Additional human beta2-microglobulin curbs HLA-B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA-B27-transgenic rats.
OBJECTIVE
Ankylosing spondylitis and related spondylarthritides are associated with HLA-B27, and also with intestinal inflammation, by unknown mechanisms. The folded HLA-B27 molecule is a trimer of heavy chain, beta2-microglobulin (beta2m), and short peptide. However, B27 heavy chain has an unusual propensity to misfold and trigger the unfolded protein response (UPR). This study was initiated to test the hypothesis that B27 misfolding plays a role in the pathogenesis of spondylarthritis.


METHODS
Rats with high transgene copy numbers of HLA-B27 heavy chain together with human beta2m (Hubeta2m) spontaneously develop colitis, peripheral arthritis, and occasional spondylitis, and those with lower transgene copy numbers remain healthy. We crossed disease-prone and healthy HLA-B27/Hubeta2m-transgenic rat lines with a healthy line, 283-2, carrying only the Hubeta2m transgene. HLA-B27 assembly was assessed by pulse-chase analysis of B27 molecules, and UPR triggering was assessed by measuring BiP/Grp78 messenger RNA (mRNA) in splenic concanavalin A blasts. Surface expression of B27 and Hubeta2m was determined by flow cytometry. Disease manifestations were identified by clinical observation, histology, and measurement of cytokine mRNA.


RESULTS
The extra Hubeta2m from the 283-2 line significantly reduced B27 misfolding and UPR triggering. Unexpectedly, however, F1 male offspring of the healthy 21-3 line crossed with the 283-2 line showed a high prevalence, severity, and duration of arthritis and spondylitis, in the absence of colitis. The arthropathy showed many features characteristic of human spondylarthritis.


CONCLUSIONS
These results suggest that B27 misfolding is associated with intestinal inflammation, but that neither B27 misfolding nor intestinal inflammation is critical to the development of B27-associated arthropathy.
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75390-8884, USA.
Tri M
TM
Tran
Martha L
ML
Dorris
Nimman
N
Satumtira
James A
JA
Richardson
Robert E
RE
Hammer
Jie
J
Shang
Joel D
JD
Taurog
D000818:Animals; D030801:Animals, Genetically Modified; D001168:Arthritis / Q000150:complications / Q000209:etiology*; D003092:Colitis / Q000150:complications; D000091342:Endoplasmic Reticulum Chaperone BiP; D015796:HLA-B27 Antigen / Q000235:genetics*; D006801:Humans; D008297:Male; D017510:Protein Folding; D051381:Rats / Q000235:genetics; D025241:Spondylarthritis / Q000150:complications / Q000209:etiology*; D013166:Spondylitis / Q000150:complications / Q000209:etiology*; D001613:beta 2-Microglobulin / Q000502:physiology*
D000091342:Endoplasmic Reticulum Chaperone BiP; D015796:HLA-B27 Antigen; C000717247:HSPA5 protein, human; D001613:beta 2-Microglobulin