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

Yongyin Li, Weibin Wang, Libo Tang, Xuanqiu He, Xin Yan, Xiaoyong Zhang, Youfu Zhu, Jian Sun, Yongquan Shi, Xiong Ma, Ian R. Mackay, M. Eric Gershwin, Ying Han, Jinlin Hou

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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)<sup>+</sup>CD4<sup>+</sup>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<sup>+</sup>CD4<sup>+</sup>T cells in PBC produced higher levels of IL-21 than healthy controls. Additionally, sorted CXCR5<sup>+</sup>CD4<sup>+</sup>T cells increased production of AMAs by autologous CD19<sup>+</sup>B cells. Indeed, elevated expression of intrahepatic chemokine (C-X-C motif) ligand 13 (CXCL13), a key chemokine of CXCR5<sup>+</sup> cells, was uniquely found within the portal tracts in PBC, accompanied by infiltrates of CD4<sup>+</sup>, CXCR5<sup>+</sup>, CD19<sup>+</sup>, and CD38<sup>+</sup> cells. Conclusion: CXCL13 promotes aggregation of CD19<sup>+</sup>B cells and CXCR5<sup>+</sup>CD4<sup>+</sup>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.

Original languageEnglish (US)
Pages (from-to)1998-2007
Number of pages10
JournalHepatology
Volume61
Issue number6
DOIs
StatePublished - Jun 1 2015

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CCR Receptors
CXC Chemokines
Biliary Liver Cirrhosis
B-Lymphocytes
Lymphocytes
Ligands
CD4 Antigens
Antibody Formation
T-Lymphocytes
Dihydrolipoyllysine-Residue Acetyltransferase
B-Lymphocyte Subsets
STAT3 Transcription Factor
Cytosine
Guanine
Serum
Immunotherapy
Immunoglobulin M
Phosphates
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Hepatology

Cite this

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. / Li, Yongyin; Wang, Weibin; Tang, Libo; He, Xuanqiu; Yan, Xin; Zhang, Xiaoyong; Zhu, Youfu; Sun, Jian; Shi, Yongquan; Ma, Xiong; Mackay, Ian R.; Gershwin, M. Eric; Han, Ying; Hou, Jinlin.

In: Hepatology, Vol. 61, No. 6, 01.06.2015, p. 1998-2007.

Research output: Contribution to journalArticle

Li, Yongyin ; Wang, Weibin ; Tang, Libo ; He, Xuanqiu ; Yan, Xin ; Zhang, Xiaoyong ; Zhu, Youfu ; Sun, Jian ; Shi, Yongquan ; Ma, Xiong ; Mackay, Ian R. ; Gershwin, M. Eric ; Han, Ying ; Hou, Jinlin. / 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. In: Hepatology. 2015 ; Vol. 61, No. 6. pp. 1998-2007.
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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. Conclusion: 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.",
author = "Yongyin Li and Weibin Wang and Libo Tang and Xuanqiu He and Xin Yan and Xiaoyong Zhang and Youfu Zhu and Jian Sun and Yongquan Shi and Xiong Ma and Mackay, {Ian R.} and Gershwin, {M. Eric} and Ying Han and Jinlin Hou",
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T1 - 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

AU - Li, Yongyin

AU - Wang, Weibin

AU - Tang, Libo

AU - He, Xuanqiu

AU - Yan, Xin

AU - Zhang, Xiaoyong

AU - Zhu, Youfu

AU - Sun, Jian

AU - Shi, Yongquan

AU - Ma, Xiong

AU - Mackay, Ian R.

AU - Gershwin, M. Eric

AU - Han, Ying

AU - Hou, Jinlin

PY - 2015/6/1

Y1 - 2015/6/1

N2 - 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. Conclusion: 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.

AB - 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. Conclusion: 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.

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