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Aim Our recent research demonstrates the existence of experimentally validated, functional novel microRNA (miRNA) transcripts that are encoded within the HLA-DRA and HLA-DRB5 loci. MicroRNAs are known to regulate the post-transcriptional expression of targeted genes. In order to better understand the physiological role of these miRNAs, we have identified computationally predicted miRNA target sites on a genome-wide scale, revealing numerous targeted mRNA transcripts and physiological processes mediated by HLA encoded miRNAs. Methods Computationally predicted miRNA target sites for two HLA encoded miRNAs (HLA-DRA, HLA-DRB5) were identified on every known gene (GENCODE 25) using miRanda and filtered to contain only those heteroduplexes with a G ⩽ −20Kcal/mol. Statistically enriched biological processes and pathways of targeted transcripts was determined using DAVID. Results The miRNA encoded within the HLA-DRA and HLA-DRB5 loci were predicted to target 930 and 181 transcripts respectively. Although these targeted transcripts are involved in numerous physiological processes, both miRNAs are found to target transcripts that are statistically enriched within biological processes related to nervous system development, including the β-amyloid (Aβ)-degrading enzyme, membrane metalloendopeptidase (MME) gene, which has been associated with Alzhemier’s disease. Both HLA-DRA and HLA-DRB have also previously been associated with Alzheimer’s disease, suggesting a potential functional link between HLA encoded miRNA and neurodegenerative processes leading to disease. Conclusions Our work demonstrates a novel functional role for the HLA genes, mediated by encoded miRNA transcripts. Our findings suggest that two miRNA encoded within the HLA-DRA and HLA-DRB5 genes, target hundreds of transcripts involved in a variety of metabolic processes, with both sets of target genes being significantly enriched within neurological processes in particular. Both HLA-DRA and the HLA-DRB5 have been associated with Alzheimer’s disease in GWAS studies and both encoded miRNA are found to target the MME gene, which has also been associated with Alzheimer’s disease. Together, these finding suggest a functional link between the class II HLA region and the etiology of Alzheimer’s disease.

The MHC region has been shown to contain a susceptibility locus for multiple sclerosis (MS). While the strongest association to date has been between HLA-DRB1∗1501 and MS, the exact nature of the MHC association in MS remains unclear. Two candidate polymorphic loci within the MHC class II region, the HLA-DMB gene and the HLA-DRA promoter, which lie close to HLA-DRB1, were therefore examined in an Australian MS population. The HLA-DMB∗0103 phenotype was increased in the MS patients (46% vs. 30%) and the frequency of the HLA-DRA promoter A allele was also increased (81% vs. 68%). When the subjects were stratified into HLA-DRB1∗1501 positive and negative individuals these associations were not significantly different. This is a result of the strong linkage disequilibrium between HLA-DRB1∗1501 and both HLA-DMB∗0103 and the HLA-DRA promoter A allele. The complete linkage between DRB1∗1501 and the HLA-DRA promoter A allele indicates that the MS susceptibility haplotype (DRB1∗1501-HLA-DQB1∗0602-HLA-DQA1∗0102) can be extended out to promoter of the HLA-DRA locus. Interactions between both HLA-DMB and the HLA-DRA promoter and other reported MS susceptibility loci were examined (TCRBV polymorphisms, HLA-DQA1 and HLA-DQB1). Some interactions between specific TCRBV polymorphisms and the HLA-DRA promoter were observed, which is consistent with other published reports suggesting an epistatic interaction between TCRBV and HLA-DRB1.

Products of specific mouse Mtv genes expressed in association with mouse MHC class II products cause the deletion of T cells expressing particular TCR Vβ gene segments. These endogenous deletion ligands have been termed superantigens due to their ability to negatively select entire T-cell families, as defined by Vβ-chain usage. In most cases, deletion is preferentially effected through interaction of the Mtv ligand with H-2E products. Although human DRα shares only 75% identity with the Eα chain of H-2E, it has previously been shown to substitute for the mouse homologue in its capacity to induce the deletion of Vβ11- and Vβ17 a-bearing T cells. In the present study, we have undertaken a more comprehensive analysis of the interaction of mixed DRα/Eβ pairs with various endogenous Mtv integrants in various mouse backgrounds, leading to negative selection of particular Vβ families. We show in this paper that transgenic DRα/Eβ can also efficiently interact with products of Mtv -7, causing deletion of both Vβ6 + and Vβ7 + cells. Deletion of Vβ11 + T cells in DRA transgenic mice carrying Mtv -8 and -9, however, was less efficient than in control H-2Ea transgenic mice. These data and those from other MHC transgenic mouse studies show that while the class II α chain can influence the interaction with superantigen, it is the identity of the β chain that seems to be critical. Sequence comparison of various HLA and H-2 molecules shown to mediate Vβ11 deletion enabled us to make tentative predictions about residues involved in superantigen binding.