Background/Purpose: Spondyloarthritis (SpA) does not display typical features of autoimmune diseases such as female predominance, presence of autoantibodies, or 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 an innate immune response. Using the HLA-B27/huβ2m transgenic rat model,¹ 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 tg rats and controls were stimulated for 6 hours with 50 ng/ml LPS, 5 µg/ml zymosan or 5 µg/ml heat-inactivated Mycobacterium tuberculosis. TNF, IL-1, IL-6, IL-10 and IL-23p19 expression was measured by qPCR. In vivo, six week old male and female HLA-B27/huβ2m tg were immunized with a low dose of M. tuberculosisin incomplete Freund’s adjuvant. Rats were followed up for 60 days and scored clinically for arthritis and spondylitis. At day 60 hind limbs and tails were analysed for inflammation, destruction and new bone formation by histology. 

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-1a, IL-1b and IL-6 in all 3 groups of rats. IL-1a and IL-1b, but not TNF or IL-6, were increased in the HLA-B27/huβ2m transgenic cells as compared to both HLA-B7/huβ2m tg 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 tg males spontaneously develop arthritis and spondylitis after 4-6 months of age with an incidence of 70% and 40%, respectively, whereas female rats do not develop disease. Immunization of male HLA-B27/huβ2m tg rats with 30 µg of M. tuberculosis was sufficient to induce arthritis and spondylitis within 2-3 weeks with an incidence of 80-100%. Moreover, HLA-B27/huβ2m tg females developed similar disease when immunized with 60 µg of M. tuberculosis. Control rats were less sensitive to low doses of M. tuberculosis. Histologically in both male and female HLA-B27/huβ2m tg rats inflammation, destruction and new bone formation was detected in both peripheral and axial joints.

Conclusion:  The transgenic expression of HLA-B27/Hub2m increases the sensitivity to innate immune stimulation as evidenced by increased IL-1a and IL-1b expression ex vivo and development of arthritis and spondylitis in vivo. These data suggest that the B27/Hub2m expression lowers the threshold for innate immune activation of the IL-1 pathway, and this alone may be sufficient to trigger experimental SpA.  

References: 1. Tran TM et. al. Arthritis Rheum 2006; 54(4):1317-27

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/innate-immune-stimulation-triggers-altered-il-1ab-gene-expression-and-experimental-spondyloarthritis-in-hla-b27hu%ce%b22m-transgenic-rats/