Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases
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Patients with autoimmune pancreatitis (AIP) characteristically show elevated serum levels of immunoglobulin G4 (IgG4) and abundant infiltration of IgG4-positive plasmacytes in the involved organs. The most common involved organ showing extrapancreatic lesions is the bile duct, which exhibits sclerosing cholangitis (SC). However, the role of IgG4 in the development of IgG4-related SC (IgG4-SC) remains unclear. To clarify the role of IgG4 in IgG4-SC, we have performed an immunohistochemical analysis of the bile duct.
Laboratory and immunohistochemical findings of liver biopsy specimens obtained from patients with IgG4-SC, primary sclerosing cholangitis (PSC), autoimmune hepatitis (AIH), and primary biliary cirrhosis (PBC) were compared. The biopsy specimens were first stained with anti-IgG1, anti-IgG4, and anti-Foxp3 (forkhead box P3) antibodies, and the ratio of IgG4-, IgG1-, and Foxp3-positive cells, respectively, to infiltrated mononuclear cells (IgG4/Mono, IgG1/Mono, Foxp3/Mono) was assessed.
The ratio of IgG4/IgG1-positive plasma cells was significantly higher in specimens obtained from patients with IgG4-SC than in those from patients with PSC, AIH, and PBC. The Foxp3/Mono ratio in patients with PBC was significantly higher than that in patients with IgG4-SC and PSC. In patients with IgG4-SC, the number of Foxp3-positive cells was significantly correlated with the number of IgG4-positive cells; in the other patient groups, there was no correlation.
The IgG4/IgG1 ratio in the liver may be a useful marker for differential diagnosis of IgG4-SC and PSC. In IgG4-SC, abundant infiltration of regulatory T cells (Tregs) may affect the switching of B cells to IgG4-producing plasmacytes, and there is a possibility that the function of Tregs is different in IgG4-SC and other liver diseases (PSC, AIH, and PBC).
- Sarles H, Sarles JC, Muratore R, Guien C. Chronic inflammatory sclerosis of the pancreas––an autonomous pancreatic disease? Am J Dig Dis. 1961;6:688–98. CrossRef
- 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. CrossRef
- Horiuchi A, Kawa S, Akamatsu T, Aoki Y, Mukawa K, Furuya N, et al. Characteristic pancreatic duct appearance in autoimmune chronic pancreatitis: a case report and review of Japanese literature. Am J Gastroenterol. 1998;93:260–3. CrossRef
- Uchida K, Okazaki K, Konishi Y Ohana M, Takakuwa H, Hajiro K, et al. Clinical analysis of autoimmune-related pancreatitis. Am J Gastroenterol. 2000;95:2788–94.
- Okazaki K, Kawa S, Kamisawa T, Naruse S, Tanaka S, Nishimori I, et al. Clinical diagnostic criteria of autoimmune pancreatitis: revised proposal. J Gastroenterol. 2006;41:626–31. CrossRef
- Okazaki K, Uchida K, Matsushita M, Takaoka M. Autoimmune pancreatitis. Intern Med. 2005;44:1215–23. CrossRef
- Kamisawa T, Egawa N, Nakajima H, Tsuruta K, Okamoto A. Extrapancreatic lesions in autoimmune pancreatitis. J Clin Gastroenterol. 2005;39:904–7. CrossRef
- Nakazawa T, Ohara H, Sano H, Ando T, Aoki S, Kobayashi S, et al. Clinical differences between primary sclerosing cholangitis and sclerosing cholangitis with autoimmune pancreatitis. Pancreas. 2005;30:20–5.
- Hamano H, Kawa S, Horiuchi A, Unno H, Furuya N, Akamatsu T, et al. High serum IgG4 concentrations in patients with sclerosing pancreatitis. N Engl J Med. 2001;344:732–8. CrossRef
- Kamisawa T, Okamoto A. Autoimmune pancreatitis: proposal of IgG4-related sclerosing disease. J Gastroenterol. 2006;41:613–25. CrossRef
- 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. CrossRef
- Nakazawa T, Ohara H, Sano H, Aoki S, Kobayashi S, Okamoto T, et al. Cholangiography can discriminate sclerosing cholangitis with autoimmune pancreatitis from primary sclerosing cholangitis. Gastrointest Endosc. 2004;60:937–44. CrossRef
- Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+ CD25high regulatory cells in human peripheral blood. J Immunol. 2001;167:1245–53.
- Dieckmann D, Plottner H, Berchtold S, Berger T, Schuler G. Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med. 2001;193:1303–10. CrossRef
- Wing K, Ekmark A, Karlsson H, Rudin A, Suri-Payer E. Characterization of human CD25+ CD4+ T cells in thymus, cord and adult blood. Immunology. 2002;106:190–9. CrossRef
- Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Sawada T, et al. CD4+ CD25bright T cells in human intestinal lamina propria as regulatory cells. J Immunol. 2004;173:3119–30.
- Miyoshi H, Uchida K, Taniguchi T, Yazumi S, Matsushita M, Takaoka M, et al. Circulating Naive and CD4+ CD25high regulatory T cells in patients with autoimmune pancreatitis. Pancreas. 2007;36:133–40. CrossRef
- Otsuki M, Chung JB, Okazaki K, Kim MH, Kamisawa T, Kawa S, et al. Asian diagnostic criteria for autoimmune pancreatitis: consensus of the Japan-Korea Symposium on Autoimmune Pancreatitis. J Gastroenterol. 2008;43:403–8. CrossRef
- 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.
- Alvarez F, Berg PA, Bianchi FB, Bianchi L, Burroughs AK, Cancado EL, et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol. 1999;31:929–38. CrossRef
- Vergani D, Alvarez F, Bianchi FB, Cançado EL, Mackay IR, Manns MP, et al. Liver autoimmune serology: a consensus statement from the committee for autoimmune serology of the International Autoimmune Hepatitis Group. J Hepatol. 2004;41:677–83. CrossRef
- Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl J Med. 2005;353:1261–73. CrossRef
- LaRusso NF, Weisnor RH, Ludwig J, MacCarty RL. Current concept: primary sclerosing cholangitis. N Engl J Med. 1984;310:899–903. CrossRef
- Yamamoto M, Takahashi H, Ohara M, Suzuki C, Naishiro Y, Yamamoto H, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16:335–40. CrossRef
- Masaki Y, Dong L, Kurose N, Kitagawa K, Morikawa Y, Yamamoto M, et al. Proposal for a new clinical entity, IgG4-positive multi-organ lymphoproliferative syndrome: Analysis of 64 cases of IgG4-related disorders. Ann Rheum Dis. 2009;68:1310–5. CrossRef
- Hayashi K, Nakazawa T, Ohara H, Ando T, Takada H, Tanaka H, et al. Autoimmune sclerosing cholangiopancreatitis with little pancreatic involvements by imaging findings. Hepatogastroenterology. 2007;54:2150–5.
- Hamano H, Kawa S, Uehara T, Ochi Y, Takayama M, Komatsu K, et al. Immunoglobulin G4–related lymphoplasmacytic sclerosing cholangitis that mimics infiltrating hilar cholangiocarcinoma: part of a spectrum of autoimmune pancreatitis? Gastrointest Endosc. 2005;62:152–7. CrossRef
- Nishino T, Oyama H, Hashimoto E, Toki F, Oi I, Kobayashi M, et al. Clinicopathological differentiation between sclerosing cholangitis with autoimmune pancreatitis and primary sclrosing cholangitis. J Gastroenterol. 2007;42:550–9. CrossRef
- Ohara H, Nakazawa T, Ando T, Joh T. Systemic extrapancreatic lesions associated with autoimmune pancreatitis. J Gastroenterol. 2007;42:15–21. CrossRef
- Uehara T, Hamano H, Kawa S, Sano K, Honda T, Ota H. Distinct clinicopathological entity autoimmune pancreatitis-associated sclerosing cholangitis. Pathol Int. 2005;55:405–11. CrossRef
- Zen Y, Harada K, Sasaki M, Sato Y, Tsuneyama K, Haratake J, et al. 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. 2004;28:1193–203. CrossRef
- Umemura T, Zen Y, Hamano H, Kawa S, Nakanuma Y, Kiyosawa K. Immunoglobin G4-hepatopathy association of immunoglobin G4-bearing plasma cells in liver with autoimmune pancreatitis. Hepatology. 2007;46:463–71. CrossRef
- Umemura T, Zen Y, Hamano H, Ichijo T, Kawa S, Nakanuma Y, et al. IgG4 associated autoimmune hepatitis: a differential diagnosis for classical autoimmune hepatitis. Gut. 2007;56:1471–2. CrossRef
- Chung H, Watanabe T, Kudo M, Maenishi O, Wakatsuki Y, Chiba T. Identification and characterization of IgG4-associated autoimmune hepatitis. Liver Int. 2010;30:222–31.
- Lan RY, Cheng C, Lian ZX, Tsuneyama K, Yang GX, Moritoki Y, et al. Liver-targeted and peripheral blood alterations of regulatory T cells in primary biliary cirrhosis. Hepatology. 2006;43:729–37. CrossRef
- Sasaki M, Ikeda H, Sawada S, Sato Y, Nakanuma Y. Naturally-occurring regulatory T cells are increased in inflamed portal tracts with cholangiopathy in primary biliary cirrhosis. J Clin Pathol. 2007;60:1102–7. CrossRef
- Sakaki M, Hiroishi K, Baba T, Ito T, Hirayama Y, Saito K, et al. Intrahepatic status of regulatory T cells in autoimmune liver diseases and chronic viral hepatitis. Hepatol Res. 2008;38:354–61. CrossRef
- Longhi MS, Hussain MJ, Mitry RR, Arora SK, Vergani GM, Vergani D, et al. Functional study of CD4+ CD25+ regulatory T cells in health and autoimmune hepatitis. J Immunol. 2006;176:4484–91.
- Longhi MS, Ma Y, Bogdanos DP, Cheeseman P, Mieli-Vergani G, Vergani D. Impairment of CD4(+)CD25(+) regulatory T-cells in autoimmune liver disease. J Hepatol. 2004;41:31–7. CrossRef
- Okazaki K, Uchida K, Ohana M, Nakase H, Uose S, Inai M, et al. Autoimmune-related pancreatitis is associated with autoantibodies and Th1/Th2 cellular immune response. Gastroenterology. 2000;118:573–81. CrossRef
- Robinson DS, Larche M, Durhan SR. Tregs and allergic disease. J Clin Invest. 2004;114:1389–97.
- Alpan O, Bachelder E, Isil E, Arnheiter H, Matzinger P. ‘Educated’ dendritic cells act as messengers from memory to naive T helper cells. Nat Immunol. 2004;5:615–22. CrossRef
- Watt JK, Hawkins K, Zhang M, Lipschitz J, Sandha G, Gong Y, et al. Transforming growth factor-beta (TGF-beta) protein levels are not elevated in the blood or bile of patients with primary sclerosing cholangitis: a pilot study. Dig Dis Sci. 2004;49:5–8. CrossRef
- Rong G, Zhou Y, Xiong Y, Zhou L, Geng H, Jiang T, et al. Imbalance between T helper type 17 and T regulatory cells in patients with primary biliary cirrhosis: the serum cytokine profile and peripheral cell population. Clin Exp Immunol. 2009;156:217–25. CrossRef
- Sakaguchi K, Kitano M, Nishimura M, Senoh T, Ohta T, Terao M, et al. Serum level of transforming growth factor-beta1 (TGF-beta1) and the expression of TGF-beta receptor type II in peripheral blood mononuclear cells in patients with autoimmune hepatitis. Hepatogastroenterology. 2004;51:1780–3.
- Allan SE, Crome SQ, Crellin NK, Passerini L, Steiner TS, Bacchetta R, et al. Activation-induced FOXP3 in human T effector cells does not suppress proliferation or cytokine production. Int Immunol. 2007;19:345–54. CrossRef
- Tran DQ, Ramsey H, Shevach EM. Induction of FOXP3 expression in naive human CD4+ FOXP3 T cells by T-cell receptor stimulation is transforming growth factor-beta dependent but does not confer a regulatory phenotype. Blood. 2007;110:2983–90. CrossRef
- Valmori D, Merlo A, Souleimanian NE, Hesdorffer CS, Ayyoub M. A peripheral circulating compartment of natural naive CD4 Tregs. J Clin Invest. 2005;115:1953–62. CrossRef
- Vukmanovic-Stejic M, Zhang Y, Cook JE, Fletcher JM, McQuaid A, Masters JE, et al. Human CD4+ CD25hiFoxp3+ regulatory T cells are derived by rapid turnover of memory populations in vivo. J Clin Invest. 2006;116:2423–33. CrossRef
- Miyara M, Yoshioka Y, Kitoh A, Shima T, Wing K, Niwa A, et al. Functional Delineation and Differentiation Dynamics of Human CD4(+) T Cells Expressing the FoxP3 Transcription Factor. Immunity. 2009;30:1–13. CrossRef
- Ito T, Hanabuchi S, Wang YH, Park WR, Arima K, Bover L, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity. 2008;28:870–80. CrossRef
- Uchida K, Okazaki K, Nishi T, Uose S, Nakase H, Ohana M, et al. Experimental immune-mediated pancreatitis in neonatally thymectomized mice immunized with carbonic anhydarase II and lactoferrin. Lab Invest. 2002;82:411–24.
- Okazaki K, Uchida K, Fukui T. Recent advances in autoimmune pancreatitis: concept, diagnosis, and pathogenesis. J Gastroenterol. 2008;43:409–18. CrossRef
- Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases
Journal of Gastroenterology
Volume 45, Issue 7 , pp 732-741
- Cover Date
- Print ISSN
- Online ISSN
- Springer Japan
- Additional Links
- Autoimmune pancreatitis
- IgG4-related diseases
- Regulatory T cell
- Sclerosing cholangitis
- Industry Sectors
- Author Affiliations
- 1. Division of Gastroenterology and Hepatology, The Third Department of Internal Medicine, Kansai Medical University, 10-15 Fumizono, Moriguchi, Osaka, 570-8507, Japan
- 2. Department of Clinical Sciences and Laboratory Medicine, Kansai Medical University, Moriguchi, Osaka, Japan
- 3. Division of Hepato-Pancreato-Biliary Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawara-cho, Sakyo-ku, Kyoto, Kyoto, 606-8507, Japan