Kaufman J, Völk H, Wallny H J
Basel Institute for Immunology, Switzerland.
Immunol Rev. 1995 Feb;143:63-88. doi: 10.1111/j.1600-065x.1995.tb00670.x.
The high polymorphism of classical Mhc molecules found in mammals is not simply the result of strong selection for pathogen resistance in the recent past, since there are virtually no examples of diseases caused by infectious pathogens for which resistance is determined by particular Mhc haplotypes, and in the best-studied case, a particular aspect of malaria in humans, the selection is remarkably weak. We discuss three possibilities to explain high polymorphism in mammals: accumulating, merging and boosting. The mammalian Mhc is complicated and redundant, so that every Mhc haplotype may give some level of resistance due to multiple classical Mhc genes as well as other disease resistance genes; this frustrates the attempts to demonstrate selection for disease resistance. We have looked at two vertebrate groups that may represent two extreme examples of selection for Mhc polymorphism. Birds, like mammals, have highly a polymorphic Mhc that determines strong allograft rejection. However, chickens have a much smaller, compact and simpler Mhc than mammals, as though the Mhc has been stripped down to the essentials during evolution. The selection on a single Mhc gene should be much stronger than on a large multigene family and, in fact, there are a number of viral diseases for which resistance and susceptibility are determined by particular chicken Mhc haplotypes. We have determined the peptide motifs for the chicken class I molecules from a number of haplotypes, which may explain some disease associations quite simply. On the other hand, salamanders have very low Mhc polymorphism and slow allograft rejection. We have isolated axolotl Mhc molecules and shown that they cosegregate with the locus that determines graft rejection in the axolotl, have only a few alleles and only weakly stimulate axolotl T lymphocytes in mixed lymphocyte culture. We believe that salamanders have classical Mhc molecules but most T cells do not recognize them, so that there is no strong selection for polymorphism.
在哺乳动物中发现的经典Mhc分子的高度多态性并非仅仅是近期对病原体抗性进行强烈选择的结果，因为几乎没有由感染性病原体引起的疾病实例表明抗性是由特定的Mhc单倍型决定的，而且在研究最充分的人类疟疾这一案例中，选择作用非常微弱。我们讨论了解释哺乳动物中高度多态性的三种可能性：积累、合并和增强。哺乳动物的Mhc复杂且冗余，以至于每个Mhc单倍型可能由于多个经典Mhc基因以及其他抗病基因而具有一定程度的抗性；这使得证明对疾病抗性的选择变得困难。我们研究了两个脊椎动物群体，它们可能代表了对Mhc多态性选择的两个极端例子。鸟类与哺乳动物一样，具有高度多态的Mhc，可决定强烈的同种异体移植排斥反应。然而，鸡的Mhc比哺乳动物的要小得多、紧凑且简单，就好像Mhc在进化过程中已被精简到了基本要素。对单个Mhc基因的选择应该比对一个大型多基因家族的选择要强得多，事实上，有许多病毒疾病的抗性和易感性由特定的鸡Mhc单倍型决定。我们已经确定了来自多个单倍型的鸡I类分子的肽基序，这可以很简单地解释一些疾病关联。另一方面，蝾螈的Mhc多态性非常低，同种异体移植排斥反应缓慢。我们已经分离出了美西螈Mhc分子，并表明它们与决定美西螈移植排斥反应的基因座共分离，只有少数等位基因，并且在混合淋巴细胞培养中只能微弱地刺激美西螈T淋巴细胞。我们认为蝾螈具有经典的Mhc分子，但大多数T细胞不识别它们，因此对多态性没有强烈的选择。
