ARS | Publication request: MHC class II DR allelic diversity in bighorn sheep

Submitted to: Gene
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 17, 2012
Publication Date: September 10, 2012
Repository URL: http://dx.doi.org/10.1016/j.gene.2012.06.048
Citation: Subramaniam, R., White, S.N., Herrmann-Hoesing, L.M., Subramaniam, S. 2012. MHC class II DR allelic diversity in bighorn sheep. Gene. GENE2012506(1):217-222.

Interpretive Summary: Bighorn sheep are more susceptible to Mannheimia haemolytica pneumonia than domestic sheep, but little is known about why that may be the case. The Major Histocompatibility Complex (MHC) Class II molecules play a key role in getting an adaptive immune response started by presenting small peptide components of invading pathogens for identification as non-self. We began testing two hypotheses about bighorn sheep immune responses by examining the expressed MHC Class II DR genes from bighorn sheep. First, if bighorn sheep have too few peptide-binding versions of MHC Class II, they might not be able to identify as many pathogens quickly and efficiently. Second, even if bighorn sheep have plenty of different gene versions, if some specific variants have impaired function then those variants might contribute to a less effective immune response. The first hypothesis does not appear to be true; bighorn sheep seem to have adequate numbers of different MHC Class II DR versions. The second hypothesis should be tested further. Specifically, computer models predict some versions of bighorn sheep MHC may have impaired dimerization function that could hinder the start of an immune response. Additional experiments will be necessary to confirm or refute these computer predictions.

Technical Abstract: We hypothesized that decreased diversity and/or unique polymorphisms in MHC class II alleles of bighorn sheep (BHS, Ovis canadensis) are responsible for lower titer of antibodies against Mannheimia haemolytica leukotoxin, in comparison to domestic sheep (DS, Ovis aries). To test this hypothesis, DRA and DRB transcripts from 24 captive BHS (Ovca-DRA and Ovca-DRB) were sequenced. Based on exon 2 (ß1 domain) sequences, eight different Ovca-DRB cDNA sequences were identified in BHS. Six of them were 100% identical to previously reported Ovca-DRB genomic DNA sequences. The new alleles DRB*23 and DRB*24, were closely related to two other Ovca-DRB exon 2 genomic DNA sequences. Nineteen out of 24 BHS (79%) Ovca-DRB exon 3 (ß2 domain) sequences were 100% identical to exon 3 sequence of DRB1 of DS (Ovar-DRB1). Ovca-DRA full length cDNA sequences exhibited >99% identity. Based upon exon 2 sequences, this BHS herd yielded higher Ovca-DRB allelic diversity than that reported in the previous study. Positively selected amino acid positions were identified in the peptide-binding groove of BHS and DS, but BHS showed more such sites. This highlights differing population histories, and may suggest differing needs for DR peptide-binding specificities. Presence of glutamine at position 52 (52Q) in some of the desert and captive BHS is predicted to alter the efficiency of DR dimerization, which may influence antigen presentation and Th cell activation. Functional assays with unique alleles should reveal whether the presentation of M. haemolytica leukotoxin peptides to Th cells by Ovca-DRB alleles is equivalent to that of Ovar-DRB1 alleles.