Molecular basis of human leukocyte antigen class II disease associations

Abstract

This chapter focuses strictly on the HLA MHC class II genes and molecules with regard to how they contribute to better delineation of the genetic associations and how the current knowledge of their structure, expression, and functions can be used to speculate on their role in the pathogenesis of disease. Because of the strong linkage disequilibrium between loci and alleles, the chapter restricts the description of the genetic associations to only the most recent data, mainly generated by molecular means, and because they supercede in precision and accuracy the previous data obtained by serological methods. Because the HLA system displays the unusual feature of strong linkage disequilibrium between loci and alleles, the genetic traits found to be associated with disease do not emerge at random. The pattern of genetic associations follow an almost constant trend. The associations gain strength each time an additional locus centromeric to the precedent is individualized. The advances made in this respect almost parallel the introduction of progressively more refined typing procedures, which allow the division of former genetic entities (loci and alleles) into additional subtypes. Among the HLA-associated diseases, or at least for those diseases in which an autoimmune process is suspected to be directly relevant to the pathogenesis, the associations are with genes and molecules of the HLA-D region (HLA class II genes and products). The most recent data assigns the disease susceptibility to common amino acid sequences present on an HLA class II molecule within its “active” site.