Naugler Christopher, Liwski Robert
Department of Pathology and Laboratory Medicine, Dalhousie University, 5788 University Avenue, Halifax, Nova Scotia, Canada B3H 2Y9.
Med Hypotheses. 2008;70(5):933-7. doi: 10.1016/j.mehy.2007.09.015. Epub 2007 Dec 11.
Human leukocyte antigens are traditionally classified by serologic or molecular techniques into a bewildering variety of alleles. It is generally believed that this allelic diversity is maintained by selection pressures for inbreeding avoidance and/or maximal immune system diversity. While the usual antigen-based classification of individual alleles may be most appropriate in the artificial situation of tissue transplantation, we hypothesize that a functional classification based on allele supertypes may represent a more biologically relevant way to view MHC diversity in the contexts of mate choice and disease pathogenesis. Furthermore, immune system diversity could be quantitatively estimated by calculating a Supertype Diversity Index (SDI) which is the number of different MHC supertypes possessed by an individual. This hypothesis generates a number of testable predictions. First, it predicts that a reduced inherited diversity of MHC allele supertypes may predispose to the development of malignancies because of a decreased native ability to present different tumor-associated antigens. Furthermore, specific autoimmune diseases may be associated with the presence or absence of a particular MHC supertype rather than a particular MHC haplotype. In transplant medicine, it is possible that unmatched alleles may trigger a weaker foreign antigen response if they are matched by allele supertype. Finally, there have been several studies documenting dissortative mating in humans for dissimilar MHC alleles. We predict that natural selection should favor maximization of the heterozygosity of allele supertypes instead of the heterozygosity of individual alleles and that the previously observed dissortative mating may actually be an adaptive strategy to maximize allele supertype diversity.
人类白细胞抗原传统上通过血清学或分子技术被分类为各种各样令人眼花缭乱的等位基因。人们普遍认为，这种等位基因多样性是由避免近亲繁殖和/或最大化免疫系统多样性的选择压力所维持的。虽然在组织移植的人工情境中，通常基于抗原的单个等位基因分类可能是最合适的，但我们假设基于等位基因超型的功能分类可能代表了一种在配偶选择和疾病发病机制背景下看待MHC多样性的更具生物学相关性的方式。此外，免疫系统多样性可以通过计算超型多样性指数（SDI）进行定量估计，该指数是个体拥有的不同MHC超型的数量。这一假设产生了许多可检验的预测。首先，它预测由于呈现不同肿瘤相关抗原的天然能力下降，MHC等位基因超型的遗传多样性降低可能易患恶性肿瘤。此外，特定的自身免疫性疾病可能与特定MHC超型的存在或缺失相关，而不是与特定的MHC单倍型相关。在移植医学中，如果不匹配的等位基因在等位基因超型上匹配，它们可能引发较弱的外来抗原反应。最后，有几项研究记录了人类中不同MHC等位基因的异交情况。我们预测自然选择应该有利于等位基因超型杂合性的最大化，而不是单个等位基因的杂合性，并且先前观察到的异交实际上可能是一种使等位基因超型多样性最大化的适应性策略。
