 mRNA expression correlates with recovery. J Immunol 149(7):2496–2505
King C, Tangye SG, Mackay CR (2008) T follicular helper (TFH) cells in normal and dysregulated immune responses. Annu Rev Immunol 26:741–766
Kitayama D, Sakamoto A, Arima M et al (2008) A role for Bcl6 in sequential class switch recombination to IgE in B cells stimulated with IL-4 and IL-21. Mol Immunol 45(5):1337–1345
Maehara T, Moriyama M, Nakashima H et al (2012a) Interleukin-21 contributes to germinal centre formation and immunoglobulin G4 production in IgG4-related dacryoadenitis and sialoadenitis, so-called Mikulicz’s disease. Ann Rheum Dis 71(12):2011–2020
Maehara T, Moriyama M, Hayashida JN et al (2012b) Selective localization of T helper subsets in labial salivary glands from primary Sjogren’s syndrome patients. Clin Exp Immunol 169:89–99
Maizels RM, Yazdanbakhsh M (2003) Immune regulation by helminth parasites: cellular and molecular mechanisms. Nat Rev Immunol 3(9):733–744
Mattoo H, Mahajan VS, Della-Torre E et al (2014) De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol 134(3):679–687
Mattoo H, Mahajan VS, Maehara T et al (2016) Clonal expansion of CD4+ cytotoxic T lymphocytes in IgG4-related disease. J Allergy Clin Immunol
Meiler F, Klunker S, Zimmermann M et al (2008) Distinct regulation of IgE, IgG4 and IgA by T regulatory cells and toll-like receptors. Allergy 63(11):1455–1463
Miyake K, Moriyama M, Aizawa K et al (2008) Peripheral CD4+ T cells showing a Th2 phenotype in a patient with Mikulicz’s disease associated with lymphadenopathy and pleural effusion. Mod Rheumatol 18(1):86–90
Morita R, Schmitt N, Bentebibel SE et al (2011) Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity 34(1):108–121
Moriyama M, Hayashida JN, Toyoshima T et al (2012) Cytokine/chemokine profiles contribute to understanding the pathogenesis and diagnosis of primary Sjogren’s syndrome. Clin Exp Immunol 169:17–26
Nakashima H, Miyake K, Moriyama M et al (2010) An amplification of IL-10 and TGF-beta in patients with IgG4-related tubulointerstitial nephritis. Clin Nephrol 73(5):385–391
Ohta N, Makihara S, Okano M et al (2012) Roles of IL-17, Th1, and Tc1 cells in patients with IgG4-related sclerosing sialadenitis. Laryngoscope 122(10):2169–2174
Ohta M, Moriyama M, Maehara T et al (2016) DNA microarray analysis of submandibular glands in IgG4-related disease indicates a role for MARCO and other innate immune related proteins. Medicine 95(7):e2853
Okazaki K, Uchida K, Ohana M et al (2000) Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology 118(3):573–581
Ozaki K, Spolski R, Feng CG et al (2002) A critical role for IL-21 in regulating immunoglobulin production. Science 298(5598):1630–1634
Punnonen J, Aversa G, Cocks BG et al (1993) Interleukin 13 induces interleukin 4-independent IgG4 and IgE synthesis and CD23 expression by human B cells. Proc Natl Acad Sci USA 90(8):3730–3734
Rapoport MJ, Jaramillo A, Zipris D et al (1993) Interleukin 4 reverses T cell proliferative unresponsiveness and prevents the onset of diabetes in nonobese diabetic mice. J Exp Med 178(1):87–99
Rispens T, Ooievaar-De Heer P, Vermeulen E et al (2009) Human IgG4 binds to IgG4 and conformationally altered IgG1 via Fc-Fc interactions. J Immunol 182(7):4275–4281
Sato Y, Kojima M, Takata K et al (2009) Systemic IgG4-related lymphadenopathy: a clinical and pathologic comparison to multicentric Castleman’s disease. Mod Pathol 22(4):589–599
Schmitz J, Owyang A, Oldham E et al (2005) IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity 23:479–490
Shevach EM, DiPaolo RA, Andersson J et al (2006) The lifestyle of naturally occurring CD4+ CD25+ Foxp3+ regulatory T cells. Immunol Rev 212:60–73
Takeda S, Haratake J, Kasai T et al (2004) IgG4-associated idiopathic tubulointerstitial nephritis complicating autoimmune pancreatitis. Nephrol Dial Transplant 19(2):474–476
Tanaka A, Moriyama M, Nakashima H et al (2012) Th2 and regulatory immune reactions contribute to IgG4 production and the initiation of Mikulicz disease. Arthritis Rheum 64(1):254–263
Van de Berg PJ, van Leeuwen E, ten Berge IJ et al (2008) Cytotoxic human CD4+ T cells. Curr Opin Immunol 20:339–343
van der Neut Kolfschoten M, Schuurman J, Losen M et al (2007) Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science 317(5844):1554–1557
Van Gorp H, Delputte PL, Nauwynck HJ (2010) Scavenger receptor CD163, a Jack-of-all-trades and potential target for cell-directed therapy. Mol Immunol 47:1650–1660
Vinuesa CG, Linterman MA, Goodnow CC et al (2010) T cells and follicular dendritic cells in germinal center B-cell formation and selection. Immunol Rev 237(1):72–89
Watanabe T, Yamashita K, Fujikawa S et al (2012) Involvement of activation of toll-like receptors and nucleotide-binding oligomerization domain-like receptors in enhanced IgG4 responses in autoimmune pancreatitis. Arthritis Rheumatol 64(3):914–924
Yamamoto M, Harada S, Ohara M et al (2005) Clinical and pathological differences between Mikulicz’s disease and Sjogren’s syndrome. Rheumatology 44(2):227–234
Zen Y, Harada K, Sasaki M et al (2004) IgG4-related sclerosing cholangitis with and without hepatic inflammatory pseudotumor, and sclerosing pancreatitis-associated sclerosing cholangitis: do they belong to a spectrum of sclerosing pancreatitis? Am J Surg Pathol 28(9):1193–1203
Zen Y, Fujii T, Harada K et al (2007) Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology 45(6):1538–1546
Zen Y, Inoue D, Kitao A et al (2009) IgG4-related lung and pleural disease: a clinicopathologic study of 21 cases. Am J Surg Pathol 33(12):1886–1893
Funding
This work was supported in part by grants from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (26293430, 26670869), the ‘Research on Measures for Intractable Diseases’ project, a matching fund subsidy from the Ministry of Health Labour and Welfare, Japan (H26-026, H26-064), the ‘Practical Research Project for Rare/Intractable Diseases,’ a matching fund subsidy from the Japan Agency for Medical Research and Development (H26-275, H26-313).
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Moriyama, M., Nakamura, S. (2016). Th1/Th2 Immune Balance and Other T Helper Subsets in IgG4-Related Disease. In: Okazaki, K. (eds) IgG4-Related Disease. Current Topics in Microbiology and Immunology, vol 401. Springer, Cham. https://doi.org/10.1007/82_2016_40
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DOI: https://doi.org/10.1007/82_2016_40
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