FCGRIIIA and IGHG (GM) Genotypes and Immunity to HSV1 in Herpes Stromal Keratitis

疱疹性基质性角膜炎中的 FCGRIIIA 和 IGHG (GM) 基因型以及对 HSV1 的免疫

• 批准号: 10507311
• 负责人: JANARDAN P PANDEY
• 金额: $ 22.65万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10507311
• 关键词: Affinity; Alleles; Alzheimer' s Disease; Alzheimer' s disease risk; Antibodies; Antibody Response; Antibody Therapy; Antigens; Binding; Blindness; Candidate Disease Gene; Cells; Chromosome 14; Chromosomes; Complex; DNA; Development; Disease; Disease Progression; Effector Cell; Epithelial Cells; Fc domain; Gene-Modified; Genes; Genetic; Genetic Variation; Genome; Genomics; Genotype; Glycoproteins; Herpesviridae; Herpesvirus 1; Human; Humoral Immunities; IGH@ gene cluster; IgG1; Immune; Immune system; Immunity; Immunobiology; Immunoglobulin G; Immunoglobulin Genes; Immunoglobulins; Immunologics; Immunotherapy; Incidence; Individual; Infection; Investigation; Keratitis; Lead; Ligation; Link; Linkage Disequilibrium; Mediating; Mus; Natural Killer Cells; Outcome; Patients; Pattern; Persons; Predisposition; Prevalence; Proteins; Receptor Gene; Risk; Risk Factors; Role; Simplexvirus; Susceptibility Gene; Testing; Therapeutic Monoclonal Antibodies; United States; Variant; Viral; Virus; antibody-dependent cell cytotoxicity; base; corneal epithelium; design; genome wide association study; genotyping technology; man; novel; receptor; response; risk variant; vaccine candidate; virtual

Herpes stromal keratitis (HSK), induced by herpes simplex virus type 1 (HSV1), is the most common cause of infectious blindness in the United States. HSV1 is a common virus and not all HSV1-infected people are equally likely to develop HSK, suggesting the involvement of host genetic factors in the development of this disorder. Immunoglobulin GM (g marker) allotypes, encoded by IGHG1, IGHG2, and IGHG3 genes on chromosome 14, are excellent candidate genes for involvement in HSK etiopathogenesis because they modulate HSV1 immunoevasion strategies. The HSV1-encoded decoy Fcg receptor (FcgR), the gE-gl glycoprotein complex, which the virus uses to thwart host’s Fc-mediated effector functions, such as antibody- dependent cellular cytotoxicity (ADCC), binds differentially to IgG antibodies expressing different GM allotypes. IgG1 proteins expressing GM 1,17 alleles have strikingly higher affinity for the viral decoy FcgR than those expressing the alternative GM 1-,3 alleles. In addition, GM genes, epistatically with cellular FcgR genes, contribute to the magnitude of ADCC of HSV1-infected cells. Based on these observations, we hypothesize that GM and FcgRIIIa genes are risk factors for HSK, and the underlying mechanisms include their contribution to the humoral immunity to HSV1 proteins and to the ADCC of HSV1-infected corneal epithelial cells. The following specific aims will test our hypothesis: Aim1: Determine if GM and FcgRIIIa genotypes are risk factors for HSK. DNA from HSK patients and controls will be characterized for several GM and FcgRIIIa alleles to assess whether these genes—individually or epistatically—are risk factors for HSK; Aim 2: Determine if the magnitude of antibody responsiveness to particular HSV1 proteins is associated with GM and FcgRIIIa alleles. We will quantitate antibody responses to HSV1-gD (a major glycoprotein and vaccine candidate) in the sera of HSK patients and controls and determine if the magnitude of antibody responsiveness is associated with GM and FcgRIIIa genotypes; Aim 3: Determine if particular allelic combinations of Fc (GM) and cellular FcgR alleles influence the level of ADCC. IgG antibody mediated ADCC is triggered upon ligation of FcγR (expressed on effector cells) to the Fc region of anti-viral IgG antibodies. It follows that genetic variation in FcγR and Fc, where virtually all GM alleles are expressed, could contribute to the differences in the magnitude of ADCC. Using HSV-gD-transfected corneal epithelial cells as target, affinity purified, allotypically disparate anti-HSV1- gD antibodies from HSK patients, and NK cells (expressing different FcgRIIIa alleles) as effectors, we will determine whether the level of ADCC is associated with particular combinations of Fcg (GM) and FcgRIIIa alleles. The results of this investigation will enhance our understanding of the genetics of Fc-mediated effector mechanisms underlying the HSV1-HSK association. This will inform improvements in the design of viral immunogens that may generate protective antibody Fc effector responses as well as in the design of the Fc region of therapeutic monoclonal antibodies for the treatment of this disorder.

单纯疱疹病毒1型（HSV 1）引起的单纯疱疹性角膜基质炎（HSK）是角膜炎的最常见原因。 美国的传染性失明HSV 1是一种常见病毒，并不是所有的HSV 1感染者都是 同样有可能发展HSK，这表明宿主遗传因素参与了这种发展。 disorder.免疫球蛋白GM（g标记）同种异型，由IGHG 1、IGHG 2和IGHG 3基因编码， 14号染色体，是参与HSK发病机制的优秀候选基因，因为它们 调节HSV 1免疫逃避策略。HSV 1编码的诱饵Fcg受体（FcgR）、gE-gl 糖蛋白复合物，该病毒用于阻碍宿主的Fc介导的效应子功能，如抗体- 依赖性细胞毒性（ADCC），与表达不同GM同种异型的IgG抗体差异性结合。 表达GM 1，17等位基因的IgG 1蛋白与病毒诱饵FcgR的亲和力显著高于表达GM 1，17等位基因的IgG 1蛋白与病毒诱饵FcgR的亲和力。 表达替代的GM 1-，3等位基因。此外，GM基因，与细胞FcgR基因， 有助于HSV 1感染细胞的ADCC的大小。基于这些观察，我们假设 GM和FcgRIIIa基因是HSK的危险因素，其潜在机制包括它们的贡献 对HSV 1蛋白的体液免疫和HSV 1感染的角膜上皮细胞的ADCC。的 以下具体目标将检验我们的假设：目标1：确定GM和FcgRIIIa基因型是否是风险因素 对于HSK。将表征来自HSK患者和对照的DNA的几种GM和FcgRIIIa等位基因， 评估这些基因是否是HSK的危险因素;目的2：确定这些基因是否是HSK的危险因素。 对特定HSV 1蛋白的抗体应答性的大小与GM和FcgRIIIa等位基因相关。 我们将定量HSV 1-gD（一种主要的糖蛋白和疫苗候选物）的血清中的抗体应答， HSK患者和对照，并确定抗体反应性的大小是否与GM相关 目的3：确定Fc（GM）和细胞FcgR等位基因的特定等位基因组合是否 影响ADCC的水平。IgG抗体介导的ADCC在FcγR（表达于 效应细胞）与抗病毒IgG抗体的Fc区的结合。因此，FcγR和Fc， 几乎所有的GM等位基因都表达，可能导致ADCC大小的差异。 以HSV-gD转染的角膜上皮细胞为靶细胞，亲和纯化同种异型不同的抗HSV 1-gD抗体， 来自HSK患者的gD抗体和NK细胞（表达不同的FcgRIIIa等位基因）作为效应物，我们将 确定ADCC的水平是否与Fcg（GM）和FcgRIIIa的特定组合相关 等位基因本研究的结果将有助于我们对Fc介导的效应子的遗传学的理解。 HSV 1-HSK关联的潜在机制。这将为病毒设计的改进提供信息， 可以产生保护性抗体Fc效应子应答的免疫原，以及Fc 用于治疗这种疾病的治疗性单克隆抗体的区域。