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
Antigen-presentation via major histocompatibility complex(MHC)to T cells is the key event to initiate adaptive immune responses.In teleosts,as in mammals,the main types of professional antigen-presenting cells(APCs)ar...Antigen-presentation via major histocompatibility complex(MHC)to T cells is the key event to initiate adaptive immune responses.In teleosts,as in mammals,the main types of professional antigen-presenting cells(APCs)are dendritic cells(DCs),monocytes/macrophages,and B cells.In the current study,flow cytometry,immunostaining and qPCR have been used to show that neutrophils in the teleost fish Atlantic salmon(Salmo salar L.)have antigen-presenting properties.The neutrophils were positive for MHC class II,CD83 and CD80/86,and upon in vitro bacterial exposure,gene expression analysis of purified neutrophils showed that IL-12p40,which is essential for proliferation of naïve T cells,was highly upregulated at both 6 and 24 h post bacterial exposure.Based on presence of MHC class II and upregulation of molecules involved in antigen presentation and T cell activation,we suggest that neutrophils in Atlantic salmon have potential to function as professional APCs.This work makes an important basis for further exploring the potential of using neutrophils to develop new,targeted immunoprophylactic measures.展开更多
The porcine major histocompatibility complex (MHC, also named swine leukocyte antigen, SLA) is associ- ated not only with immune responsibility and disease suscep- tibility, but also with some reproductive and product...The porcine major histocompatibility complex (MHC, also named swine leukocyte antigen, SLA) is associ- ated not only with immune responsibility and disease suscep- tibility, but also with some reproductive and productive traits such as growth rate and carcass composition. As yet system- atical research on SLA expression profile is not reported. In order to illustrate SLA expression comprehensively and deepen our understanding of its function, we outlined the expression profile of SLA in 51 tissues of Landrace by ana- lyzing a large amount of ESTs produced by “Sino-Danish Porcine Genome Project”. In addition, we also compared the expression profile of SLA in several tissues from different development stages and from another breed (Erhualian). The result shows: (i) classical SLA genes are highly expressed in immune tissues and middle part of intestine; (ii) although SLA-3 is an SLA Ia gene, its expression abundance and pat- tern are quite different from those of the other two SLA Ia genes. The same phenomenon is seen in HLA-C expression, suggesting that the two genes may function similarly and undergo convergent evolution; (iii) except in jejunum, the antigen presenting genes are more highly expressed in breed Erhualian than in Landrace. The difference might associate with the higher resistance to bad conditions (including pathogens) of Erhualian and higher growth rates of Land- race.展开更多
Cytotoxic T cells targeting cancer neoantigens harboring driver mutations can lead to durable tumor regression in an HLAIdependent manner.However,it is difficult to extend the population of patients who are eligible f...Cytotoxic T cells targeting cancer neoantigens harboring driver mutations can lead to durable tumor regression in an HLAIdependent manner.However,it is difficult to extend the population of patients who are eligible for neoantigen-based immunotherapy,as immunogenic neoantigen-HLA pairs are rarely shared across different patients.Thus,a way to find other human leukocyte antigen(HLA)alleles that can also present a clinically effective neoantigen is needed.Recently,neoantigen-based immunotherapy targeting the KRAS G12D mutation in patients with HLA-C*08:02 has shown effectiveness.In a proof-ofconcept study,we proposed a combinatorial strategy(the combination of phylogenetic and structural analyses)to find potential HLA alleles that could also present KRAS G12D neoantigen.Compared to in silico binding prediction,this strategy avoids the uneven accuracy across different HLA alleles.Our findings extend the population of patients who are potentially eligible for immunotherapy targeting the KRAS G12D mutation.Additionally,we provide an alternative way to predict neoantigen-HLA pairs,which maximizes the clinical usage of shared neoantigens.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.
文摘Antigen-presentation via major histocompatibility complex(MHC)to T cells is the key event to initiate adaptive immune responses.In teleosts,as in mammals,the main types of professional antigen-presenting cells(APCs)are dendritic cells(DCs),monocytes/macrophages,and B cells.In the current study,flow cytometry,immunostaining and qPCR have been used to show that neutrophils in the teleost fish Atlantic salmon(Salmo salar L.)have antigen-presenting properties.The neutrophils were positive for MHC class II,CD83 and CD80/86,and upon in vitro bacterial exposure,gene expression analysis of purified neutrophils showed that IL-12p40,which is essential for proliferation of naïve T cells,was highly upregulated at both 6 and 24 h post bacterial exposure.Based on presence of MHC class II and upregulation of molecules involved in antigen presentation and T cell activation,we suggest that neutrophils in Atlantic salmon have potential to function as professional APCs.This work makes an important basis for further exploring the potential of using neutrophils to develop new,targeted immunoprophylactic measures.
文摘The porcine major histocompatibility complex (MHC, also named swine leukocyte antigen, SLA) is associ- ated not only with immune responsibility and disease suscep- tibility, but also with some reproductive and productive traits such as growth rate and carcass composition. As yet system- atical research on SLA expression profile is not reported. In order to illustrate SLA expression comprehensively and deepen our understanding of its function, we outlined the expression profile of SLA in 51 tissues of Landrace by ana- lyzing a large amount of ESTs produced by “Sino-Danish Porcine Genome Project”. In addition, we also compared the expression profile of SLA in several tissues from different development stages and from another breed (Erhualian). The result shows: (i) classical SLA genes are highly expressed in immune tissues and middle part of intestine; (ii) although SLA-3 is an SLA Ia gene, its expression abundance and pat- tern are quite different from those of the other two SLA Ia genes. The same phenomenon is seen in HLA-C expression, suggesting that the two genes may function similarly and undergo convergent evolution; (iii) except in jejunum, the antigen presenting genes are more highly expressed in breed Erhualian than in Landrace. The difference might associate with the higher resistance to bad conditions (including pathogens) of Erhualian and higher growth rates of Land- race.
基金supported by the National Natural Science Foundation of China(31870728,31470738,and 32000611)the National Basic Research Program of China(2014CB910103)+1 种基金the Fundamental Research Funds for the Central Universities(2042020kfxg02)the China Postdoctoral Science Foundation(2018M642918)。
文摘Cytotoxic T cells targeting cancer neoantigens harboring driver mutations can lead to durable tumor regression in an HLAIdependent manner.However,it is difficult to extend the population of patients who are eligible for neoantigen-based immunotherapy,as immunogenic neoantigen-HLA pairs are rarely shared across different patients.Thus,a way to find other human leukocyte antigen(HLA)alleles that can also present a clinically effective neoantigen is needed.Recently,neoantigen-based immunotherapy targeting the KRAS G12D mutation in patients with HLA-C*08:02 has shown effectiveness.In a proof-ofconcept study,we proposed a combinatorial strategy(the combination of phylogenetic and structural analyses)to find potential HLA alleles that could also present KRAS G12D neoantigen.Compared to in silico binding prediction,this strategy avoids the uneven accuracy across different HLA alleles.Our findings extend the population of patients who are potentially eligible for immunotherapy targeting the KRAS G12D mutation.Additionally,we provide an alternative way to predict neoantigen-HLA pairs,which maximizes the clinical usage of shared neoantigens.
