T cell receptor gene rearrangements of T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis (PBC): Oligoclonality of PBC‐derived T cell clones

Moebius, Ulrich; Manns, Michael P.; Heß, Georg; Kober, Gabriela; Büschenfelde, K H Meyer zum; Meuer, Stefan

doi:10.1002/eji.1830200426

Cited by 95 publications

(50 citation statements)

References 44 publications

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“…These observations led to the use of anti-TCR mAbs and vaccination with synthetic peptides of the CDR2 and CDR3 TCR regions; both proved beneficial in experimental allergic encephalomyelitis (33,35). Limited TCR gene rearrangements have been found in lymphocytes infiltrating brains of multiple sclerosis patients (36), synovial tissues of rheumatoid arthritis patients (37), liver of primary biliary cirrhosis (38), and in the thyroid ofthyroiditis patients (39). In multiple sclerosis plaques a dominant CDR3 sequence identical with that of TCR clones specific for myelin basic protein has been found (40).…”

Section: Discussionmentioning

confidence: 99%

Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis. Restricted V alpha/beta rearrangements may indicate antigen-driven selection.

et al. 1993

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Section: Discussionmentioning

confidence: 99%

Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis. Restricted V alpha/beta rearrangements may indicate antigen-driven selection.

et al. 1993

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“…The study of TCR b gene rearrangements of cell clones obtained from PBC liver biopsies demonstrated different degrees of oligoclonality of the infiltrating T cells. 114,115 The use of TCR Vb or Jb genes by PDC-E2 [163][164][165][166][167][168][169][170][171][172][173][174][175][176] -reactive T-cell clones is also highly diverse with GXG or GXS motifs found within the complementaritydetermining region 3 (CDR3) of all T-cell clones. 116 When autoreactive T-cell frequencies are compared among different tissues of patients with PBC, PDC-E2 163-176 -reactive precursor T cells are 100-150-fold more represented in the hilar lymph nodes and the liver compared to the peripheral blood, possibly with changes in different disease stages.…”

Section: Immunopathogenesis Of Pbcmentioning

confidence: 99%

Genes and (auto)immunity in primary biliary cirrhosis

et al. 2005

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Primary biliary cirrhosis (PBC) is a chronic autoimmune cholestatic liver disease most commonly encountered in postmenopausal women; it is characterized by high-titer serum autoantibodies to mitochondrial antigens, elevated serum IgM, progressive destruction of intrahepatic bile ducts, and ultimately liver cirrhosis and failure. The cytopathic mechanisms leading to the selective destruction of intrahepatic cholangiocytes are still largely unknown. The current theory on the pathogenesis of PBC indicated that environmental factors might trigger autoimmunity in genetically susceptible individuals. In fact, genetic predisposition is critical to disease onset and progression, yet peculiar among autoimmune diseases, as indicated by the lack of a strong association with major histocompatibility complex haplotypes. Further, the recently reported concordance rate among monozygotic twins strenghtens the importance of genetic factors, while also indicating that additional factors, possibly infectious agents or xenobiotics, intervene to trigger the disease. In this review, the available data regarding the genetic factors associated with PBC susceptibility and progression, as well as the available evidence regarding the immunomediated pathogenesis of PBC, will be critically illustrated and discussed.

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“…It mimics human viral and autoimmune hepatitis in many aspects (8)(9)(10). Con A-induced hepatitis is accompanied by an increase in the serum concentration of several cytokines, including TNF-α, IFN-γ, IL-6, and IL-1.…”

Section: Introductionmentioning

confidence: 99%

The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury

Klein¹,

Wüstefeld²,

Assmus³

et al. 2005

J. Clin. Invest.

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Increasing evidence demonstrates that IL-6 has a protective role during liver injury. IL-6 activates intracellular pathways via the gp130 receptor. In order to identify IL-6-gp130 pathways involved in mediating liver protection, we analyzed hepatocyte-specific gp130 knockout mice in a concanavalin A-induced (Con A-induced) model of immune-mediated hepatitis. We demonstrated that IL-6-gp130-dependent pathways in hepatocytes alone are sufficient for triggering protection in Con A-induced hepatitis. gp130-STAT3 signaling in hepatocytes mediates the IL-6-triggered protective effect. This was demonstrated by analysis of IL-6-induced protection in mice selectively deficient for gp130-dependent STAT1/3 or gp130-SHP2-RAS signaling in hepatocytes. To identify IL-6-gp130-STAT1/3 dependently expressed liver-protective factors, we performed gene array analysis of hepatic gene expression in hepatocyte-specific gp130 -/-mice as well as in gp130-STAT1/3-and gp130-SHP2-RAS-MAPK-deficient mice. The mouse IL-8 ortholog KC (also known as Gro-α) and serum amyloid A2 (SAA2) was identified as differentially IL-6-gp130-STAT3-regulated genes. Hepatic expression of KC and SAA2 mediate the liver-protective potential of IL-6, since treatment with recombinant KC or serum SAA2 effectively reduced liver injury during Con A-induced hepatitis. In summary, this study defines IL-6-gp130-STAT3-dependent gene expression in hepatocytes that mediates IL-6-triggered protection in immune-mediated Con A-induced hepatitis. Additionally, we identified the IL-6-gp130-STAT3-dependent proteins KC and SAA2 as new candidates for therapeutic targets in liver diseases.

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T cell receptor gene rearrangements of T lymphocytes infiltrating the liver in chronic active hepatitis B and primary biliary cirrhosis (PBC): Oligoclonality of PBC‐derived T cell clones

Cited by 95 publications

References 44 publications

Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis. Restricted V alpha/beta rearrangements may indicate antigen-driven selection.

Analysis of T cell receptor repertoire of muscle-infiltrating T lymphocytes in polymyositis. Restricted V alpha/beta rearrangements may indicate antigen-driven selection.

Genes and (auto)immunity in primary biliary cirrhosis

The IL-6–gp130–STAT3 pathway in hepatocytes triggers liver protection in T cell–mediated liver injury

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