Advertisement

Pathophysiology

Chapter

Abstract

During the discovery process of IgG4-related disease (IgG4-RD), the bile duct appeared to be one of the target organs commonly affected by this condition [1–3]. Sclerosing cholangitis is a central biliary manifestation of IgG4-RD [1–3]. Although clinical manifestations of IgG4-RD vary widely among patients, underlying immune reactions and pathophysiology are supposed to be similar in any organs given the almost identical histopathological changes. Similar to other immune-mediated conditions, a likely pathogenetic mechanism is that the disease develops in genetically susceptible individuals exposed to external or endogenous antigens [4]. In this review, our current understanding of the molecular features of this emerging biliary disease is summarized. Data obtained from not only IgG4-related sclerosing cholangitis (IgG4-SC) but also IgG4-RD at other anatomical sites are discussed [4, 5].

Keywords

Autoimmune pancreatitis IgG4-related disease T cell B cell Pathogenesis 

Abbreviations

IgG4-AIP

IgG4-related autoimmune pancreatitis

IgG4-RD

IgG4-related disease

IgG4-SC

IgG4-related sclerosing cholangitis

PSC

Primary sclerosing cholangitis

Notes

Conflict of Interest

None to declare.

References

  1. 1.
    Zen Y, Nakanuma Y. IgG4 cholangiopathy. Int J Hepatol. 2012;2012:472376.CrossRefPubMedGoogle Scholar
  2. 2.
    Ghazale A, Chari ST, Zhang L, Smyrk TC, Takahashi N, Levy MJ, et al. Immunoglobulin G4-associated cholangitis: clinical profile and response to therapy. Gastroenterology. 2008;134:706–15.CrossRefPubMedGoogle Scholar
  3. 3.
    Bjornsson E, Chari ST, Smyrk TC, Lindor K. Immunoglobulin G4 associated cholangitis: description of an emerging clinical entity based on review of the literature. Hepatology. 2007;45:1547–54.CrossRefPubMedGoogle Scholar
  4. 4.
    Hart PA, Zen Y, Chari ST. Recent advances in autoimmune pancreatitis. Gastroenterology. 2015;149:39–51.CrossRefPubMedGoogle Scholar
  5. 5.
    Zen Y, Kawakami H, Kim JH. IgG4-related sclerosing cholangitis: all we need to know. J Gastroenterol. 2016;51:295–312.CrossRefPubMedGoogle Scholar
  6. 6.
    Kawa S, Ota M, Yoshizawa K, Horiuchi A, Hamano H, Ochi Y, et al. HLA DRB10405-DQB10401 haplotype is associated with autoimmune pancreatitis in the Japanese population. Gastroenterology. 2002;122:1264–9.CrossRefPubMedGoogle Scholar
  7. 7.
    Park do H, Kim MH, Oh HB, Kwon OJ, Choi YJ, Lee SS, et al. Substitution of aspartic acid at position 57 of the DQbeta1 affects relapse of autoimmune pancreatitis. Gastroenterology. 2008;134:440–6.CrossRefPubMedGoogle Scholar
  8. 8.
    Chang MC, Jan IS, Liang PC, Jeng YM, Yang CY, Tien YW, et al. Cystic fibrosis transmembrane conductance regulator gene variants are associated with autoimmune pancreatitis and slow response to steroid treatment. J Cyst Fibros. 2015;14:661–7.CrossRefPubMedGoogle Scholar
  9. 9.
    Chang MC, Chang YT, Tien YW, Liang PC, Jan IS, Wei SC, et al. T-cell regulatory gene CTLA-4 polymorphism/haplotype association with autoimmune pancreatitis. Clin Chem. 2007;53:1700–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Chang MC, Jan IS, Liang PC, Jeng YM, Yang CY, Tien YW, et al. Human cationic trypsinogen but not serine peptidase inhibitor, Kazal type 1 variants increase the risk of type 1 autoimmune pancreatitis. J Gastroenterol Hepatol. 2014;29:2038–42.CrossRefPubMedGoogle Scholar
  11. 11.
    Umemura T, Ota M, Hamano H, Katsuyama Y, Muraki T, Arakura N, et al. Association of autoimmune pancreatitis with cytotoxic T-lymphocyte antigen 4 gene polymorphisms in Japanese patients. Am J Gastroenterol. 2008;103:588–94.CrossRefPubMedGoogle Scholar
  12. 12.
    Umemura T, Ota M, Hamano H, Katsuyama Y, Kiyosawa K, Kawa S. Genetic association of Fc receptor-like 3 polymorphisms with autoimmune pancreatitis in Japanese patients. Gut. 2006;55:1367–8.CrossRefPubMedCentralPubMedGoogle Scholar
  13. 13.
    Yoshida K, Toki F, Takeuchi T, Watanabe S, Shiratori K, Hayashi N. Chronic pancreatitis caused by an autoimmune abnormality. Proposal of the concept of autoimmune pancreatitis. Dig Dis Sci. 1995;40:1561–8.CrossRefPubMedGoogle Scholar
  14. 14.
    Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and a Th1/Th2-type cellular immune response. Gastroenterology. 2000;118:573–81.CrossRefPubMedGoogle Scholar
  15. 15.
    Aalberse RC, Stapel SO, Schuurman J, Rispens T. Immunoglobulin G4: an odd antibody. Clin Exp Allergy. 2009;39:469–77.CrossRefPubMedGoogle Scholar
  16. 16.
    de Buy Wenniger LJ, Culver EL, Beuers U. Exposure to occupational antigens might predispose to IgG4-related disease. Hepatology. 2014;60(4):1453.CrossRefPubMedCentralPubMedGoogle Scholar
  17. 17.
    Zen Y, Fujii T, Harada K, Kawano M, Yamada K, Takahira M, et al. Th2 and regulatory immune reactions are increased in immunoglobin G4-related sclerosing pancreatitis and cholangitis. Hepatology. 2007;45:1538–46.CrossRefPubMedGoogle Scholar
  18. 18.
    Zen Y, Nakanuma Y. Pathogenesis of IgG4-related disease. Curr Opin Rheumatol. 2011;23:114–8.CrossRefPubMedGoogle Scholar
  19. 19.
    Kleinewietfeld M, Hafler DA. Regulatory T cells in autoimmune neuroinflammation. Immunol Rev. 2014;259:231–44.CrossRefPubMedCentralPubMedGoogle Scholar
  20. 20.
    Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS. Regulatory T-cells in autoimmune diseases: challenges, controversies and–yet–unanswered questions. Autoimmun Rev. 2015;14:105–16.CrossRefPubMedGoogle Scholar
  21. 21.
    Maillette de Buy Wenniger LJ, Doorenspleet ME, Klarenbeek PL, Verheij J, Baas F, Elferink RP, et al. Immunoglobulin G4+ clones identified by next-generation sequencing dominate the B cell receptor repertoire in immunoglobulin G4 associated cholangitis. Hepatology. 2013;57:2390–8.CrossRefPubMedGoogle Scholar
  22. 22.
    Jeannin P, Lecoanet S, Delneste Y, Gauchat JF, Bonnefoy JY. IgE versus IgG4 production can be differentially regulated by IL-10. J Immunol. 1998;160:3555–61.PubMedGoogle Scholar
  23. 23.
    Akiyama M, Suzuki K, Yamaoka K, Yasuoka H, Takeshita M, Kaneko Y, et al. Number of circulating follicular helper 2 T cells correlates with IgG4 and Interleukin-4 levels and plasmablast numbers in IgG4-related disease. Arthritis Rheumatol. 2015;67:2476–81.CrossRefPubMedGoogle Scholar
  24. 24.
    Akiyama M, Yasuoka H, Yamaoka K, Suzuki K, Kaneko Y, Kondo H, et al. Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease. Arthritis Res Ther. 2016;18:167.CrossRefPubMedCentralPubMedGoogle Scholar
  25. 25.
    Akiyama M, Suzuki K, Yasuoka H, Kaneko Y, Yamaoka K, Takeuchi T. Follicular helper T cells in the pathogenesis of IgG4-related disease. Rheumatology (Oxford). 2018;57(2):236–45.CrossRefGoogle Scholar
  26. 26.
    Maehara T, Moriyama M, Nakashima H, Miyake K, Hayashida JN, Tanaka A, et al. 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. 2012;71:2011–9.CrossRefPubMedGoogle Scholar
  27. 27.
    Zen Y, Nakanuma Y. IgG4-related disease: a cross-sectional study of 114 cases. Am J Surg Pathol. 2010;34:1812–9.CrossRefPubMedGoogle Scholar
  28. 28.
    Esposito I, Born D, Bergmann F, Longerich T, Welsch T, Giese NA, et al. Autoimmune pancreatocholangitis, non-autoimmune pancreatitis and primary sclerosing cholangitis: a comparative morphological and immunological analysis. PLoS One. 2008;3:e2539.CrossRefPubMedCentralPubMedGoogle Scholar
  29. 29.
    Tsuboi H, Nakai Y, Iizuka M, Asashima H, Hagiya C, Tsuzuki S, et al. DNA microarray analysis of labial salivary glands in IgG4-related disease: comparison with Sjogren’s syndrome. Arthritis Rheumatol. 2014;66:2892–9.CrossRefPubMedGoogle Scholar
  30. 30.
    Zen Y, Liberal R, Nakanuma Y, Heaton N, Portmann B. Possible involvement of CCL1-CCR8 interaction in lymphocytic recruitment in IgG4-related sclerosing cholangitis. J Hepatol. 2013;59:1059–64.CrossRefPubMedGoogle Scholar
  31. 31.
    Soler D, Chapman TR, Poisson LR, Wang L, Cote-Sierra J, Ryan M, et al. CCR8 expression identifies CD4 memory T cells enriched for FOXP3+ regulatory and Th2 effector lymphocytes. J Immunol. 2006;177:6940–51.CrossRefPubMedGoogle Scholar
  32. 32.
    Muller T, Beutler C, Pico AH, Otten M, Durr A, Al-Abadi H, et al. Increased T-helper 2 cytokines in bile from patients with IgG4-related cholangitis disrupt the tight junction-associated biliary epithelial cell barrier. Gastroenterology. 2013;144:1116–28.CrossRefPubMedGoogle Scholar
  33. 33.
    Khosroshahi A, Carruthers MN, Deshpande V, Unizony S, Bloch DB, Stone JH. Rituximab for the treatment of IgG4-related disease: lessons from 10 consecutive patients. Medicine (Baltimore). 2012;91:57–66.CrossRefGoogle Scholar
  34. 34.
    Hart PA, Topazian MD, Witzig TE, Clain JE, Gleeson FC, Klebig RR, et al. Treatment of relapsing autoimmune pancreatitis with immunomodulators and rituximab: the Mayo Clinic experience. Gut. 2013;62:1607–15.CrossRefPubMedGoogle Scholar
  35. 35.
    Sumimoto K, Uchida K, Kusuda T, Mitsuyama T, Sakaguchi Y, Fukui T, et al. The role of CD19+ CD24high CD38high and CD19+ CD24high CD27+ regulatory B cells in patients with type 1 autoimmune pancreatitis. Pancreatology. 2014;14:193–200.CrossRefPubMedGoogle Scholar
  36. 36.
    van de Veen W, Stanic B, Yaman G, Wawrzyniak M, Sollner S, Akdis DG, et al. IgG4 production is confined to human IL-10-producing regulatory B cells that suppress antigen-specific immune responses. J Allergy Clin Immunol. 2013;131:1204–12.CrossRefPubMedGoogle Scholar
  37. 37.
    Mattoo H, Mahajan VS, Della-Torre E, Sekigami Y, Carruthers M, Wallace ZS, et al. De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4-related disease. J Allergy Clin Immunol. 2014;134:679–87.CrossRefPubMedCentralPubMedGoogle Scholar
  38. 38.
    Wallace ZS, Mattoo H, Carruthers M, Mahajan VS, Della Torre E, Lee H, et al. Plasmablasts as a biomarker for IgG4-related disease, independent of serum IgG4 concentrations. Ann Rheum Dis. 2015;74:190–5.CrossRefPubMedGoogle Scholar
  39. 39.
    Nirula A, Glaser SM, Kalled SL, Taylor FR. What is IgG4? A review of the biology of a unique immunoglobulin subtype. Curr Opin Rheumatol. 2011;23:119–24.CrossRefPubMedGoogle Scholar
  40. 40.
    van der Neut Kolfschoten M, Schuurman J, Losen M, Bleeker WK, Martinez-Martinez P, Vermeulen E, et al. Anti-inflammatory activity of human IgG4 antibodies by dynamic Fab arm exchange. Science. 2007;317:1554–7.CrossRefPubMedGoogle Scholar
  41. 41.
    Zen Y, Britton D, Mitra V, Pike I, Heaton N, Quaglia A. A global proteomic study identifies distinct pathological features of IgG4-related and primary sclerosing cholangitis. Histopathology. 2015;68:796–809.CrossRefPubMedGoogle Scholar
  42. 42.
    Culver EL, Sadler R, Bateman AC, Makuch M, Cargill T, Ferry B, et al. Increases in IgE, eosinophils, and mast cells can be used in diagnosis and to predict relapse of IgG4-related disease. Clin Gastroenterol Hepatol. 2017;15(9):1444–1452.e6.CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Yamamoto M, Shimizu Y, Takahashi H, Yajima H, Yokoyama Y, Ishigami K, et al. CCAAT/enhancer binding protein alpha (C/EBPalpha)(+) M2 macrophages contribute to fibrosis in IgG4-related disease? Mod Rheumatol. 2015;25:484–6.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media Singapore 2019

Authors and Affiliations

  1. 1.Department of Diagnostic PathologyKobe University Graduate School of MedicineKobeJapan

Personalised recommendations