Abstract
Background
Aberrant activation of follicular helper T (TFH) and B cells is associated with the development of autoimmune diseases. However, little is known about the potential role of these cells in the development of primary biliary cirrhosis (PBC).
Aim
This study aimed at characterizing the numbers of different subsets of circulating Tfh and B cells as well as evaluating their potential association with the levels of immunoglobulins and autoantibodies in newly diagnosed PBC patients.
Methods
The numbers of circulating CD27+, CD38+, CD86+ and CD95+ B cells as well as inducible T cell costimulator (ICOS)+ and programmed death-1 (PD-1)+, IL-21+ TFH cells were examined in 58 patients with newly diagnosed PBC and 30 matched healthy controls (HCs).
Results
The numbers of circulating CD38+CD19+, CD86+CD19+, and CD95+CD19+ B cells; CD3+CD4+CXCR5+ICOS+ and CD3+CD4+CXCR5+PD-1+ Tfh cells; and the levels of serum IL-21 in the PBC patients were significantly greater, but the numbers of CD27+CD19+ B cells were significantly less than those in the HCs (p < 0.05). The numbers of CD3+CD4+CXCR5+ICOS+ Tfh cells were positively correlated with the numbers of CD38+CD19+ and CD86+CD38+CD19+ B cells and the levels of serum anti-mitochondrial antibodies against M2 antigen (AMA-M2), AMA and immunolgubin M (IgM) in the PBC patients. The levels of serum IL-21 were positively correlated with the levels of serum AMA-M2, AMA, IgG and IgM, but negatively with the numbers of CD27+CD19+ B cells in the PBC patients.
Conclusions
Increased numbers of circulating ICOS+ and IL-21+ Tfh and CD38+ plasma cells may be exhibited by patients with recent diagnoses of PBC.
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References
Lindor KD, Gershwin ME, Poupon R, et al. Primary biliary cirrhosis. Hepatology. 2009;50:291–308.
Saito H, Takahashi A, Abe K, et al. Autoantibodies by line immunoassay in patients with primary biliary cirrhosis. Fukushima J Med Sci. 2012;58:107–116.
Hirschfield GM, Chapman RW, Karlsen TH, Lammert F, Lazaridis KN, Mason AL. The genetics of complex cholestatic disorders. Gastroenterology. 2013;144:1357–1374.
McNally RJ, James PW, Ducker S, James OF. Seasonal variation in the patient diagnosis of primary biliary cirrhosis: further evidence for an environmental component to etiology. Hepatology. 2011;54:2099–2103.
Selmi C, Bowlus CL, Gershwin ME, Coppel RL. Primary biliary cirrhosis. Lancet. 2011;377:1600–1609.
Takahashi T, Miura T, Nakamura J, et al. Plasma cells and the chronic nonsuppurative destructive cholangitis of primary biliary cirrhosis. Hepatology. 2012;55:846–855.
Dhirapong A, Lleo A, Yang GX, et al. B cell depletion therapy exacerbates murine primary biliary cirrhosis. Hepatology. 2011;53:527–535.
Zhao LD, Li Y, Smith MF Jr, et al. Expressions of BAFF/BAFF receptors and their correlation with disease activity in Chinese SLE patients. Lupus. 2010;19:1534–1549.
Zhong X, Tumang JR, Gao W, Bai C, Rothstein TL. PD-L2 expression extends beyond dendritic cells/macrophages to B1 cells enriched for V(H)11/V(H)12 and phosphatidylcholine binding. Eur J Immunol. 2007;37:2405–2410.
Agematsu K. Memory B cells and CD27. Histol Histopathol. 2000;15:573–576.
Bernuzzi F, Fenoglio D, Battaglia F, et al. Phenotypical and functional alterations of CD8 regulatory T cells in primary biliary cirrhosis. J Autoimmun. 2010;35:176–180.
Zhang W, Sharma R, Ju ST, et al. Deficiency in regulatory T cells results in development of antimitochondrial antibodies and autoimmune cholangitis. Hepatology. 2009;49:545–552.
Patakas A, Platt AM, Butcher JP, et al. Putative existence of reciprocal dialogue between Tfh and B cells and its impact on infectious and autoimmune disease. Immunol Lett. 2011;138:38–46.
Zhang X, Ing S, Fraser A, et al. Follicular helper T cells: new insights into mechanisms of autoimmune diseases. Ochsner J.. 2013;13:131–139.
Linterman MA, Liston A, Vinuesa CG. T-follicular helper cell differentiation and the co-option of this pathway by non-helper cells. Immunol Rev. 2012;247:143–159.
Riella LV, Paterson AM, Sharpe AH, Chandraker A. Role of the PD-1 pathway in the immune response. Am J Transplant. 2012;12:2575–2587.
Chen J, Wang F, Cai Q, et al. A novel anti-human ICOSL monoclonal antibody that enhances IgG production of B cells. Monoclon Antib Immunodiagn Immunother. 2013;32:125–131.
Crotty S. Follicular helper CD4 T cells (TFH). Annu Rev Immunol. 2011;29:621–663.
Nurieva RI, Chung Y, Martinez GJ, et al. Bcl6 mediates the development of T follicular helper cells. Science. 2009;325:1001–1005.
Yu D, Rao S, Tsai LM, et al. The transcriptional repressor Bcl-6 directs T follicular helper cell lineage commitment. Immunity. 2009;31:457–468.
Feng X, Wang D, Chen J, et al. Inhibition of aberrant circulating Tfh cell proportions by corticosteroids in patients with systemic lupus erythematosus. PLoS ONE. 2012;7:e51982.
Medicetty S, Wiktor D, Lehman N, et al. Percutaneous adventitial delivery of allogeneic bone marrow-derived stem cells via infarct-related artery improves long-term ventricular function in acute myocardial infarction. Cell Transplant. 2012;21:1109–1120.
Zotos D, Coquet JM, Zhang Y, et al. IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism. J Exp Med. 2010;207:365–378.
Baldursdottir TR, Bergmann OM, Jonasson JG, Ludviksson BR, Axelsson TA, Bjornsson ES. The epidemiology and natural history of primary biliary cirrhosis: a nationwide population-based study. Eur J Gastroenterol Hepatol. 2012;24:824–830.
Aoki N, Kido M, Iwamoto S, et al. Dysregulated generation of follicular helper T cells in the spleen triggers fatal autoimmune hepatitis in mice. Gastroenterology. 2011;140:1322–1333.
Feng X, Wang D, Chen J, et al. Inhibition of aberrant circulating Tfh cell proportions by corticosteroids in patients with systemic lupus erythematosus. PLoS ONE. 2012;7:e51982.
Odendahl M, Jacobi A, Hansen A, et al. Disturbed peripheral B lymphocyte homeostasis in systemic lupus erythematosus. J Immunol. 2000;165:5970–5979.
Reinehr R, Gorg B, Hongen A, Haussinger D. CD95-tyrosine nitration inhibits hyperosmotic and CD95 ligand-induced CD95 activation in rat hepatocytes. J Biol Chem. 2004;279:10364–10373.
Horst A, Hunzelmann N, Arce S, et al. Detection and characterization of plasma cells in peripheral blood: correlation of IgE+ plasma cell frequency with IgE serum titre. Clin Exp Immunol. 2002;130:370–378.
Linterman MA, Vinuesa CG. T follicular helper cells during immunity and tolerance. Prog Mol Biol Transl Sci. 2010;92:207–248.
Eto D, Lao C, DiToro D, et al. IL-21 and IL-6 are critical for different aspects of B cell immunity and redundantly induce optimal follicular helper CD4 T cell (Tfh) differentiation. PLoS ONE. 2011;6:e17739.
Pene J, Gauchat JF, Lecart S, et al. Cutting edge: IL-21 is a switch factor for the production of IgG1 and IgG3 by human B cells. J Immunol. 2004;172:5154–5157.
Morita R, Schmitt N, Bentebibel SE, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34:108–121.
Ding Y, Li J, Yang P, et al. IL-21 promotes germinal center reaction by skewing the Tfr/Tfh balance in autoimmune BXD2 mice. Arthritis Rheumatol. 06/06/2014 (Epub ahead of print). doi:10.1002/art.38735.
Acknowledgments
Supported by grants from the National Natural Science Foundation of China (no. 30972610 and 81273240), Jilin Province Science and Technology Agency (no. 20110716), the Health Department Research Projects in Jilin Province (2009Z054) and Norman Bethune Program of Jilin University (2012206).
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Li Wang, Xiguang Sun and Pingwei Zhao made equal contributions to this study.
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Wang, L., Sun, X., Qiu, J. et al. Increased Numbers of Circulating ICOS+ Follicular Helper T and CD38+ Plasma Cells in Patients with Newly Diagnosed Primary Biliary Cirrhosis. Dig Dis Sci 60, 405–413 (2015). https://doi.org/10.1007/s10620-014-3372-3
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DOI: https://doi.org/10.1007/s10620-014-3372-3