The three other hypothesis listed in the second category above implicate, in one way or another, antigen presentation by HLA molecules. They postulate that the basis of HLA-disease association is an immune response to putative self- or foreign antigens as a mechanism of HLA-disease association is difficult to reconcile with a considerable body of scientific data.
First, the cause effect fidelity between HLA alleles and particular disease is often challenged. For example, HLA-DRB1*0401, the best known for its association with rheumathoid arthritis, association with type I diabetes as well. Thus, an individual HLA allele can promiscuously associate with distinc diseases that do not share pathogenesis, target tissues or putative antigens.
Second, allele-associated diseaase can demonstrate species non-specifity such as HLA-DRB1*0401, which associates with human rheumathoid arthritis, confers suceptibility to inflammatory arthritis in mice as well. Such”trans-species susceptibility” is difficult to reconcile with HLA-restricted antigen presentation.
Third, significant HLA-allele based associations have been observed in conditions that do not involve antigen recognition or any immune-based pathogenesis.
Finally, antigen presentation-based hypothesis cannot easily explain allele-dose impact on disease severity or offer a plausible explanation for allele-dose effects on concordance rates in monozygotic twins . Thus, HLA-restricted antigen presentation, a common thread in most of the prevailing hypotheses addressing HLA-disease association, appears to be inharmonious with many observation concerning the biology, epidemiology and evolution of HLA molecules.