Alcoholic patients have a high incidence of hepatitis C virus （HCV） infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of ...Alcoholic patients have a high incidence of hepatitis C virus （HCV） infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of virally infected cells in the liver is related to the HCV- induced inability of the immune system to recognize infected cells and to develop the immune responses. This review covers the effects of HCV proteins and ethanol on major histocompatibility complex （MHC） class Ⅰ- and class Ⅱ-restricted antigen presentation. Here, we discuss the liver which functions as an immune privilege organ; factors, which affect cleavage and loading of antigenic peptides onto MHC class I and class ~I in hepatocytes and dendritic cells, and the modulating effects of ethanol and HCV on antigen presentation by liver cells. Altered antigen presentation in the liver limits the ability ＇of the immune system to clear HCV and infected cells and contributes to disease progression. HCV by itself affects dendritic cell function, switching their cytokine profile to the suppressive phenotype of interleukin-10 （IL-10） and transforming growth factor beta （TGFβ） predominance, preventing cell maturation and allostimulation capacity. The synergistic action of ethanol with HCV results in the suppression of MHC class Ⅱ-restricted antigen presentation. In addition, ethanol metabolism and HCV proteins reduce proteasome function and interferon signaling, thereby suppressing the generation of peptides for MHC class I -restricted antigen presentation. Collectively, ethanol exposure further impairs antigen presentation in HCV-infected liver cells, which may provide a partial explanation for exacerbations and the poor outcome of HCV infection in alcoholics.展开更多
Major histocompatibility complex （MHC） genes are critical members in both innate and adaptive immunity, and the association between their polymorphism and disease resistance has been reported in many teleosts. In th...Major histocompatibility complex （MHC） genes are critical members in both innate and adaptive immunity, and the association between their polymorphism and disease resistance has been reported in many teleosts. In the present study, we first investigated the genetic variation at the MHC II β gene in orange-spotted grouper （Epinephelus coioides） after a challenge with Singapore grouper iridovirus （SGIV）. The results reveal that a high polymorphism level of the MHC II β gene （H = 1.000; K = 20.206; π=0.081） and at least three loci exist in grouper. The rate of dN/dS in the peptide-binding region （PBR） and non-PBR were both 〉1, suggesting the loci were evolving under positive selection. A high ratio of heterozygous individuals （37.26 %） and high rate of dN/dS were discovered, suggesting that both heterozygote advantage and frequency-dependent selection might result in the high polymorphism levels in MHC II β genes in grouper. A total of 33 MHC II β alleles were identified from 40 high-susceptibility （HS） and 40 high-re- sistance group （HR） individuals, and 15 alleles were used in the association analysis. Three alleles, EPCO-DBB＊0302, EPCO-DBB＊0307, EPCO-DBB＊0603, and EPCO- DBB＊1001 were significantly associated with resistance ability to SG1V, and the EPCO-DBB＊0607 and EPCO-DBB＊1303 alleles were associated with susceptibility （P 〈 0.05）. To further confirm the association, another independent challenge experiment was performed. The result of association analysis in the verification test found that only EPCO-DBB＊1001 alleles were significantly asso- ciated with resistance to SGIV （P 〈 0.05）, while the other alleles showed no significance （P 〉 0.05） in the frequency distribution between HR and HS groups. Therefore, the EPCO-DBB＊ 1001 alleles could be used as a disease resis- tance-related MHC marker in the molecular marker-assisted selective breeding program of grouper.展开更多
基金Supported by Development funds from Section of Gastroenterology/Hepatology, Internal Medicine, University of Nebraska Medical Center
文摘Alcoholic patients have a high incidence of hepatitis C virus （HCV） infection. Alcohol consumption enhances the severity of the HCV disease course and worsens the outcome of chronic hepatitis C. The accumulation of virally infected cells in the liver is related to the HCV- induced inability of the immune system to recognize infected cells and to develop the immune responses. This review covers the effects of HCV proteins and ethanol on major histocompatibility complex （MHC） class Ⅰ- and class Ⅱ-restricted antigen presentation. Here, we discuss the liver which functions as an immune privilege organ; factors, which affect cleavage and loading of antigenic peptides onto MHC class I and class ~I in hepatocytes and dendritic cells, and the modulating effects of ethanol and HCV on antigen presentation by liver cells. Altered antigen presentation in the liver limits the ability ＇of the immune system to clear HCV and infected cells and contributes to disease progression. HCV by itself affects dendritic cell function, switching their cytokine profile to the suppressive phenotype of interleukin-10 （IL-10） and transforming growth factor beta （TGFβ） predominance, preventing cell maturation and allostimulation capacity. The synergistic action of ethanol with HCV results in the suppression of MHC class Ⅱ-restricted antigen presentation. In addition, ethanol metabolism and HCV proteins reduce proteasome function and interferon signaling, thereby suppressing the generation of peptides for MHC class I -restricted antigen presentation. Collectively, ethanol exposure further impairs antigen presentation in HCV-infected liver cells, which may provide a partial explanation for exacerbations and the poor outcome of HCV infection in alcoholics.
基金supported by China Postdoctoral Science Foundation Funded Project(2015M572380)National Basic Research Program of China(973)(2012CB114402)
文摘Major histocompatibility complex （MHC） genes are critical members in both innate and adaptive immunity, and the association between their polymorphism and disease resistance has been reported in many teleosts. In the present study, we first investigated the genetic variation at the MHC II β gene in orange-spotted grouper （Epinephelus coioides） after a challenge with Singapore grouper iridovirus （SGIV）. The results reveal that a high polymorphism level of the MHC II β gene （H = 1.000; K = 20.206; π=0.081） and at least three loci exist in grouper. The rate of dN/dS in the peptide-binding region （PBR） and non-PBR were both 〉1, suggesting the loci were evolving under positive selection. A high ratio of heterozygous individuals （37.26 %） and high rate of dN/dS were discovered, suggesting that both heterozygote advantage and frequency-dependent selection might result in the high polymorphism levels in MHC II β genes in grouper. A total of 33 MHC II β alleles were identified from 40 high-susceptibility （HS） and 40 high-re- sistance group （HR） individuals, and 15 alleles were used in the association analysis. Three alleles, EPCO-DBB＊0302, EPCO-DBB＊0307, EPCO-DBB＊0603, and EPCO- DBB＊1001 were significantly associated with resistance ability to SG1V, and the EPCO-DBB＊0607 and EPCO-DBB＊1303 alleles were associated with susceptibility （P 〈 0.05）. To further confirm the association, another independent challenge experiment was performed. The result of association analysis in the verification test found that only EPCO-DBB＊1001 alleles were significantly asso- ciated with resistance to SGIV （P 〈 0.05）, while the other alleles showed no significance （P 〉 0.05） in the frequency distribution between HR and HS groups. Therefore, the EPCO-DBB＊ 1001 alleles could be used as a disease resis- tance-related MHC marker in the molecular marker-assisted selective breeding program of grouper.
