Risk of CFS Due to IgG Receptor Genes that Impair ADCC

 描述（由申请人提供）：慢性疲劳综合征（CFS）有一个遗传成分，占风险的38%，但这种风险尚未与特定基因联系起来。许多CFS患者有慢性病毒感染的问题。PI提出，抗体受体基因的等位基因变异导致CFS患者对慢性病毒的脆弱性。当病毒感染变成慢性时，自然杀伤（NK）细胞的K细胞亚群识别针对病毒蛋白的抗体，并通过抗体依赖性细胞介导的细胞毒性（ADCC）杀死感染的细胞。ADCC受损与CFS的免疫病理学一致：患者难以控制EBV、H。HHV-6和HCMV慢性病毒感染。Fc-IgG受体（FcR）使K细胞能够识别与细胞结合的抗体并杀死感染的细胞。FcR的等位基因多态性损害ADCC。NK细胞表达两种激活性FcR，CD 16 A和CD 32 C，有时表达抑制性FcR，CD 32 B。Hudig和Barao博士假设，由于CD 16 A、CD 32 C和CD 32 B的遗传变异，CFS患者的ADCC低于健康个体，并且特定的等位基因是家族性CFS的重要疾病决定因素。FcRs和其他蛋白表达的表型变异也可能降低患者的ADCC。PI在淋巴细胞毒性方面具有丰富的经验，其合作者丹尼尔L。Peterson，MD，是世界著名的CFS临床医生。目的1：确定损害ADCC的FcR基因型是否是CFS的危险因素。主要受体CD 16 A有2个等位基因，158 V是最佳的，158 F对ADCC不太有效。另一种受体CD 32 C也具有ORF和终止等位基因;后者不编码CD 32 C并产生受损的表型。CD 32 C的染色体缺失导致K细胞抑制性CD 32 B表达。PI将：a）确定CFS患者相对于健康家庭成员和无关对照的等位基因多态性; B）评估CFS严重性的“损害”等位基因;和c）检查具有2至4个CFS亲属的家庭中疾病的CD 16 A F/F、CD 32 Cstop/stop或CD 32 Cdel的遗传。如果是这样，这些等位基因是CFS的候选危险因素。S.K.安德森，博士，国家癌症研究所正在合作进行基因鉴定。目的2：确定FcR细胞表型和低ADCC是否是CFS的危险因素。血液中K细胞的数量和NK中K细胞的频率变化很大。CD 16 A和CD 32 C的细胞密度也会影响ADCC。PI将：a）通过流式细胞术测定CD 16 A、CD 32 C和CD 32 B的K细胞的数量、频率和MFI; B）通过51 Cr测定和CD 107 a测量ADCC。他们预计CFS患者将具有与CD 16 A F/F、CD 32 C stop/stop和CD 32 Cdel相关的低ADCC。创新：PI将首次确定家族性CFS的特定遗传贡献。该项目的新元素包括：1）FcR等位基因多态性; 2）CFS中K细胞的表型; 3）CFS患者的ADCC。临床意义：本研究将确定可能受益于ADCC增强疗法的CFS患者亚组，例如，MMT 6和ADAM 17抑制剂和抗CD 137共刺激。

 DESCRIPTION (provided by applicant): Chronic fatigue syndrome (CFS) has a genetic component that contributes up to 38% of the risk, but this risk is yet to be linked to specific genes. Many CFS patients have problems with chronic viral infections. The PIs propose that allelic variances in antibody receptor genes contribute to the vulnerability of CFS patients to chronic viruses. When viral infections become chronic, the K-cell subset of natural killer (NK) cells recognizes antibodies to viral proteins and kills infected cells by antibody-dependent cell-mediated cytotoxicity (ADCC). Impaired ADCC is consistent with the immunopathology of CFS: patients have difficulties controlling EBV, H. simplex I&II, HHV-6 and HCMV chronic viral infections. Fc-IgG receptors (FcRs) enable K-cells to recognize antibodies bound to cells and to kill infected cells. Allelic polymorphisms of FcRs impair ADCC. K cells express two activating FcRs, CD16A & CD32C, and sometimes an inhibitory FcR, CD32B. Drs. Hudig and Barao hypothesize that CFS patients have lower ADCC than healthy individuals due to genetic variations of CD16A, CD32C and CD32B and that particular alleles are significant disease-determining factors in familial CFS. Phenotypic variations of expression of FcRs and other proteins may also lower the patients' ADCC. The PIs have extensive experience with lymphocyte cytotoxicity and their collaborator, Daniel L. Peterson, MD, is a world-renowned CFS clinician. Aim 1: To determine if FcR genotypes that impair ADCC are risk factors for CFS. The main receptor CD16A has 2 alleles, 158V that is optimal and 158F that is less effective for ADCC. Another receptor CD32C also has ORF and stop alleles; the latter encodes no CD32C and creates an impaired phenotype. Chromosomal deletion of CD32C causes inhibitory CD32B expression by K-cells. The PIs will: a) determine the allelic polymorphisms of CFS patients vs. healthy family members and unrelated controls; b) evaluate 'impairing' alleles with CFS severity; and c) examine families with 2 to 4 relatives with CFS for inheritance of CD16A F/F, CD32Cstop/stop or CD32Cdel with disease. If so, these alleles are candidate risk factors for CFS. S.K. Anderson, Ph.D., NCI, is collaborating for the genetic characterizations. Aim 2: To determine if FcR cell phenotype(s) and low ADCC are risk factors for CFS. The number of K-cells in blood and the frequency of K-cells among NKs vary widely. Cellular densities of CD16A and CD32C also will affect ADCC. The PIs will: a) determine the numbers, frequencies and MFIs of K-cells for CD16A, CD32C and CD32B by flow cytometry; b) measure ADCC by 51Cr assays and CD107a. They expect that CFS patients will have low ADCC that correlates with CD16A F/F, CD32C stop/stop and CD32Cdel. Innovation: The PIs will determine for the first time a specific genetic contribution to familial CFS. New elements of the project include: 1) FcR allelic polymorphisms; 2) phenotypes of K-cells in CFS; and 3) the ADCC of CFS patients. Clinical significance: This study will identify subsets of CFS patients who may benefit from ADCC-enhancing therapies, e.g., MMT 6 & ADAM17 inhibitors and anti-CD137 co-stimulation.