[Objective] This study aimed to investigate the changes of the transcriptional levels of molecules associated with endogenous antigen processing and presenta- tion in porcine skin-derived dendritic cells infected with...[Objective] This study aimed to investigate the changes of the transcriptional levels of molecules associated with endogenous antigen processing and presenta- tion in porcine skin-derived dendritic cells infected with PCV2 in vivo. [Method] Healthy 40-day-old Landrace piglets were infected with porcine circovirus type 2 （PCV2） and euthanized on the 34, 7rd, 14th, 21st and 35th d post inoculation （DPI）. The porcine skin-derived dendritic cells （DCs） were collected to analyze the transcrip- tional levels of molecules （LMP7, UBP, MHC-I, calreticulin） associated with endogenous antigen processing and presentation by using real-time fluorescent quantitative PCR （real-time FQ-PCR）. [Result] The results showed that the level of LMP7 mR- NAs was reduced significantly on the 3DPI （P〈0.05）; the level of UBP mRNAs was consistently up-regulated, which increased significantly on the 21DPI and 35DPI （P〈 0.05）; the level of MHC-I mRNAs was significantly down-regulated on the 7DPI （P〈 0.05）; the level of calreticulin mRNAs was up-regulated slightly without significant dif- ference. [Conclusion] PCV2 can inhibit the endogenous antigen processing and presentation ability of porcine skin-derived DCs at early stages of infection.展开更多
Background It has been confirmed that defective expression of human leukocyte antigen class Ⅰ （HLA-Ⅰ） molecules can contribute to the immune evasion of cancer cells in some types of cancer. The aim of this study w...Background It has been confirmed that defective expression of human leukocyte antigen class Ⅰ （HLA-Ⅰ） molecules can contribute to the immune evasion of cancer cells in some types of cancer. The aim of this study was to examine the expression of HLA class Ⅰ antigen and the antigen-processing machinery （APM） components in esophageal squamous cell carcinoma （ESCC） and their role in high risk human papillomavirus （HPV） infection, and to analyze their association with histopathological characteristics in the Kazak ethnic group.Methods A total of 50 formalin-fixed, paraffin-embedded ESCC lesions were collected from the First Affiliated Hospital of Xinjiang Medical University, China. The expression levels of HLA-Ⅰ antigen and APM components were determined by immunohistochemistry; the HPV DNA were detected using polymerase chain reaction （PCR）.Results A high frequency of down-regulation or loss of expression of HLA and APM components were found in esophageal cancer in Kazak people. HLA-Ⅰ, TAP1, CNX, LMP7, Erp57, Tapasin and ERAP1 were down-regulated in 68%,44%, 48%, 40%, 52%, 32% and 20% of ESCC lesions then, respectively. The loss of expression of HLA-Ⅰ antigen was significantly correlated with part of the APM components and positively correlated with high risk HPV16 infection. TAP1,CNX, LMP7, Erp57 and Tapasin loss were significantly associated with tumor grading, lymph node metastasis and depth of invasion （P〈0.05）.Conclusion Our results suggest that APM component defects are a mechanism underlying HLA-Ⅰ antigen down-regulation in ESCC lesions, and indicate that the loss expression of HLA-Ⅰ and APM components will become an important marker of ESCC and analysis of HLA-Ⅰ and APM component expression can provide useful prognostic information for patients with ESCC from the Kazak ethnic group.展开更多
Acute primary immune responses tend to focus on few immunodominant determinants using a very limited number of T cell clones for expansion, whereas chronic inflammatory responses generally recruit a large number of di...Acute primary immune responses tend to focus on few immunodominant determinants using a very limited number of T cell clones for expansion, whereas chronic inflammatory responses generally recruit a large number of different T cell clones to attack a broader range of determinants of the invading pathogens or the inflamed tissues. In T cell-mediated organ-specific autoimmune disease, a transition from the acute to the chronic phase contributes to pathogenesis, and the broadening process is called determinant spreading. The cellular components catalyzing the spreading reaction are not identified. It has been suggested that autoreactive B cells may play a central role in diversifying autoreactive T cell responses, possibly through affecting antigen processing and presentation. The clonal identity and diversity of the B cells and antibodies seem critical in regulating T cell activity and subsequent tissue damage or repair. Here, we use two autoimmune animal models, experimental autoimmune thyroiditis （EAT） and type 1 diabetes （T1D）, to discuss how autoreactive B cells or antibodies alter the processing and presentation of autoantigens to regulate specific T cell response. Cellular ＆ Molecular Immunology. 2005;2（3）：169-175.展开更多
Background:Allergic eosinophilic asthma(EA)and eosinophilic granulomatosis with polyangiitis(EGPA)share significant overlaps in both epidemiology and pathogenesis,suggesting a potential link between the two con-dition...Background:Allergic eosinophilic asthma(EA)and eosinophilic granulomatosis with polyangiitis(EGPA)share significant overlaps in both epidemiology and pathogenesis,suggesting a potential link between the two con-ditions.Despite these associations,the underlying molecular and cellular mechanisms driving their connection remain poorly understood.Methods:We retrieved GSE143303 of EA and GSE144302 of EGPA from the GEO database and conducted dif-ferential expression analysis as well as functional enrichment analysis to identify differentially expressed genes(DEGs)and potential pathogenic pathways.A protein-protein interaction(PPI)network was generated using the STRING database.Key hub genes were determined through cytoHubba.We added two publicly reported EA and EGPA-related transcriptome datasets,GSE117038 and GSE119136,for mutual verification.Subsequent valida-tion was performed via immune infiltration assessment utilizing CIBERSORT.Results:In total,267 DEGs were identified,in which HSP90AA1,HSPA8,CCND1,RPS20,CD74,RPL5,RPS6,RHOA,RPS3A and FLT3LG are the top 10 hub genes,while the antigen processing and presentation pathway and leukocyte cell-cell adhesion pathway were the potential influential pathways.Increased naïve B cells and M1 type of Macrophages were detected in EA patients through immune infiltration analysis.Conclusions:Utilizing bioinformatics techniques,this study is the initial investigation to uncover the shared mechanisms involving the antigen processing and presentation pathway and leukocyte adhesion pathways in the progression of both EA and EGPA.It may offer potential biomarkers for future studies on the underlying path-ogenesis and treatment of EA and EGPA as well as eosinophilia related co-morbidities.展开更多
Background:Dermatomyositis(DM)is an idiopathic inflammatory myopathy(IIM).In this study,we investigated the mRNAs and long noncoding RNAs(lncRNAs)in muscle biopsy specimens that are differentially expressed among pati...Background:Dermatomyositis(DM)is an idiopathic inflammatory myopathy(IIM).In this study,we investigated the mRNAs and long noncoding RNAs(lncRNAs)in muscle biopsy specimens that are differentially expressed among patients with DM,patients with other IIM,and healthy controls(HCs).Methods:In total,three patients with DM,10 patients with other IIM,and three HCs were included.Muscle biopsy specimens were collected for RNA-sequencing.Gene ontology and pathway analyses were employed to characterize the biological processes and signaling pathways.Results:Compared with HCs,372 differentially expressed mRNAs were identified within the DM group,including 275 upregulated and 97 downregulated ones.Moreover,692 differentially expressed lncRNAs were identified in the DM group compared with HCs,of which 407 were upregulated and 285 were downregulated.Bioinformatic analysis indicated that the type-Ⅰ interferon signaling pathway and biological processes of innate immunity were significantly influenced by the differentially expressed mRNAs.Notably,11 of the top 20 upregulated mRNAs were involved in the type-Ⅰ interferon signaling pathway.Reverse transcription polymerase chain reaction analysis verified the RNA-sequencing data.Target gene prediction analysis suggested that the lncRNA NONHSAG043573.2 potentially targeting transporter associated with antigen processing 1,a key regulator of interferon signaling genes,might play an important role in the pathogenesis of DM.Conclusions:Our study assessed the transcriptomic profiles of differentially expressed mRNAs and lncRNAs in the DM muscle tissue and revealed that the upregulated mRNAs are significantly involved in the innate immune response and the type-Ⅰ interferon signaling pathway,which might play important roles in the pathogenesis of DM.展开更多
Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple scleros...Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple sclerosis(MS)have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis(EAE).However,unexpectedly,progranulin-deficient mice(Grn^(−/−))were resistant to EAE,and this resistance was fully restored by wild-type bone marrow transplantation.FACS analyses revealed a loss of MHC-II-positive antigenpresenting cells in Grn^(−/−)mice and a reduction in the number of CD8+and CD4+T-cells along with a strong increase in the number of scavenger receptor class B(CD36+)phagocytes,suggesting defects in antigen presentation along with a compensatory increase in phagocytosis.Indeed,bone marrow-derived dendritic cells from Grn^(−/−)mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation.An increase in the number of CD36+phagocytes was associated with increased local inflammation at the site of immunization,stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes,an increase in the phagocytosis of E.coli particles and latex beads and defects in the clearance of the material.Hence,the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation,and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.展开更多
Objective To investigate the distribution of antigen processing genes transporter associated with antigen processing (TAP), low molecular weight proteasome (LMP2) and HLA DM in the Shanghai population and to explor...Objective To investigate the distribution of antigen processing genes transporter associated with antigen processing (TAP), low molecular weight proteasome (LMP2) and HLA DM in the Shanghai population and to explore the possible role of these genes in the genetic susceptibility to autoimmune diseases IgA nephropathy(IgAN) and multiple sclerosis(MS) Methods Eighty normal Shanghai Chinese, 60 patients with IgAN and 21 patients with MS were randomly selected and genotyped for antigen processing genes (TAP1, TAP2, LMP2, HLA DMA and DMB) using polymerase chain reaction sequence specific oligonucleotide (PCR SSO) and polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) Two locus linkage disequilibrium analysis was performed Results Four TAP1, 6 TAP2, 2 LMP2, 3 DMA and 4 DMB alleles were observed Statistically significant associations were found between TAP1B TAP2A, TAP1B LMP2H and TAP2D HLA DMA *0101 ( Pc <0 01) There was no association between antigen processing genes and either IgAN or MS Conclusion The polymorphisms of antigen processing genes in this Shanghai population are similar to those observed in the other ethnic populations No association was found between IgAN or MS and any antigen processing genes tested in Shanghai population展开更多
基金Supported by Natural Science Foundation of Beijing "Effect of porcine skin-derived dendritic cells on PCV infection" (6062006)Beijing Organization Department Project"Influence of PCV infection on bone marrow cell differentiation" (20061D0502100282)~~
文摘[Objective] This study aimed to investigate the changes of the transcriptional levels of molecules associated with endogenous antigen processing and presenta- tion in porcine skin-derived dendritic cells infected with PCV2 in vivo. [Method] Healthy 40-day-old Landrace piglets were infected with porcine circovirus type 2 （PCV2） and euthanized on the 34, 7rd, 14th, 21st and 35th d post inoculation （DPI）. The porcine skin-derived dendritic cells （DCs） were collected to analyze the transcrip- tional levels of molecules （LMP7, UBP, MHC-I, calreticulin） associated with endogenous antigen processing and presentation by using real-time fluorescent quantitative PCR （real-time FQ-PCR）. [Result] The results showed that the level of LMP7 mR- NAs was reduced significantly on the 3DPI （P〈0.05）; the level of UBP mRNAs was consistently up-regulated, which increased significantly on the 21DPI and 35DPI （P〈 0.05）; the level of MHC-I mRNAs was significantly down-regulated on the 7DPI （P〈 0.05）; the level of calreticulin mRNAs was up-regulated slightly without significant dif- ference. [Conclusion] PCV2 can inhibit the endogenous antigen processing and presentation ability of porcine skin-derived DCs at early stages of infection.
基金This study was supported by the grants from the National Natural Science Foundation of China （No. 81060164） and the Xinjiang Uygur Autonomous Region Fund（No.2009211B14）.
文摘Background It has been confirmed that defective expression of human leukocyte antigen class Ⅰ （HLA-Ⅰ） molecules can contribute to the immune evasion of cancer cells in some types of cancer. The aim of this study was to examine the expression of HLA class Ⅰ antigen and the antigen-processing machinery （APM） components in esophageal squamous cell carcinoma （ESCC） and their role in high risk human papillomavirus （HPV） infection, and to analyze their association with histopathological characteristics in the Kazak ethnic group.Methods A total of 50 formalin-fixed, paraffin-embedded ESCC lesions were collected from the First Affiliated Hospital of Xinjiang Medical University, China. The expression levels of HLA-Ⅰ antigen and APM components were determined by immunohistochemistry; the HPV DNA were detected using polymerase chain reaction （PCR）.Results A high frequency of down-regulation or loss of expression of HLA and APM components were found in esophageal cancer in Kazak people. HLA-Ⅰ, TAP1, CNX, LMP7, Erp57, Tapasin and ERAP1 were down-regulated in 68%,44%, 48%, 40%, 52%, 32% and 20% of ESCC lesions then, respectively. The loss of expression of HLA-Ⅰ antigen was significantly correlated with part of the APM components and positively correlated with high risk HPV16 infection. TAP1,CNX, LMP7, Erp57 and Tapasin loss were significantly associated with tumor grading, lymph node metastasis and depth of invasion （P〈0.05）.Conclusion Our results suggest that APM component defects are a mechanism underlying HLA-Ⅰ antigen down-regulation in ESCC lesions, and indicate that the loss expression of HLA-Ⅰ and APM components will become an important marker of ESCC and analysis of HLA-Ⅰ and APM component expression can provide useful prognostic information for patients with ESCC from the Kazak ethnic group.
文摘Acute primary immune responses tend to focus on few immunodominant determinants using a very limited number of T cell clones for expansion, whereas chronic inflammatory responses generally recruit a large number of different T cell clones to attack a broader range of determinants of the invading pathogens or the inflamed tissues. In T cell-mediated organ-specific autoimmune disease, a transition from the acute to the chronic phase contributes to pathogenesis, and the broadening process is called determinant spreading. The cellular components catalyzing the spreading reaction are not identified. It has been suggested that autoreactive B cells may play a central role in diversifying autoreactive T cell responses, possibly through affecting antigen processing and presentation. The clonal identity and diversity of the B cells and antibodies seem critical in regulating T cell activity and subsequent tissue damage or repair. Here, we use two autoimmune animal models, experimental autoimmune thyroiditis （EAT） and type 1 diabetes （T1D）, to discuss how autoreactive B cells or antibodies alter the processing and presentation of autoantigens to regulate specific T cell response. Cellular ＆ Molecular Immunology. 2005;2（3）：169-175.
基金funded by National Natural Science Foundation of China(NO.82370083).
文摘Background:Allergic eosinophilic asthma(EA)and eosinophilic granulomatosis with polyangiitis(EGPA)share significant overlaps in both epidemiology and pathogenesis,suggesting a potential link between the two con-ditions.Despite these associations,the underlying molecular and cellular mechanisms driving their connection remain poorly understood.Methods:We retrieved GSE143303 of EA and GSE144302 of EGPA from the GEO database and conducted dif-ferential expression analysis as well as functional enrichment analysis to identify differentially expressed genes(DEGs)and potential pathogenic pathways.A protein-protein interaction(PPI)network was generated using the STRING database.Key hub genes were determined through cytoHubba.We added two publicly reported EA and EGPA-related transcriptome datasets,GSE117038 and GSE119136,for mutual verification.Subsequent valida-tion was performed via immune infiltration assessment utilizing CIBERSORT.Results:In total,267 DEGs were identified,in which HSP90AA1,HSPA8,CCND1,RPS20,CD74,RPL5,RPS6,RHOA,RPS3A and FLT3LG are the top 10 hub genes,while the antigen processing and presentation pathway and leukocyte cell-cell adhesion pathway were the potential influential pathways.Increased naïve B cells and M1 type of Macrophages were detected in EA patients through immune infiltration analysis.Conclusions:Utilizing bioinformatics techniques,this study is the initial investigation to uncover the shared mechanisms involving the antigen processing and presentation pathway and leukocyte adhesion pathways in the progression of both EA and EGPA.It may offer potential biomarkers for future studies on the underlying path-ogenesis and treatment of EA and EGPA as well as eosinophilia related co-morbidities.
基金National Natural Science Foundation of China,Grant/Award Numbers:81601086,81771358Military Training Injury Prevention Project,Grant/Award Number:21XLS28。
文摘Background:Dermatomyositis(DM)is an idiopathic inflammatory myopathy(IIM).In this study,we investigated the mRNAs and long noncoding RNAs(lncRNAs)in muscle biopsy specimens that are differentially expressed among patients with DM,patients with other IIM,and healthy controls(HCs).Methods:In total,three patients with DM,10 patients with other IIM,and three HCs were included.Muscle biopsy specimens were collected for RNA-sequencing.Gene ontology and pathway analyses were employed to characterize the biological processes and signaling pathways.Results:Compared with HCs,372 differentially expressed mRNAs were identified within the DM group,including 275 upregulated and 97 downregulated ones.Moreover,692 differentially expressed lncRNAs were identified in the DM group compared with HCs,of which 407 were upregulated and 285 were downregulated.Bioinformatic analysis indicated that the type-Ⅰ interferon signaling pathway and biological processes of innate immunity were significantly influenced by the differentially expressed mRNAs.Notably,11 of the top 20 upregulated mRNAs were involved in the type-Ⅰ interferon signaling pathway.Reverse transcription polymerase chain reaction analysis verified the RNA-sequencing data.Target gene prediction analysis suggested that the lncRNA NONHSAG043573.2 potentially targeting transporter associated with antigen processing 1,a key regulator of interferon signaling genes,might play an important role in the pathogenesis of DM.Conclusions:Our study assessed the transcriptomic profiles of differentially expressed mRNAs and lncRNAs in the DM muscle tissue and revealed that the upregulated mRNAs are significantly involved in the innate immune response and the type-Ⅰ interferon signaling pathway,which might play important roles in the pathogenesis of DM.
基金supported by the Deutsche Forschungsgemeinschaft(CRC1080,A3 to IT and MSCRC1039 to IT)the research funding program“Landesoffensive zur Entwicklung wissenschaftlich-ökonomischer Exzellenz”(LOEWE)of the State of Hessen,Research Center for Translational Medicine and Pharmacology,TMP.
文摘Progranulin is a secreted neurotrophin that assists in the autophagolysosomal pathways that contribute to MHC-mediated antigen processing,pathogen removal,and autoimmunity.We showed that patients with multiple sclerosis(MS)have high levels of circulating progranulin and that its depletion in a mouse model by a monoclonal antibody aggravates MS-like experimental autoimmune encephalomyelitis(EAE).However,unexpectedly,progranulin-deficient mice(Grn^(−/−))were resistant to EAE,and this resistance was fully restored by wild-type bone marrow transplantation.FACS analyses revealed a loss of MHC-II-positive antigenpresenting cells in Grn^(−/−)mice and a reduction in the number of CD8+and CD4+T-cells along with a strong increase in the number of scavenger receptor class B(CD36+)phagocytes,suggesting defects in antigen presentation along with a compensatory increase in phagocytosis.Indeed,bone marrow-derived dendritic cells from Grn^(−/−)mice showed stronger uptake of antigens but failed to elicit antigen-specific T-cell proliferation.An increase in the number of CD36+phagocytes was associated with increased local inflammation at the site of immunization,stronger stimulation-evoked morphological transformation of bone marrow-derived macrophages to phagocytes,an increase in the phagocytosis of E.coli particles and latex beads and defects in the clearance of the material.Hence,the outcomes in the EAE model reflect the dichotomy of progranulin-mediated immune silencing and autoimmune mechanisms of antigen recognition and presentation,and our results reveal a novel progranulin-dependent pathway in autoimmune encephalomyelitis.
文摘Objective To investigate the distribution of antigen processing genes transporter associated with antigen processing (TAP), low molecular weight proteasome (LMP2) and HLA DM in the Shanghai population and to explore the possible role of these genes in the genetic susceptibility to autoimmune diseases IgA nephropathy(IgAN) and multiple sclerosis(MS) Methods Eighty normal Shanghai Chinese, 60 patients with IgAN and 21 patients with MS were randomly selected and genotyped for antigen processing genes (TAP1, TAP2, LMP2, HLA DMA and DMB) using polymerase chain reaction sequence specific oligonucleotide (PCR SSO) and polymerase chain reaction restriction fragment length polymorphism (PCR RFLP) Two locus linkage disequilibrium analysis was performed Results Four TAP1, 6 TAP2, 2 LMP2, 3 DMA and 4 DMB alleles were observed Statistically significant associations were found between TAP1B TAP2A, TAP1B LMP2H and TAP2D HLA DMA *0101 ( Pc <0 01) There was no association between antigen processing genes and either IgAN or MS Conclusion The polymorphisms of antigen processing genes in this Shanghai population are similar to those observed in the other ethnic populations No association was found between IgAN or MS and any antigen processing genes tested in Shanghai population
