Arthritis & Rheumatism, Volume 63,
November 2011 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Chicago, Illinois November 4-9, 2011.
The Role of Gut Microflora and Autoreactive CD4 T Cells in the Development of Spondyloarthritis and Inflammatory Bowel Disease in Beta-Glucan-Treated SKG Mice.
Ruutu1, Merja, Velasco1, Jared, Aguirre2, Daniel, Benham1, Helen, Morrison2, Mark, McGuckin3, Michael, Thomas1, Ranjeny
Although spondyloarthritis and inflammatory bowel disease (IBD) co-exist in human spondyloarthropathies (SpA) the mechanism is unclear. Despite shared genetic associations, only a subset of patients develops spondyloarthritis and IBD, and either may present first. Autoimmune cross-reactivity towards joint and gut antigens may occur. Alternatively there may be coincident or sequential development of joint and gut autoreactivity driven by common innate mechanisms, potentially triggered by infection. The SKG ZAP-70W163C mutation of the BALB/c strain reduces T cell receptor signaling, altering sensitivity of developing thymocytes to negative and positive selection, and enriching the peripheral repertoire with IL-17-skewed autoreactive T cells. When otherwise healthy SKG mice are housed in microbially clean (spf) conditions, systemic administration of 1,3-D beta-glucan (curdlan) triggers arthritis of wrists and ankles, spondylitis of tail and lumbar spine, Crohn's-like ileitis and unilateral anterior uveitis. To elucidate the mechanism underlying the involvement of multiple organs after a single trigger, we sought the contribution of the gut microflora, and of CD4+ autoreactive T cells to arthritis, spondylitis and ileitis in this model.
SKG mice housed in spf or rederived to germ free conditions were injected i.p. once with 3 ug curdlan. Arthritis, general appearance and weight loss were scored for 10 weeks. Organ pathology was determined by H&E staining of paraffin-embedded tissue sections at sacrifice between 1 and 10 weeks after injection of curdlan. Sera were analyzed for autoantibodies. CD4+ T cells were transferred from lymph nodes and spleen of SKG mice treated 1 week previously with curdlan, to immunodeficient mice.
Under spf conditions, histological analysis of tissues showed that arthritis and spondylitis developed simultaneously and progressively from 1 week after curdlan injection, associated with the development of anti-proteoglycan and anti-collagen type II autoantibodies. In contrast, there was no histological evidence of ileitis until 610 weeks after curdlan injection. All recipients of CD4+ T cells from SKG mice treated 1 week previously with curdlan developed arthritis and spondylitis but not ileitis. However, immunodeficient recipients of CD4+ T cells also developed colitis. Under germ free conditions, arthritis and spondylitis were markedly attenuated.
After systemic exposure to beta-glucan, SKG mice develop sequential features of SpA. Arthritis and spondylitis, transferable with CD4+ T cells and associated with autoimmunity to cartilage antigens, develops first, followed by ileitis. The failure of CD4+ T cells to transfer ileitis early in disease argues against T cell cross-reactivity towards joint and small intestinal autoantigens. The lack of arthritis in germ free conditions suggests, however, that gut microflora mediate systemic effects of curdlan, potentially through adjuvant effects on joint autoantigen presentation.
To cite this abstract, please use the following information:
Ruutu, Merja, Velasco, Jared, Aguirre, Daniel, Benham, Helen, Morrison, Mark, McGuckin, Michael, et al; The Role of Gut Microflora and Autoreactive CD4 T Cells in the Development of Spondyloarthritis and Inflammatory Bowel Disease in Beta-Glucan-Treated SKG Mice. [abstract]. Arthritis Rheum 2011;63 Suppl 10 :1705