ARD: Paradoxical effects of endoplasmic reticulum aminopeptidase 1 deficiency on HLA-B27 and its role as an epistatic regulator in experimental spondyloarthritis

OBJECTIVE: To examine the functional basis of epistasis between endoplasmic reticulum (ER) aminopeptidase 1 (ERAP1) and HLA-B27 in experimental spondyloarthritis (Epistasis is a phenomenon in genetics in which the effect of genetic mutations Depends on the presence or absence of a mutation in one or more other genes, i.
e.
the effect of the mutation depends on the genetic background in which it arises
.
)
.

_{Methods: ERAP1} knockout rats were created using genome editing and housed with HLA-B27/human β2m (HLA-B27 Tg) and HLA-B7 Tg rats
.
Immunoprecipitation and immunoblotting, flow cytometry, allogeneic T cell proliferation assay, and gene expression analysis were used to determine the effect of ERAP1 deficiency on HLA allografts
.
Animals were examined for clinical features of disease and tissues were assessed by histology
.

Results: ERAP1 deficiency increased the ratio of folded to unfolded (without β2m ) HLA _- B27 heavy chains, had the opposite effect on HLA-B7, and reduced HLA-B27 misfolding, whereas cell surface free HLA-B27 Heavy chain dimer and monomer increase
.
The effects of ERAP1 deficiency persisted during HLA-B27 upregulation and reduced ER stress
.
ERAP1 deficiency reduced arthritis prevalence by two-thirds in HLA-B27 Tg rats without reducing gastrointestinal inflammation
.
Dendritic cell abnormalities caused by HLA-B27, including reduced allogeneic T-cell stimulation and loss of CD103+/MHC class II+ cells, were not rescued by ERAP1 deficiency, whereas excessive Il23a upregulation was alleviated
.

Conclusions: ERAP1 deficiency reduces HLA-B27 misfolding and improves folding, while having opposite effects on HLA-B7
.
Partial protection of HLA-B27 Tg rats from spondyloarthritis is consistent with genetic evidence that loss of function and/or reduced expression of ERAP1 reduces the risk of ankylosing spondylitis
.
Functional studies support the notion that the effects of ERAP1 on HLA-B27 and spondyloarthritis may be the result of how the peptides affect the biology of this allotype rather than their role as antigenic determinants
.

Source: Tran, TM, Gill, T.
, Bennett, J.
, Hong, S.
, Holt, V.
, Lindstedt, AJ, Bakshi, S.
, Sikora, K.
, Taurog, JD, Breban, M.
, Navid , F.
and Colbert, RA (2022), Paradoxical Effects of Endoplasmic Reticulum Aminopeptidase 1 Deficiency on HLA-B27 and its Role as an Epistatic Modifier in Experimental Spondyloarthritis.
Arthritis Rheumatol.
Accepted Author Manuscript.
https://doi.
org/10.
1002 /art.
42327