The early onset of type 1 autoimmune hepatitis has a strong genetic influence: role of HLA and KIR genes

Podhorzer, Ariel; Paladino, Natalia; Cuarterolo, Miriam; Fainboim, Hugo; Paz, Suzanne; Theiler, G.; Capucchio, M.; López, Susana; Machicote, Andrés; Montal, Silvina; Podestá, Gustavo; Fainboim, Leonardo

doi:10.1038/gene.2016.7

Cited by 21 publications

(24 citation statements)

References 42 publications

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“…The conditions used to identify the presence or absence of each KIR gene have been documented previously ( 20 ). Briefly, two PCR amplifications were performed: PCR-1 amplified the combined D1 and D2 domains and PCR-2 amplified the transmembrane and cytoplasmic regions.…”

Section: Methodsmentioning

confidence: 99%

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The Clinical Features of Patients with Chronic Hepatitis C Virus Infections Are Associated with Killer Cell Immunoglobulin-Like Receptor Genes and Their Expression on the Surface of Natural Killer Cells

et al. 2018

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Killer cell immunoglobulin-like receptor (KIR) genes are known to play a role in the acute phase of hepatitis C virus (HCV) infection. The present study investigated their roles in chronic HCV (CHCV) infection by analyzing the phenotypes and function of natural killer (NK) and T cells that express KIRs. T cells from CHCV patients showed a more differentiated phenotype, and NK cells exhibited an activated profile. These observations are consistent with the increased expression of the degranulation marker CD107a observed after PMA stimulation. We explored the correlations between the expression of KIR genes and lectin type-C receptors with clinical factors that predict progression to fibrosis and cirrhosis. The expression levels of KIR2DS3 and the functional alleles of KIR2DS4-FL were increased in patients with intermediate and high viral loads. Homozygous KIR2DS4 was also associated with the presence of cirrhosis. In the group of individuals with a shorter infection time who developed cirrhosis, we detected decreased expression of KIR3DL1 in CD56dim NK cells in the presence of its ligand. Similarly, in the group of patients with late CHCV infections complicated with cirrhosis, we detected lower expression of the strong inhibitory receptor NKG2A in CD56bright NK cells. We also detected an increase in NKG2C expression in CD56dim NK cells in CHCV patients who displayed high necroinflammatory activity. Decreased KIR3DL2 expression in CD56dim and CD56bright NK cells was associated with a high body mass index, and KIR3DL2 expression may be one factor associated with the more rapid progression of CHCV to fibrosis in patients.

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Section: Methodsmentioning

confidence: 99%

“…The overall memory CD8 + T cell compartment consists of central and memory subsets, which are recognized based on their phenotype and function ( 18 , 19 ). Recently, we reported high levels of KIR receptor expression in peripheral blood and liver CD3 + CD56 + cells and in liver T cells ( 20 ).…”

Section: Introductionmentioning

confidence: 99%

The Clinical Features of Patients with Chronic Hepatitis C Virus Infections Are Associated with Killer Cell Immunoglobulin-Like Receptor Genes and Their Expression on the Surface of Natural Killer Cells

et al. 2018

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“…AIH is characterized by high levels of hypergammaglobulinaemia and hepatic inflammatory infiltrates, leading to potential cirrhosis . While environmental parameters are implicated, immunological dysfunction plays a crucial role in the pathogenesis of AIH . However, the exact mechanisms of autoimmune responses remain unclear.…”

Section: Introductionmentioning

confidence: 99%

Dysregulated TFR and TFH cells correlate with B‐cell differentiation and antibody production in autoimmune hepatitis

Zhang

Dai

et al. 2020

J Cellular Molecular Medi

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Follicular helper T (TFH) cell provides germinal centre (GC) B cell with critical signals for autoantibody production in the immunopathogenesis and progression of autoimmune hepatitis (AIH). However, the immunoregulatory functions of follicular regulatory T (TFR) cell in AIH are still unclear. The numbers of circulating TFR/ TFH cells were measured in AIH patients. Moreover, we established experimental autoimmune hepatitis (EAH) model to examine the function of TFR cells on B-cell differentiation and autoantibody production in vivo and vitro. AIH patients had significantly increased numbers of TFH cells and decreased numbers of TFR cells as well as imbalanced TFR/TFH-type cytokines (IL-10, TGF-β1 and IL-21) compared with healthy controls (HCs). In addition, TFR cell numbers negatively correlated with TFH cell numbers. Also, serum hypergammaglobulinaemia (IgG and IgM) concentrationnegatively correlated the levels of serum IL-21, but positively correlated with the levels of serum IL-10 in AIH patients. Furthermore, in comparison with control group, significantly higher frequencies of spleen TFR cells but lower frequencies of spleen TFH cells were detected in the EAH group. Further analysis found that TFR cells simultaneously express the phenotypic characteristics of Treg and TFH cells, but exercise as negative regulators of autoantibody production in vitro culture. Our findings demonstrated that dysregulated between TFR and TFH cells might cause excessive production of autoantibodies and destruction of the immune homeostasis, leading to the immunopathological process in AIH.

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“…Recently, we showed that expression of KIR genes on T cells is primarily restricted to liver T cells, potentially representing highly differentiated T cells.…”

Section: Introductionmentioning

confidence: 99%

Intrahepatic and peripheral blood phenotypes of natural killer and T cells: differential surface expression of killer cell immunoglobulin‐like receptors

et al. 2018

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Deep characterization of the frequencies, phenotypes and functionalities of liver and peripheral blood natural killer (NK), natural killer T (NKT) and T cells from healthy individuals is an essential step to further interpret changes in liver diseases. These data indicate that CCR7, a chemokine essential for cell migration through lymphoid organs, is almost absent in liver NK and T cells. CD56 NK cells, which represent half of liver NK cells, showed lower expression of the inhibitory molecule NKG2A and an increased frequency of the activation marker NKp44. By contrast, a decrease of CD16 expression with a potential decreased capacity to perform antibody-dependent cellular cytotoxicity was the main difference between liver and peripheral blood CD56 NK cells. Liver T cells with an effector memory or terminally differentiated phenotype showed an increased frequency of MAIT cells,T-cell receptor-γδ (TCR-γδ) T cells and TCR-αβ CD8 cells, with few naive T cells. Most liver NK and T cells expressed the homing markers CD161 and CD244. Liver T cells revealed a unique expression pattern of killer cell immunoglobulin-like receptors (KIR) receptors, with increased degranulation ability and higher secretion of interferon-γ. Hence, the liver possesses a large amount of memory and terminally differentiated CD8 cells with a unique expression pattern of KIR activating receptors that have a potent functional capacity as well as a reduced amount of CCR7, which are unable to migrate to regional lymph nodes. These results are consistent with previous studies showing that liver T (and also NK) cells likely remain and die in the liver.

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The early onset of type 1 autoimmune hepatitis has a strong genetic influence: role of HLA and KIR genes

Cited by 21 publications

References 42 publications

The Clinical Features of Patients with Chronic Hepatitis C Virus Infections Are Associated with Killer Cell Immunoglobulin-Like Receptor Genes and Their Expression on the Surface of Natural Killer Cells

The Clinical Features of Patients with Chronic Hepatitis C Virus Infections Are Associated with Killer Cell Immunoglobulin-Like Receptor Genes and Their Expression on the Surface of Natural Killer Cells

Dysregulated TFR and TFH cells correlate with B‐cell differentiation and antibody production in autoimmune hepatitis

Intrahepatic and peripheral blood phenotypes of natural killer and T cells: differential surface expression of killer cell immunoglobulin‐like receptors

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