Human Leukocyte Antigen (HLA) part 48

One of the most conspicuous features in the HLA fold is a prominent cusp-shaped  prominence in the α2 domain of class I HLA molecules, and its tri-dimensionally equivalent β1 domain  in class II HLA molecules. The cusp in both molecules involved allele-diversity regions. Similarly, shaped structures have been preserved in the entire major histocompatibility complex gene product family, irrespective of whether or not they can present antigens. Importantly, cusp regions in several HLA molecules have been found to act as ligands that perform non-antigen  presentation functions. For example,  ligands for natural killer cell receptors have been identified in the cusp regions of both classical and non classical (HLA-E) class I HLA molecules. Thus, the cusp region, whose peculiar tri-dimensional shape has been carefully conserved through major histocompatibility complex evolution independent  of antigen presentation, is a hub for signal transduction ligands that interact with a variety of non-HLA receptors and activate important biologic functions. In class II and classical class I HLA molecules, the cusp contains allelic  hypervariable region. Antigen presentation  per se cannot explain HLA-disease association. The major histocompatibility complex  cusp theory proposes that  HLA molecules may promote diseases due to their allele-specific biologic effects independent of antigen presentation function of HLA. Therefore, the blame cannot be applied exclusively to the antigen presentation fuction  of HLA molecules.