Role of innate immunity cytokines in systemic lupus and systemic onset arthritis

Abstract

Cytokines of the innate immune system, like TNF and type I interferon (IFN-alpha/beta), have been described to be key players in autoimmunity. IFN-alpha/beta may drive many of the immune alterations described in systemic lupus erythematosus (SLE), a prototype autoimmune disease characterized by a break of tolerance to nuclear components. The recognition of the fundamental role of immature dendritic cells (DCs) in the control of peripheral tolerance led to the hypothesis that SLE may be driven through unabated DC activation. Indeed, CD14+ monocytes isolated from SLE blood, but not those from healthy individuals, act as DCs. Their activation is driven by IFN-α secreted by plasmacytoid DCs that have been shown to infiltrate SLE skin lesions. The importance of IFN-α in SLE is further shown by the presence of an IFN-α signature in the blood of all SLE patients, and by its extinction upon therapy with high-dose steroids. The excess of IFN-α may also contribute to the hypergammaglobulinemia that characterizes SLE patients, as pDCs triggered with virus induce activated B cells to differentiate into plasma cells. We have also explored the role of an innate immunity cytokine, interleukin-1 (IL-1), in the pathogenesis of systemic onset juvenile idiopathic arthritis (SOJIA), one of the major forms of chronic inflammatory arthritis in childhood. Our results indicate that this cytokine is at the center of SOJIA pathogenesis, as these patients produce an excess of IL-1 and treatment with IL-1 receptor antagonist (IL-1Ra) results in disease resolution.