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

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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.