Schroeder H W, Zhu Z B, March R E, Campbell R D, Berney S M, Nedospasov S A, Turetskaya R L, Atkinson T P, Go R C, Cooper M D, Volanakis J E
Department of Medicine, Institute, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA.
Mol Med. 1998 Feb;4(2):72-86.
A common genetic basis for IgA deficiency (IgAD) and common variable immunodeficiency (CVID) is suggested by their occurrence in members of the same family and the similarity of the underlying B cell differentiation defects. An association between IgAD/CVID and HLA alleles DR3, B8, and A1 has also been documented. In a search for the gene(s) in the major histocompatibility complex (MHC) that predispose to IgAD/CVID, we analyzed the extended MHC haplotypes present in a large family with 8 affected members.
We examined the CVID proband, 72 immediate relatives, and 21 spouses, and determined their serum immunoglobulin concentrations. The MHC haplotype analysis of individual family members employed 21 allelic DNA and protein markers, including seven newly available microsatellite markers.
Forty-one (56%) of the 73 relatives by common descent were heterozygous and nine (12%) were homozygous for a fragment or the entire extended MHC haplotype designated haplotype 1 that included HLA- DR3, -C4A-0, -B8, and -A1. The remarkable prevalence of haplotype 1 was due in part to marital introduction into the family of 11 different copies of the haplotype, eight sharing 20 identical genotype markers between HLA-DR3 and HLA-B8, and three that contained fragments of haplotype 1.
Crossover events within the MHC indicated a susceptibility locus for IgAD/CVID between the class III markers D821/D823 and HLA-B8, a region populated by 21 genes that include tumor necrosis factor alpha and lymphotoxins alpha and beta. Inheritance of at least this fragment of haplotype 1 appears to be necessary for the development of IgAD/CVID in this family.
IgA 缺陷（IgAD）和常见变异型免疫缺陷（CVID）在同一家族成员中出现，且潜在的 B 细胞分化缺陷相似，提示它们存在共同的遗传基础。IgAD/CVID 与 HLA 等位基因 DR3、B8 和 A1 之间的关联也有文献记载。为了寻找主要组织相容性复合体（MHC）中易患 IgAD/CVID 的基因，我们分析了一个有 8 名患病成员的大家庭中存在的扩展 MHC 单倍型。
我们检测了 CVID 先证者、72 名直系亲属和 21 名配偶，并测定了他们的血清免疫球蛋白浓度。对个体家庭成员的 MHC 单倍型分析采用了 21 个等位基因 DNA 和蛋白质标记，包括 7 个新获得的微卫星标记。
73 名有共同血缘关系的亲属中，41 名（56%）为指定单倍型 1（包括 HLA - DR3、-C4A-0、-B8 和 -A1）片段或整个扩展 MHC 单倍型的杂合子，9 名（12%）为纯合子。单倍型 1 的显著流行部分归因于该单倍型的 11 个不同拷贝通过婚姻进入该家族，其中 8 个在 HLA - DR3 和 HLA - B8 之间共享 20 个相同的基因型标记，3 个包含单倍型 1 的片段。
MHC 内的交叉事件表明，在 III 类标记 D821/D823 和 HLA - B8 之间存在 IgAD/CVID 的易感基因座，该区域有 21 个基因，包括肿瘤坏死因子α以及淋巴毒素α和β。在这个家族中，至少继承这种单倍型 1 的片段似乎是 IgAD/CVID 发病所必需的。
