de Almeida Denise E, Holoshitz Joseph
Department of Internal Medicine; University of Michigan Medical Center; Ann Arbor, MI USA.
Self Nonself. 2011 Jan;2(1):43-48. doi: 10.4161/self.2.1.15757. Epub 2011 Jan 1.
Half a century after the major histocompatibility complex (MHC) was discovered, its functional roles in health and disease remain poorly understood. Many hallmarks of the MHC, including its unusual evolution, structurefunction properties of its gene products and allele-specific associations with dozens of diseases and health traits cannot be convincingly explained by the tenets of existing paradigms. It is therefore becoming increasingly apparent that in order to better understand MHC-health/disease association-a phenomenon that impacts the health of millions-heterodox ideas are critically needed. Here we propose a testable, novel theory concerning the functional role of MHC molecules in health and disease. At the focus of this theory is an evolutionarily-conserved, tri-dimensional cusp-like prominence ('kink'), found in the midst of one of the two α helices that form the perimeter of the groove of all MHC molecules. Based on structural, functional and evolutionary considerations, as well as our recent experimental data, it is proposed here that the MHC cusp region is enriched in allele-specific signal transduction ligands that interact with non-MHC cell surface receptors and trigger signaling events. Aberrations in these pathways could lead to disease development, or affect the severity of such diseases.
主要组织相容性复合体（MHC）被发现半个世纪后，其在健康与疾病中的功能作用仍未得到充分理解。MHC的许多特征，包括其异常的进化、基因产物的结构功能特性以及与数十种疾病和健康特征的等位基因特异性关联，都无法用现有范式的原则令人信服地解释。因此，越来越明显的是，为了更好地理解MHC与健康/疾病的关联——这一影响数百万人健康的现象——急需非正统的观点。在此，我们提出了一个关于MHC分子在健康与疾病中功能作用的可检验的新理论。该理论的核心是在构成所有MHC分子凹槽周边的两条α螺旋之一中间发现的一个进化保守的三维尖状突出（“扭结”）。基于结构、功能和进化方面的考虑以及我们最近的实验数据，本文提出MHC尖区富含等位基因特异性信号转导配体，这些配体与非MHC细胞表面受体相互作用并触发信号事件。这些途径的异常可能导致疾病发展，或影响此类疾病的严重程度。
