Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Fungal beta-Glucan Triggers Spondyloarthropathy and Crohn's Disease in SKG Mice.
Ruutu4, Merja, Yadav4, Bijesh, Thomas4, Gethin, Steck2, Roland, Strutton3, Geoffrey, Tran4, Ai, Velasco4, Jared
Recent genome-wide association studies reveal candidate genes for ankylosing spondylitis, psoriatic arthritis and Crohn's disease associated with proinflammatory cytokine production promoting T-helper 17 cells, including IL1R2, IL12B, IL23R, CCR6, JAK2, STAT3 and Card9. However, the functional correlates of these polymorphisms are unclear. This pathway is activated after dectin-1 signaling during fungal infection. Since skg ZAP70 mutant mice over-express these cytokines, and were reported as a model of rheumatoid arthritis triggered by fungal infection, we investigated whether skg mice develop spondyloarthropathy after systemic administration of fungal beta-glucan.
Skg mice and control BALB/c mice were injected i.p. or s.c. once with 3 mg 1,3-beta-glucan (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. Paws and spines were examined after sacrifice by radiography and micro-CT.
After curdlan administration, BALB/c mice developed mild self-limiting arthritis of the ankles and wrists. By contrast, in skg mice, conjunctivitis, and progressive inflammatory arthritis of ankles and wrists, swelling of the soft tissue of the feet and typical sausage digits were evident from 3 weeks after injection. Over time, the mice developed hunching of the upper body, tail deformity, weight loss and abdominal bloating, but no diarrhea. Histologically and by imaging, we observed severe inflammation and progressive destruction of sacroiliac and vertebral facet joints, longitudinal ligaments and intervertebral discs with new bone formation, as well as enthesitis of Achilles tendon and plantar fascia in curdlan-treated but not naïve skg mice. Analysis of tissues over time showed that inflammation first appeared in ankles, wrists and para-vertebral ligaments from 1 week after injection. Around 6 weeks later, mice began to develop unilateral uveitis and Crohn's-like ileitis with granulomas and crypt abscesses. In contrast, the colon was not inflamed.
These characteristic features indicate that after systemic exposure to beta-glucan, skg mice develop a disease closely resembling human spondyloarthropathy. Since the zap70 mutation decreases T cell receptor signaling and required for disease perpetuation, these data strongly suggest that polymorphisms enhancing signaling of the beta-glucan molecular pattern (present in pollens, fungi and many bacteria), coupled with defects in antigen presentation or T cell response, may increase spondyloarthropathy risk in humans.
To cite this abstract, please use the following information:
Ruutu, Merja, Yadav, Bijesh, Thomas, Gethin, Steck, Roland, Strutton, Geoffrey, Tran, Ai, et al; Fungal beta-Glucan Triggers Spondyloarthropathy and Crohn's Disease in SKG Mice. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1446