CD8αβ T Cells Are Not Essential to the Pathogenesis of Arthritis or Colitis in HLA-B27 Transgenic Rats

Abstract

The class I MHC allele HLA-B27 is highly associated with the human spondyloarthropathies, but the basis for this association remains poorly understood. Transgenic rats with high expression of HLA-B27 develop a multisystem inflammatory disease that includes arthritis and colitis. To investigate whether CD8αβ T cells are needed in this disease, we depleted these cells in B27 transgenic rats before the onset of disease by adult thymectomy plus short-term anti-CD8α mAb treatment. This treatment induced profound, sustained depletion of CD8αβ T cells, but failed to suppress either colitis or arthritis. To address the role of CD8α+β− cells, we studied four additional groups of B27 transgenic rats treated with: 1) continuous anti-CD8α mAb, 2) continuous isotype-matched control mAb, 3) the thymectomy/pulse anti-CD8α regimen, or 4) no treatment. Arthritis occurred in ∼40% of each group, but was most significantly reduced in severity in the anti-CD8α-treated group. In addition to CD8αβ T cells, two sizeable CD8α+β− non-T cell populations were also reduced by the anti-CD8α treatment: 1) NK cells, and 2) a CD4+CD8+CD11b/c+CD161a+CD172a+ monocyte population that became expanded in diseased B27 transgenic rats. These data indicate that HLA-B27-retricted CD8+ T cells are unlikely to serve as effector cells in the transgenic rat model of HLA-B27-associated disease, in opposition to a commonly invoked hypothesis concerning the role of B27 in the spondyloarthropathies. The data also suggest that one or more populations of CD8α+β− non-T cells may play a role in the arthritis that occurs in these rats.

Additional human β2‐microglobulin curbs HLA–B27 misfolding and promotes arthritis and spondylitis without colitis in male HLA–B27–transgenic rats

“…Rats were typed for HLA-B27, HLA-B7, and Hu␤ 2 m by enzyme-linked immunosorbent assay detection of HLA-B27 in serum and/or by dot blot of genomic DNA, as previously described (9,13,18,22). Transgene homo-or hemizygosity was identified by quantitative dot blot.…”

“…Flow cytometric analysis was carried out as previously described (13). Data were analyzed using FACSCalibur or FACScan instruments (BD BioSciences, San Jose, CA) and CellQuest software, version 3.3.…”

“…Neither gastrointestinal inflammation nor arthritis develop in these B27-transgenic rats when raised under germ-free conditions, whereas epididymo-orchitis and skin lesions are found (11,12). On the inbred LEW background, the prevalence of colitis in the B27-transgenic rats approaches 100%, whereas arthritis occurs in ϳ40% of the males and in a lower proportion of the females, and the onset of arthritis follows the onset of diarrhea by an average of ϳ1 month (13). These and other results have suggested that in this line of B27-transgenic rats, gut and joint inflammation are pathogenetically related.…”

Disease-associated polymorphisms in ERAP1 do not alter endoplasmic reticulum stress in patients with ankylosing spondylitis

“…9 The HLA-B27-transgenic rat model also suggests a role for HLA-B27 independent of antigen presentation in this model, since depletion of CD8 T cells had no effect on disease development in this model. 22 Polymorphisms in those ERAP1 alleles associated with AS encode protein differences that lead to altered rates of ERAP1 enzyme activity. 2 Furthermore, we have demonstrated gene-gene interaction between ERAP1 and HLA-B27 in AS.…”

“…AS was defined according to the modified New York criteria. 22 Patient demographics, erythrocyte sedimentation rate, C-reactive protein and Bath Ankylosing Spondylitis Disease Activity Index scores are described in detail in Table 1. Thirteen of the 49 patients have taken TNF inhibitors at the time of blood collection; all other patients had not received TNF inhibitor therapy.…”