title: Chemokine (C-X-C motif) ligand 13 promotes intrahepatic chemokine (C-X-C motif) receptor 5+ lymphocyte homing and aberrant B-cell immune responses in primary biliary cirrhosis.
abstract: The serological hallmark of primary biliary cirrhosis (PBC) is the presence of high titer and specific antimitochondrial antibodies (AMAs). Although there is no global immune defect in patients with PBC, there is widespread dysregulated B-cell function, including increased sera levels of immunoglobulin M and enhanced B-cell responses to cytosine-phosphate-guanine stimulation. The mechanisms involved in this B-cell dysfunction have remained unknown. To address this issue, we focused on identifying the frequencies of B-cell subsets in patients with PBC and the mechanisms that lead to B-cell dysregulation, including the relationships with chemokine (C-X-C motif) receptor 5 (CXCR5)(+) CD4(+) T cells. Herein, we report that elevations of both serum and intrahepatic interleukin-21 (IL-21) were found in patients with PBC and, in particular, promoted B-cell proliferation, signal transducer and activator of transcription 3 phosphorylation and AMA production in vitro. More important, upon stimulation with recombinant E2 subunit of pyruvate dehydrogenase complex, CXCR5(+) CD4(+) T cells in PBC produced higher levels of IL-21 than healthy controls. Additionally, sorted CXCR5(+) CD4(+) T cells increased production of AMAs by autologous CD19(+) B cells. Indeed, elevated expression of intrahepatic chemokine (C-X-C motif) ligand 13 (CXCL13), a key chemokine of CXCR5(+) cells, was uniquely found within the portal tracts in PBC, accompanied by infiltrates of CD4(+) , CXCR5(+) , CD19(+) , and CD38(+) cells.
  
  
  CONCLUSIONS
  CXCL13 promotes aggregation of CD19(+) B cells and CXCR5(+) CD4(+) T cells, which directs the aberrant AMA response by IL-21. These data have implications for potential immunotherapy and also reflect the unique lymphoid biology in liver of PBC.
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Yongyin
authors: Y
authors: Li
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Weibin
authors: W
authors: Wang
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Libo
authors: L
authors: Tang
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Xuanqiu
authors: X
authors: He
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Xin
authors: X
authors: Yan
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Xiaoyong
authors: X
authors: Zhang
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Youfu
authors: Y
authors: Zhu
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.
authors: Jian
authors: J
authors: Sun
authors: Division of Hepatology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
authors: Yongquan
authors: Y
authors: Shi
authors: Division of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
authors: Xiong
authors: X
authors: Ma
authors: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors: Ian R
authors: IR
authors: Mackay
authors: Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis, CA, USA.
authors: M Eric
authors: ME
authors: Gershwin
authors: Division of Hepatology, Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an, China.
authors: Ying
authors: Y
authors: Han
authors: State Key Laboratory of Organ Failure Research, Guangdong Provincial Key Laboratory of Viral Hepatitis Research, Department of Infectious Diseases and Hepatology Unit, Nanfang Hospital, Southern Medical University, Guangzhou, China.|Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Zhejiang University, Hangzhou, China.
authors: Jinlin
authors: J
authors: Hou
mesh_terms: D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000502:physiology*; D015704:CD4 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D054382:Chemokine CXCL13 / Q000378:metabolism*; D006801:Humans; D007378:Interleukins / Q000378:metabolism; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000378:metabolism; D054380:Receptors, CXCR5 / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: D018941:Antigens, CD19; D015704:CD4 Antigens; C110663:CXCL13 protein, human; C095085:CXCR5 protein, human; D054382:Chemokine CXCL13; D007378:Interleukins; D054380:Receptors, CXCR5; D000098546:Interleukin-21
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