Gorillas with Spondyloarthropathies Express an MHC Class I Molecule with Only Limited Sequence Similarity to HLA-B27 that Binds Peptides with Arginine at P2

Abstract

The human MHC class I gene, HLA-B27, is a strong risk factor for susceptibility to a group of disorders termed spondyloarthropathies (SpAs). HLA-B27-transgenic rodents develop SpAs, implicating HLA-B27 in the etiology of these disorders. Several nonhuman primates, including gorillas, develop signs of SpAs indistinguishable from clinical signs of humans with SpAs. To determine whether SpAs in gorillas have a similar HLA-B27-related etiology, we analyzed the MHC class I molecules expressed in four affected gorillas. Gogo-B01, isolated from three of the animals, has only limited similarity to HLA-B27 at the end of the α1 domain. It differs by several residues in the B pocket, including differences at positions 45 and 67. However, the molecular model of Gogo-B*0101 is consistent with a requirement for positively charged residues at the second amino acid of peptides bound by the MHC class I molecule. Indeed, the peptide binding motif and sequence of individual ligands eluted from Gogo-B*0101 demonstrate that, like HLA-B27, this gorilla MHC class I molecule binds peptides with arginine at the second amino acid position of peptides bound by the MHC class I molecule. Furthermore, live cell binding assays show that Gogo-B*0101 can bind HLA-B27 ligands. Therefore, although most gorillas that develop SpAs express an MHC class I molecule with striking differences to HLA-B27, this molecule binds peptides similar to those bound by HLA-B27.

A Single Polymorphic Residue Within the Peptide-Binding Cleft of MHC Class I Molecules Determines Spectrum of Tapasin Dependence

“…Analysis of B2705 and B27H114D as to tapasin dependence for peptide loading revealed that wild-type B2705 resembles B44D114H, whereas B27H114D behaves like wild-type B4402. In the absence of tapasin, B2705 efficiently binds the reporter peptide, GRIDK PILK, a high-affinity ligand for B2705 (20). A high concentration (12.8 M) of unlabeled peptide was not sufficient to out-compete the reporter peptide binding (Fig.…”

The ABCs of MHC

“…49 Some associations between autoimmune diseases and MHC have also been reported in nonhuman primate populations. 50,51 However, since these diseases have relatively little effect on reproductive success, it is unlikely that autoimmune diseases have much effect on the distribution of MHC alleles in humans or nonhuman primates.…”

Comparative Pathology of Aging Great Apes

“…2 More sophisticated studies of gorilla leukocyte antigens determined that a class one allele identical to HLA B27 does not exist in gorillas. 258 However, molecular reconstruction of a gorilla class one protein, GoGo-B01, showed binding domains similar to HLA B27, and functional studies showed the ability of GoGo-B01 to bind proteins bound by HLA B27. The role of GoGo-B01 in IA in gorillas needs further investigation, as both affected and unaffected gorillas have this allele.…”