Background Spondyloarthritis (SpA) does not display the typical features of autoimmune diseases such as female predominance, presence of autoantibodies and clinical response to T- and/or B cell targeting biologicals. Despite the strong association with MHC class I, CD8 T cells are not required for disease induction in the HLA-B27/huβ2m transgenic rat model. Moreover, the capability of HLA-B27 to misfold and thereby induce endoplasmatic reticulum stress and the direct recognition of HLA-B27 homodimers by NK cells suggest pathogenic mechanisms which may be independent of classical acquired immune responses. Therefore, we and others propose that SpA may be primarily driven by the innate immune response.
Objectives Using the HLA-B27/huβ2m transgenic rat model , we investigated this hypothesis by studying the effect of innate immune stimulation on ex vivo cytokine expression and in vivo development of arthritis and spondylitis.
Methods Splenocytes and bone marrow cells isolated from HLA-B27/huβ2m transgenic rats, HLA-B7/huβ2m transgenic control rats and Lewis wild-type rats, were stimulated for 6 hours with 50 ng/ml LPS, 5 μg/ml zymosan or 5 μg/ml Mycobacterium tuberculosis. TNF, IL-1, IL-6, IL-10 and IL-23p19 expression was measured by qPCR. For in vivo analysis, six week old male and female HLA-B27/huβ2m transgenic rats and HLA-B7/huβ2m transgenic control rats were immunized with low doses (30, 60 or 90 ug) of M. tuberculosis in incomplete Freund's adjuvant. Rats were followed up for 60 days and scored clinically for arthritis and spondylitis.
Results In vitro stimulation of splenocytes with zymosan and with M. tuberculosis, but not with LPS, strongly induced gene expression of pro-inflammatory cytokines such as TNF, IL-1alpha, IL-1beta and IL-6 in all 3 rat strains. IL-1alpha and IL-1beta, but not TNF or IL-6, were increased in the HLA-B27/huβ2m transgenic cells as compared to both HLA-B7/huβ2m transgenic and wild-type controls upon ex vivo stimulation. IL-10 and IL23p19 expression could not be detected in any of the groups after stimulation. In vivo, non-immunized HLA-B27/huβ2m transgenic males spontaneously develop arthritis and spondylitis after 4-6 months of age with an incidence of 70% and 40%, respectively, whereas female rats did not develop disease. Immunization of 6 weeks old male HLA-B27/huβ2m transgenic rats with 30 μg of M. tuberculosis was sufficient to induce development of arthritis and spondylitis within 2-3 weeks with an incidence of 80-100%. Moreover, HLA-B27/huβ2m transgenic females also developed spondylitis and arthritis with the same disease onset, severity and incidence when immunized with 60 μg of M. tuberculosis. Control rats were less sensitive to these low doses of M. tuberculosis.
Conclusions The transgenic over-expression of HLA-B27/Hub2m increases the sensitivity to innate immune stimulation as evidenced by increased IL-1alpha and IL-1beta expression ex vivo and development of arthritis and spondylitis in vivo. These data indicate that innate immune activation can trigger experimental SpA.
Tran TM et. al. Arthritis Rheum 2006; 54(4):1317-27
Disclosure of Interest None declared
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