Document text
Principal Investigator: Mary N. Carrington
Organization: DIVISION OF BASIC SCIENCES - NCI
Fiscal Year: 2021
Award: $603,715
Funding agency: National Cancer Institute
HLA class I molecules present antigenic peptides to CD8 T cells, eliciting an adaptive immune response. Peptide loading of HLA class I molecules takes place within the peptide loading complex (PLC) and tapasin is a critical component of the PLC, which performs its peptide "editing" function by association with peptide-empty HLA class I, stabilizing its structure, and promoting dissociation of low affinity peptides. HLA class I allotypes vary in level of cell surface expression in the absence of tapasin. Some allotypes are expressed at very low levels on the surface of tapasin-deficient cells (tapasin-dependent allotypes), while others exhibit normal expression on these cells (tapasin-independent allotypes). We have quantified the level of TD across common HLA allotypes and tested the functional significance of differential HLA class I TD and its impact on disease. Ex vivo examination of cytotoxic T cell responses to the entire HIV-1 proteome from infected subjects indicates that tapasin-dependent allotypes present a more limited set of distinct peptides than do tapasin-independent allotypes. This suggests that variation in tapasin dependence may impact the strength of the immune responses by altering peptide repertoire size. In support of this model, we observed that individuals carrying HLA class I genotypes characterized by greater tapasin independence progress more slowly to AIDS and maintain lower viral loads, presumably due to increased breadth of peptide presentation. Thus, tapasin dependence level may serve as a means to restrict or expand breadth of the HLA-I peptide repertoire across humans, ultimately influencing immune responses to pathogens and vaccines. Plasmodium falciparum malaria remains a leading cause of morbidity and mortality in sub-Saharan Africa, particularly in children. As a result of thousands of years of co-evolution, malaria has exerted strong selective pressure on the human genome. To date, immunogenetic correlates of malaria susceptibility have been elusive. Prior studies have identified numerous host genetic variants that influence susceptibility to malaria, most of which impact the structure and function of erythrocytes. However, only a small proportion of the genetic resistance to malaria is explained by these known variants. Variation within the HLA locus been shown to play an important role in the susceptibility to and outcomes of numerous infections, but its influence on immunity to P. falciparum malaria is unclear. Increasing evidence indicates that acquired immunity to P. falciparum is mediated in part by the cellular immune response, including NK cells, CD4 and CD8 T cells, and semi-invariant gammadelta T cells. HLA molecules expressed by these lymphocytes influence the epitopes recognized by P. falciparum-specific T cells, and class I HLA molecules also serve as ligands for inhibitory receptors including KIR. Here we assessed the relationship of HLA class I and II alleles to the risk of P. falciparum infection and symptomatic malaria in a cohort of 892 Ugandan children and adults followed prospectively via both active and passive surveillance. We identified two HLA class I alleles, HLA-B5301 and HLA-C0602, that were associated with a higher prevalence of P. falciparum infection. Notably, no class I or II HLA alleles were found to be associated with protection from P. falciparum parasitemia or symptomatic malaria. Our findings support a role for class I HLA molecules in influencing the establishment or clearance of parasitemia, and strengthen the evidence that cellular immunity is an important component of a protective response to P. falciparum. The association of HLA-C0602 and HLA-B5301 with a higher risk of parasitemia could reflect greater KIR- mediated inhibition leading to dampened cellular immunity at pre-erythrocytic stages or an attenuated clearance of parasites via antibody dependent cellular cytotoxicity. Indeed, in a follow-up study, we found that presence of HLA-C2 and HLA-Bw4, ligands for inhibitory KIR2DL1 and KIR3DL1, respectively, increased the likelihood of P. falciparum parasitemia in an additive manner. Individuals homozygous for HLA-C2, which mediates strong inhibition via KIR2DL1, had the highest odds of parasitemia, HLA-C1-C2 heterozygotes had intermediate odds, and individuals homozygous for HLA-C1, which mediates weaker inhibition through KIR2DL2-3, had the lowest odds of parasitemia. In addition, higher surface expression of HLA-C, the ligand for inhibitory KIR2DL1-2-3, was associated with a higher likelihood of parasitemia. Together these data indicate that stronger KIR-mediated inhibition confers a higher risk of P. falciparum parasitemia and suggest that KIR-expressing effector cells play a role in mediating antiparasite immunity. Moreover, our findings suggest an important role for the cellular immune response in restricting P. falciparum infection, perhaps during the earliest stages of infection, before blood-stage parasitemia is established. These findings represent a novel genetic determinant of malaria susceptibility and further our understanding of anti- malarial immunity with implications for vaccine design. Genes encoding the human leukocyte antigen (HLA) complex are highly polymorphic. It was previously hypothesized that greater diversity in HLA loci, which are responsible for antigen presentation to immune cells, could protect against infections (heterozygosity advantage hypothesis), by resulting in a higher probability of a robust cytotoxic T lymphocyte response to pathogens. This hypothesis has been confirmed by reports showing that heterozygosity at HLA loci is linked to better control of pathogenic infections. For example, heterozygosity at HLA class I loci has been observed to be associated with a slower progression to AIDS after infection with HIV. A corollary of the heterozygote advantage hypothesis postulates that individuals who are heterozygous at HLA loci will have a lower risk of cancer development due to an increased ability to recognize exogenous antigens and de novo endogenous mutations in cancer and its precursors. In support of this hypothesis, some studies have reported on the association between zygosity at HLA loci and cancers of hematopoietic origin (eg, subtypes of non-Hodgkin lymphoma). Whether heterozygosity advantage is evident for cancers caused by infectious agents is less well understood. In particular, investigation of the role of zygosity at HLA loci in progression to cancer and its precursors given chronic carriage of an oncogenic infection has never been reported. We utilized DNA from more than 10 000 Taiwanese individuals with current or past HBV infection to examine the association between HLA diversity and critical natural history steps in the progression from HBV infection to hepatocellular carcinoma (HCC). Individuals were classified as homozygotes at a given locus when imputed to carry the same 4-digit allele for the 2 HLA alleles at that locus. We found that Increase in number of homozygous HLA class II loci was associated with an increased risk of chronic HBV infection. Among chronic HBV carriers, increase in number of homozygous HLA class II loci was also associated with an increased risk of HBV-associated HCC. For individual HLA loci, HLA-DQB1 homozygosity was significantly associated with HCC risk. We also found that zygosity affects risk of HCC through its ability to affect viral control. In summary, our study is the first to report evidence linking HLA zygosity with HBV-related liver cancer. Our findings offer new evidence in support of an important role for diversity in proteins involved in immunosurveillance in the development of HBV-related HCC. Whether HLA zygosity is also important for other infection-related cancers and solid tumors not caused by infection merits further investigation.
Terms: <0-11 years old><21+ years old><AIDS><AIDS Virus><Ab-dependent cellular cytotoxicity><Acquired Immune Deficiency><Acquired Immune Deficiency Syndrome><Acquired Immune Deficiency Syndrome Virus><Acquired Immuno-Deficiency Syndrome><Acquired Immunodeficiency Syndrome><Acquired Immunodeficiency Syndrome Virus><Acquired Immunologic Deficiency Syndrome><Adult><Adult Human><Affect><Affinity><Africa South of the Sahara><Alleles><Allelomorphs><Anti-Malarials><Antigen Presentation><Antigenic Determinants><Antigens><Antimalarial Agents><Antimalarial Drugs><Antimalarials><Attenuated><Autoimmune Diseases><Binding><Binding Determinants><Biological><Biological Function><Biological Process><Blood><Blood Reticuloendothelial System><Blood erythrocyte><Blood group antigen f><Blood leukocyte><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><Cancer Cause><Cancer Etiology><Cancers><Cell Body><Cell Mediated Immunology><Cell surface><Cell-Mediated Immunity><Cell-Mediated Lympholytic Cells><Cells><Cellular Immunity><Characteristics><Child><Child Youth><Children (0-21)><Chronic><Chronic Hepatitis B><Class I Antigens><Class I Major Histocompatibility Antigens><Class II Antigens><Class II Major Histocompatibility Antigens><Communicable Diseases><Complex><Complex Class 1><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Cytotoxic cell><DNA><Data><Data Bases><Data Set><Databases><Dataset><Deoxyribonucleic Acid><Dependence><Development><Digit><Digit structure><Disease><Disease Outcome><Disorder><Dissociation><Education><Educational aspects><Effector Cell><Epitopes><Erythrocytes><Erythrocytic><Evolution><Exhibits><F antigen><Falciparum Malaria><Follow-Up Studies><Followup Studies><Gene variant><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic Determinism><Genetic Polymorphism><Genetic defect><Genotype><Goals><HBV><HBeAg><HIV><HIV-1><HIV-I><HIV1><HL-A Antigens><HLA Antigens><Haplotypes><Hematologic Cancer><Hematologic Malignancies><Hematologic Neoplasms><Hematological Malignancies><Hematological Neoplasms><Hematological Tumor><Hematopoietic Cancer><Hepatic Cancer><Hepatitis B Virus><Hepatitis B e Antigens><Hepatitis Be Antigens><Hepatocarcinoma><Hepatocellular Carcinoma><Hepatocellular cancer><Hepatoma><Heterozygote><High Prevalence><Histocompatibility Antigens Class I><Histocompatibility Antigens Class II><Homologous Serum Hepatitis Virus><Homozygote><Human><Human Characteristics><Human Genome><Human Immunodeficiency Virus Type 1><Human Immunodeficiency Viruses><Human Leukocyte Antigens><Human Nature><Human immunodeficiency virus 1><I-A Antigen><Ia Antigens><Ia-Like Antigens><Immune><Immune Globulins><Immune Response Antigens><Immune Response Genes><Immune Surveillance><Immune mediated therapy><Immune response><Immune-Response-Associated Antigens><Immunes><Immunity><Immunogenetics><Immunoglobulins><Immunologic Receptors><Immunologic Surveillance><Immunologic Surveillances><Immunological Receptors><Immunological Surveillance><Immunological Surveillances><Immunological response><Immunologically Directed Therapy><Immunosurveillance><Immunotherapy><Individual><Infection><Infection-Related Malignancy><Infection-Related Malignant Neoplasm><Infectious Agent><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Inflammatory><Innate Immune Response><Investigation><Ir Gene><K Cells><K lymphocyte><KIR3DL1><Killer Cells><Knowledge><LAV-HTLV-III><Laboratories><Leukocyte Antigens><Leukocytes><Leukocytes Reticuloendothelial System><Ligands><Link><Liver Cells Carcinoma><Lymphadenopathy-Associated Virus><Lymphatic cell><Lymphocyte><Lymphocytic><MHC Class I Molecule><MHC Class I Protein><MHC Class II Molecule><MHC Class II Protein><MHC class I antigen><MHC class II antigen><Major Histocompatibility Complex Class 1><Major Histocompatibility Complex Class II><Malaria><Malignant Hematologic Neoplasm><Malignant Neoplasms><Malignant Tumor><Malignant neoplasm of liver><Marrow erythrocyte><Marrow leukocyte><Mediating><Messenger RNA><Modeling><Modern Man><Molecular><Molecular Interaction><Morbidity><Morbidity - disease rate><Mutation><NK Cells><NK cell receptor NKB1><NKB1 receptor><Natural History><Natural Killer Cells><Non-Hodgkin's Lymphoma><Nonhodgkins Lymphoma><Oncogenic><Outcome><P falciparum><P. falciparum><P.falciparum><Paludism><Parasitemia><Parasites><Pathogenicity><Peptides><Plasmodium Infections><Plasmodium falciparum><Plasmodium falciparum Malaria><Play><Position><Positioning Attribute><Predisposition><Primary carcinoma of the liver cells><Probability><Property><Proteins><Proteome><Receptor Protein><Red Blood Cells><Red Cell><Reporting><Research Resources><Resistance><Resources><Risk><Role><Signal Pathway><Solid Neoplasm><Solid Tumor><Specificity><Structure><Sub-Saharan Africa><Subsaharan Africa><Surface><Susceptibility><T cell response><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><TAP-A protein><Testing><Transplantation><Vaccine Design><Vaccines><Variant><Variation><Viral><Viral Burden><Viral Load><Viral Load result><Virus-HIV><White Blood Cells><White Cell><acquired immunity><adaptive immune response><adulthood><allele variant><allelic variant><anti-cancer immunotherapy><anti-malarial agents><anti-malarial drugs><antibody dependent cell mediated cytotoxicity><antibody dependent cytotoxicity><antibody-dependent cell cytotoxicity><antibody-dependent cellular cytotoxicity><antibody-mediated cytotoxicity><anticancer immunotherapy><autoimmune condition><autoimmune disorder><blood corpuscles><cancer immunotherapy><cancer risk><chronic HBV infection><chronic hepatitis B virus infection><cohort><data base><developmental><differential expression><differentially expressed><e Antigens><genetic association><genetic determinant><genetic resistance><genetic variant><genome mutation><genomic variant><heterozygosity><high risk><host response><human disease><human whole genome><immune receptor><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunogen><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><infection related cancer><infectious organism><interest><killer T cell><liver cancer><liver carcinoma><lymph cell><mRNA><malignancy><malignant liver tumor><mortality><neoplasm/cancer><non-Hodgkins disease><novel><parasaetemia><pathogen><peptide I><polymorphism><pressure><prospective><receptor><resistant><response><social role><tapasin><therapeutic target><thymus derived lymphocyte><tool><transcriptional differences><transplant><white blood cell><white blood corpuscle><youngster>