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Immunoglobulin GM (γ marker) Allotypes and Immunity to HSV1 in Alzheimer’s Disease

阿尔茨海默病中免疫球蛋白 GM（γ 标记）同种异型和对 HSV1 的免疫

基本信息

批准号：
10464940
负责人：
JANARDAN P PANDEY
金额：
$ 36.7万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10464940
关键词：
Affinity African American Alleles Alzheimer&apos s Disease Alzheimer&apos s disease patient Alzheimer&apos s disease risk American Antibodies Antibody Response Antigen-Antibody Complex Apolipoprotein E Brain Diseases Candidate Disease Gene Cells Chromosome 14 Chromosomes Complex Cystic Fibrosis DNA Dementia Development Disease Disease Progression Elderly Environmental Risk Factor Etiology European Exclusion Fc domain Frequencies GTP-Binding Protein alpha Subunits, Gs Gene-Modified Genes Genetic Genetic Variation Genotype Glycoproteins Haplotypes Heavy-Chain Immunoglobulins Herpesviridae Herpesvirus 1 Humoral Immunities IgG1 Immune Immune system Immunity Immunobiology Immunoglobulin G Immunoglobulins Immunologic Surveillance Immunologics Immunotherapy Infection International Investigation Late Onset Alzheimer Disease Ligation Link Literature Mediating Meta-Analysis Neurons Pathogenesis Pathway interactions Patients Phagocytes Population Population Group Predisposition Prevalence Proteins Receptor Gene Reporting Risk Role Simplexvirus Susceptibility Gene Testing United States National Institutes of Health Viral Virus Waxes aged antibody-dependent cell cytotoxicity antibody-dependent cellular phagocytosis apolipoprotein E-4 base cohort genome wide association study genotyping technology interest novel pathogen receptor response risk variant study population vaccine candidate virtual

项目摘要

Alzheimer’s disease (AD) is a heterogeneous and complex disorder and both genetic and environmental factors are likely to be involved in its etiology. Hundreds of putative susceptibility genes for late-onset AD have been reported, but the majority of these claims—with the exception of the e4 allele of the apolipoprotein E gene—have not been consistently replicated. Furthermore, the functional significance of the majority of the positional candidate genes in AD pathogenesis is not clear. One putative environmental (viral) factor that has been implicated in AD etiology is herpes simplex virus type 1 (HSV1). An infectious etiology for AD would suggest that the genes of the host immune system might also mediate the putative pathways towards the development of this disorder. Indeed, the genome-wide association studies (GWAS) and meta-analyses of AD have reported many risk-conferring genes that are enriched in the immune system pathways. The GWAS of AD, however, do not evaluate a major gene complex of the immune system—GM (g marker) allotypes encoded by immunoglobulin heavy chain G (IGHG) genes on chromosome 14. HSV1 is a ubiquitous herpesvirus. Clearly, not all HSV1-infected people are equally likely to develop AD-related complications, suggesting the involvement of host genetic factors in the HSV1-spurred dementia. Immunoglobulin GM allotypes are excellent candidate genes for modifying the HSV1-AD association, because they modulate the HSV1 immunoevasion strategies and, epistatically with Fcg receptor (FcgR) genes, contribute to the magnitude of antibody-dependent cellular cytotoxicity of HSV1-infected cells. In a recent study, we have shown that a GM genotype was associated with a 4-fold increased risk of AD. This association was independent of apolipoprotein e4 genotype and other AD risk genes. Based on these observations, we hypothesize that GM genes are risk factors for AD, and the underlying mechanisms include their influence on the magnitude of humoral immunity to HSV1 proteins and antibody-dependent cellular phagocytosis (ADCP) of neuronal cells. The following specific aims will test our hypothesis: 1) Determine if GM genotypes are risk factors for Alzheimer’s disease. DNA from a large study population of AD patients and controls will be characterized for several GM alleles to confirm our preliminary findings; 2) Determine if the magnitude of antibody responsiveness to particular HSV1 proteins is associated with GM alleles. We will quantitate antibody responses to HSV1-gD (a major glycoprotein and vaccine candidate) in the sera of AD patients and controls and determine if the magnitude of antibody responsiveness is associated with GM allotypes; 3) Determine if particular allelic combinations of Fc (GM) and cellular FcgR alleles influence the level of ADCP. Using biotinylated HSV-gD as target, we will determine whether the level of ADCP is associated with particular combinations of Fcg (GM) and FcgRIIa alleles. Results of this investigation may begin to answer the question: Why the prevalence of HSV1 infection does not correlate with the prevalence of AD in the population?

阿尔茨海默病（AD）是一种遗传性和环境性的异质性复杂疾病