FAULTY IMMUNE REGULATION IN AUTISM

自闭症患者的免疫调节错误

• 批准号: 2674877
• 负责人: REED P. WARREN
• 金额: $ 25.26万
• 依托单位: UTAH STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-02-01 至 2001-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2674877
• 关键词: T lymphocyte; autoimmune disorder; autoimmunity; caucasian American; child (0-11); clinical research; drug adverse effect; early infantile autism; genetic markers; histocompatibility typing; human subject; immunogenetics; nervous system disorder epidemiology; nervous system infection; polymerase chain reaction; tissue /cell culture; viral vaccines

DESCRIPTION (Adapted from applicant's abstract): Mounting evidence suggests that the symptoms associated with some cases of autism may result from a genetically-determined immune deficiency and/or an autoimmune mechanism. Circumstantial evidence for this hypothesis stems from the number of features that autism shares with established immune deficiencies and autoimmune disorders including: genetic predisposition, general immune imbalances, association with the HLA or the major hitocompatibillity complex (MHC) on chromosome 6, association with viral and other infections, demonstration of cell-mediated immunity and serum antibodies against proteins of the central nervous system, and an uneven sex distribution (autism is 4-5 times more frequent in boys than in girls). The investigator's laboratory has made several findings during the initial and first renewal periods of this project providing additional evidence for the immunodeficiency-autoimmune hypothesis for some cases of autism. These include an association of the MHC with autism including an increased frequency of the C4B null allele with the resultant reduced plasma levels and reduced C4 function, supporting the concept of immune susceptibility to a microorganism or a pathogen. The investigators have also found an elevated representation of the extended MHC haplotype B44-SC30-DR4. The MHC was associated with a stronger history of infections in the autistic patients. Some of the autistic subjects demonstrated decreased levels of immunoglobulin A which also appeared to be associated with a gene within the MHC. Finally, the investigators have observed DR+ (activated) T cells in some of the patients (which confirmed an earlier finding by another laboratory) and an altered T cell receptor (TRC) Vbeta profile including increased frequencies of the Vbetas 8.1, 8.2 and 13. The DR4 (DRb1*0401) portion of the extended haplotype b44-SC30-DR4 shares a common amino acid sequence motif in the third hypervariable region (HVR-3) with several other extended haplotypes. This shared motif, seen in more than 50% of the autistic subjects, provides a plausible explanation for the possible existence of immune deficiency or autoimmune-disease in some autistic subjects. This renewal project will: 1) investigate association of the MHC with autistic subjects located in an area other than northern Utah; 2) study, using molecular genetic technology, whether another gene, within the extended haplotype in proximity to the C4B gene of the MHC, rather than the C4B gene itself, is primarily associated with autism; 3) explore evidence for and against the possibility that immune deficiency is related to autism by allowing a pathogen or microorganism to persist and damage the brain or interfere with normal brain function; and 4) determine whether or not autoimmune processes are associated with the development of autism. These studies may lead to a new treatment approach for autism.

描述（根据申请人的摘要改编）：安装证据表明 与某些自闭症病例相关的症状可能是由 遗传确定的免疫缺陷和/或自身免疫机制。 该假设的间接证据源于 自闭症与已建立的免疫缺陷和 自身免疫性疾病包括：遗传易感性，一般免疫 不平衡，与HLA或主要的HinoCompatibillity Complex的关联 （MHC）在6染色体上，与病毒和其他感染相关， 细胞介导的免疫和血清抗体的证明 中枢神经系统的蛋白质和性别分布不平坦 （男孩的自闭症的频率是女孩的4-5倍）。 这 调查员的实验室在首发期间已经做出了一些发现， 该项目的首次续签期为 某些自闭症病例的免疫缺陷 - 自动免疫性假设。 这些 包括MHC与自闭症的关联，包括增加 C4B无效等位基因的频率降低血浆水平 并降低了C4功能，支持免疫易感性的概念 微生物或病原体。 调查人员还发现 扩展的MHC单倍型B44-SC30-DR4的高度表示。 MHC 与自闭症中感染的史相关 患者。 一些自闭症受试者显示出降低的水平 免疫球蛋白A似乎也与基因有关 MHC。 最后，研究人员观察到DR+（激活）T细胞 一些患者（证实了另一个患者的发现 实验室）和改变的T细胞受体（TRC）VBETA轮廓包括 VBETAS 8.1、8.2和13的频率增加。DR4（DRB1*0401） 扩展单倍型B44-SC30-DR4的一部分共享一个常见的氨基酸 其他几个 扩展单倍型。 这个共享的主题，在超过50％的 自闭症受试者，为可能的可能性提供了合理的解释 某些自闭症中存在免疫缺陷或自身免疫性疾病 主题。 这个更新项目将：1）调查MHC的关联 自闭症受试者位于犹他州北部以外的地区； 2） 研究，使用分子遗传技术，无论是另一个基因 与MHC的C4B基因接近的扩展单倍型，而不是 C4B基因本身主要与自闭症有关。 3）探索证据 因为免疫缺陷与自闭症有关 通过允许病原体或微生物持续存在并破坏大脑或 干扰正常的大脑功能； 4）确定是否 自身免疫过程与自闭症的发展有关。 这些 研究可能会导致一种新的自闭症治疗方法。