GENETICS OF IGA AND OTHER IMMUNOGLOBULIN DEFICIENCIES

IGA 和其他免疫球蛋白缺陷的遗传学

• 批准号: 6829682
• 负责人: CHESTER Allan ALPER
• 金额: $ 23.15万
• 依托单位: IMMUNE DISEASE INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-12-01 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6829682
• 关键词: MHC class I antigen; MHC class II antigen; clinical research; family genetics; gene frequency; genetic mapping; genetic markers; genetic models; genetic susceptibility; genotype; human subject; immune response genes; immunogenetics; immunoglobulin A; immunoglobulin genes; inborn immunodeficiency; major histocompatibility complex

Patients with IgA deficiency may have severe anaphylactic reactions to transfused blood and increased susceptibility to infections. It is known that 4 conserved extended major histocompatibility haplotypes are increased in frequency among IgA-deficient patients. This project will further define the genetics of IgA deficiency and a group of closely related and more common deficiencies of IgD, of IgG3 and of IgG4 by first identifying susceptibility and non-susceptibility conserved extended haplotypes. We will use known sequences and polymorphisms (microsatellites, SNPs, etc.) to preliminarily localize susceptibility genes for each of the immunoglobulin deficiencies by prospective study of individuals with ancient recombinant haplotypes or fragments of extended haplotypes who have immunoglobulin deficiencies. Nucleotide sequences in chromosomal regions identified in these studies will be determined in susceptibility and non-susceptibility extended haplotypes in order to identify candidate susceptibility genes as open reading frames. Polymorphisms will be corrected with those of patients with deficiencies but without extended haplotypes. Expression of genes in the region will be assessed in cells of the peripheral blood mononuclear cells of deficient and normal persons, including affected B cell subsets and their immediate progenitors and, if differences are found, these will be correlated with the presence of deficiency. From the study of appropriate family members who have immunoglobulin deficiencies and using analytic tools that we have developed, we shall construct a general genetic and population genetic model for IgA deficiency and each of the other MHC-determined immunoglobulin deficiencies and estimate MHC and non-MHC gene frequencies and confirm modes of inheritance. We will determine prevalences of deficiencies in their sibs, MHC-identical sibs , parents and clildren and compare these with those predicted by the model to validate the model.

伊加缺乏症患者可能对输血有严重的过敏反应，并增加感染的易感性。 已知IgA缺陷患者中4种保守的扩展主要组织相容性单倍型的频率增加。 该项目将通过首先鉴定易感性和非易感性保守扩展单倍型，进一步确定伊加缺乏症和一组密切相关且更常见的IgD、IgG3和IgG4缺乏症的遗传学。 我们将使用已知的序列和多态性（微卫星，SNP等）。通过对具有免疫球蛋白缺陷的古老重组单倍型或扩展单倍型片段的个体的前瞻性研究，初步定位每种免疫球蛋白缺陷的易感基因。将在易感性和非易感性扩展单倍型中确定这些研究中鉴定的染色体区域中的核苷酸序列，以将候选易感性基因鉴定为开放阅读框。 多态性将被校正为具有缺陷但没有扩展单倍型的患者的多态性。 将在缺陷和正常人的外周血单核细胞中评估该区域的基因表达，包括受影响的B细胞亚群及其直接祖细胞，如果发现差异，则将其与缺陷的存在相关联。 通过对患有免疫球蛋白缺乏症的适当家庭成员的研究，并使用我们开发的分析工具，我们将构建伊加缺乏症和其他每种MHC确定的免疫球蛋白缺乏症的通用遗传和群体遗传模型，并估计MHC和非MHC基因频率并确认遗传模式。 我们将确定其同胞、MHC相同的同胞、父母和近亲中缺陷的患病率，并将这些与模型预测的缺陷进行比较，以验证模型。