Correlation between dendritic cell functional defect and spondylarthritis phenotypes in HLA–B27/HUMAN β₂‐microglobulin–transgenic rat lines

Abstract

Objective. To examine the functional capacity of dendritic cells (DCs) from a panel of HLA-B27/human ␤ 2 -microglobulin (Hu␤ 2 m)-transgenic rat lines and crosses with varying susceptibilities to spondylarthritis (SpA)-like disease.Methods. Mature splenic DCs were isolated from HLA-B27-transgenic, HLA-B7-transgenic, and/or Hu␤ 2 m-transgenic rats and tested for support of allogeneic proliferation, compared with nontransgenic controls (all male rats on Lewis background). Graded numbers of DCs were cultured with allogeneic lymph node CD4؉ T cells (dark agouti background). Proliferation was assayed by incorporation of tritiated deoxythymidine after 2-4 days of culture.Results. Allogeneic proliferation stimulated by DCs from the healthy HLA-B27/Hu␤ 2 m-transgenic line 21-3 and from the healthy Hu␤ 2 m-transgenic line 283-2 was weakly decreased (21-3) or close to normal (283-2) as compared with that observed with control nontransgenic Lewis rat DCs. In contrast, the ability of DCs from (21-3 ؋ 283-2)F 1 rats, which develop a dramatic SpA phenotype, to stimulate allogeneic proliferation was markedly defective. When DC-induced allogeneic proliferation was compared among different transgenic lines and crosses with distinct levels of susceptibility to SpA-like disease, stimulatory capacity was inversely correlated with disease susceptibility.Conclusion. In HLA-B27/Hu␤ 2 m-transgenic rats, a defective functional capacity of DCs correlates with susceptibility to SpA. Since it was previously demonstrated that defective DC function is not a consequence of disease, it could well be a principal factor in the spontaneous development of SpA in these lines.

Whole-blood Gene Expression Profiling in Ankylosing Spondylitis Shows Upregulation of Toll-like Receptor 4 and 5

“…However, the other observed differentially expressed transcripts and pathways in this study also could play an important role in the pathogenesis of AS. For example, the observed dysregulations in the dendritic cell maturation pathway may provide further support for the importance of defective functional capacity of dendritic cells in SpA37.…”

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

“…Defective dendritic cell function has been observed consistently in the disease-prone lines of the transgenic rats (29)(30)(31)(32). Moreover, B27-restricted T cells have been difficult to identify even in the healthy transgenic rat lines (ref.…”

The Role of HLA-B27 in Spondyloarthritis

“…In Dr. Breban's experiments, splenic dendritic cells from the disease-prone transgenic lines, but not from the other transgenic lines, show impaired induction of proliferation of allogeneic CD4+ T cells, impaired immunologic synapse formation, impaired cytoskeletal function, and increased induction of Th17+ T cells (unpublished data and 88,89,90 lymphocyte reaction in patients with SpA was first reported over 30 years ago 92,93 . ) In Dr. Sartor's experiments, intestinal APC (including B cells) from B27 transgenic rats showed less induction of CD4+ T cell IFN-g production, but were less responsive to the IL-10-or transforming growth factor-ß-induced suppression, and splenic APC showed increased TNF production in response to TLR signaling 94,95,96 .…”