In this report, we have shown that deficiency of the IL-1ra gene causes autoimmunity and arthritis, emphasizing the importance of IL-1/IL-1ra balance in maintaining normal physiology of the joints and homeostasis of the immune system. We found that the expression of proinflammatory cytokines such as IL-1β, IL-6, and TNF-α was augmented in IL-1ra−/−
mouse joints compared with wild-type mice. In this regard, it is noteworthy that low levels of IL-1α and IL-1β were expressed constitutively in the normal joints without any stimulation (). Thus, the fact that proinflammatory cytokine expression was enhanced in IL-1ra−/−
mice suggests that IL-1 activity is suppressed by IL-1ra under physiological conditions, and disruption of the IL-1ra gene exaggerates the action of the basal level IL-1. This excess IL-1 signal, as well as overproduced proinflammatory cytokines, is considered to cause inflammation by enhancing infiltration of inflammatory cells into synovial tissues, increasing permeability of blood vessels, activating synovial lining cells to produce collagenases and metalloproteases, and activating osteoclasts to destruct the bony structure 2
It is known that these cytokines can also activate the immune system by enhancing recruitment of immune cells, activating both T cells and B cells, and enhancing antigen presentation 1920
. This cytokine overproduction may also explain why autoimmunity developed in these mice. This autoimmune reaction against self-IgGs and synovial components may also be involved in the development of arthritis 21
. Consistent with this notion, we found that IL-1ra−/−
mice on the C57BL/6J background developed arthritis at a high incidence when these mice were immunized with IIC, suggesting hyperresponsiveness of the immune system in IL-1ra−/−
mice (Saijo, S., R. Horai, and Y. Iwakura, unpublished observation). We also observed earlier onset and more severe phenotype of the disease on a DBA/1 background (Saijo, S., and Y. Iwakura, unpublished observation). Recently, Ma et al. reported a similar observation 22
. These observations indicate that IL-1ra plays an important role in the regulation of the immune system.
The incidence of arthritis was high only in IL-1ra−/−
mice on the BALB/cA background, and incidence in the C57BL/6J or 129 × C57BL/6J hybrid background mice was low. These observations indicate that susceptibility to arthritis differs among strains, suggesting that genes other than IL-1ra are involved in the development of arteritis. In this regard, Nicklin et al. recently found that arthritis developed in IL-1ra−/−
mice on the 129 × MF1 Swiss albino hybrid background, although they did not observe any joint abnormality in those mice 22a
. Thus, IL-1ra−/−
mice seem to develop tissue specific inflammation depending on their genetic backgrounds. These additional pathogenic genes are now under investigation.
So far, several lines of evidence have suggested that aberration of IL-1α, IL-1β, and IL-1ra genes, which form a gene cluster on the long arm of chromosome 2, are involved in inflammatory and autoimmune diseases in humans. For example, IL-1α polymorphism was detected in humans, and a specific variant was suggested to be associated with juvenile RA 23
. Epidemiological studies have also invoked a possibility that IL-1ra is involved in the epithelial cell manifestations of diseases such as ulcerative colitis, systemic lupus erythematosus, psoriasis, lichen sclerosus, alopecia areata, and severity of Sjögren's syndrome, as these conditions are associated with a particular type of IL-1ra gene polymorphism 242526272829
. In addition, imbalance between IL-1ra and IL-1β production was observed in RA patients 3031
. RA patients exhibited a lower ratio of IL-1ra/IL-1β in plasma, even at baseline, in comparison with osteoarthritis or osteomyelitis patients 32
. This observation suggests that IL-1ra production may be relatively deficient or inadequate in RA patients. Thus, it is tempting to speculate that IL-1ra gene deficiency is also involved in the development of arthritis in humans. However, so far IL-1ra gene polymorphism has not been reported in RA in humans. We are now examining this possibility in RA patients with familial history.
Various animal disease models have been developed to elucidate the ethiopathogenesis of RA in humans. It is well known that antigens cross-reactive with synovial components, such as IIC, and mycobacteria and streptococcal cell wall components induce arthritis in animals 333435
mice, which have a mutation in the fas
gene, develop arthritis spontaneously due to development of autoimmunity 36
. Besides these models, we recently developed an HTLV-I transgenic mouse model in which autoimmunity was caused by the action of the tax
. In this report, we have shown a novel RA model, the BALB/cA IL-1ra−/−
mouse. As the joint pathology and the immunological status in this model closely resembles that of RA patients and the penetrance is complete, these mice should also provide another useful model for RA in humans.