Spondylarthritis in HLA–B27/human β₂‐microglobulin–transgenic rats is not prevented by lack of CD8

Abstract

Objective. HLA-B27 predisposes to spondylarthritis by an unknown mechanism. A logical candidate mechanism is through recognition of B27 by CD8؉ T cells. The purpose of this study was to examine the effects of a lack of CD8 on the spondylarthritis that develops in B27/human ␤ 2 -microglobulin (Hu␤ 2 m)-transgenic rats.Methods. A missense mutation in the CD8a gene that causes a loss of CD8␣ expression was identified in offspring of a male Sprague-Dawley rat that had been treated with the mutagen N-ethyl-N-nitrosourea. The mutation was crossed into B27/Hu␤ 2 m-transgenic lines on the Lewis background. CD8a -/-and CD8a ؉/-progeny were compared on a mixed SD-LEW background as well as after at least 10 backcrosses to LEW rats. CD8 function was assessed by generating cytolytic T lymphocytes (CTLs) against allogeneic DA strain antigens.Results. Homozygous mutant rats showed normal CD8a and CD8b messenger RNA levels but no detectable expression of either protein and an almost complete abrogation of the allogeneic CTL response. Two disease phenotypes previously observed in different B27/ Hu␤ 2 m-transgenic lines also occurred in the respective CD8a -/--transgenic rat lines. There was no significant difference in disease prevalence or severity between CD8a -/-rats and CD8a ؉/-rats. Conclusion. All of the previously described disease manifestations in HLA-B27/Hu␤ 2 m-transgenic rats arise in the absence of any functional CD8؉ T cells. It thus seems unlikely that classic T cell recognition of HLA-B27 is of primary importance in this animal model. The possibility of a secondary role of a CD8-dependent mechanism cannot be entirely excluded.

The interplay between HLA-B27 and ERAP1/ERAP2 aminopeptidases: from anti-viral protection to spondyloarthritis

“…Unlike another related disease, namely ReA [12], AS is not usually preceded by microbial infections, even though the intestinal microbiota has been evoked recently to have an inciting role on B27-restricted T cell responses [13]. Furthermore, the HLA-B27 transgenic rat model seems to disprove the possibility that HLA-B27 is uniquely responsible for disease because of its classical antigen-presenting functions, given that the lack of CD8 1 T cells does not prevent spondyloarthritis in this context [14]. The HLA-B27 family consists of more than 160 alleles (https://www.ebi.ac.uk/cgi-bin/ipd/imgt/hla/allele.cgi), whose ancestral subtype is the HLA-B*2705 that is distributed Fig.…”

The relation between ER stress and HLA-B27 misfolding

“…Also, spondyloarthritislike phenotype from occurring in rats cannot be avoided with antibodymediated CD8+ T-cell depletion and a chemically induced mutation in the CD8a gene. These findings are supported with that there will be no developing arthritis or colitis in CD4+ T cells efficiently transfer colitis to athymic nude rats if high level of HLA-B27 /hβ2m expression is carried on the bone marrow [38,54,55].…”

HLA-B27 and Ankylosing Spondylitis

“…In these observations, May et al use monoclonal antibody to deplete CD8+ T cells from peripheral circulation, however, arthritis and colitis still develop in the HLA-B27 transgenic rat (May et al,2003). In addition, the same conclusion was obtained by the chemical deletion of CD8a gene expression which eliminated CD8+ T cells from peripheral blood (Taurog et al, 2009). The other observation revealed that CD4+ T cells, when transferred to athymic nude rat which had high level of HLA-B27/h2m expression in the bone marrow, developed arthritis (Taurog et al, 1999).…”