Chronic inflammatory diseases fall into two categories: either "autoimmune" or "auto-inflammatory" [1]. Although nearly all autoimmune diseases have an inflammatory component, as in rheumatoid arthritis, in autoimmune diseases, the primary defect is the auto-reactive T-cell. The term "auto-inflammatory diseases" encompasses several local and systemic diseases due to monocyte dysfunction, each responsive to blocking interleukin-beta (IL-1β) or blocking the IL-1 receptor using the IL-1 receptor antagonist. The best example is Familial Mediterranean Fever since manifestations of this disease include fever, fatigue, painful inflamed serosal and synovial tissues, biochemical markers of systemic inflammation, and hematological responses of neutrophilia [2]. Other auto-inflammatory diseases are due to single amino acid mutations in the protein "cryopyrin" [3] and are called "cryopyrinopathies"; the same syndromes are also termed "cryopyrin associated periodic syndromes" (CAPS). Systemic inflammation can be lethal, and the best example is septic shock. However, septic shock represents exogenously induced inflammation or simply "exogenous inflammation." Although many laboratory studies use bacterial products to stimulate IL-1β production, in the clinical sense, auto-inflammation is the result of IL-1-induced IL-1 or IL-1 induction of other cytokines such as IL-17. Either IL-1α or IL-1β can be the driving component in auto-inflammation. For example, in patients with neonatal onset multi-inflammatory disease (NOMID) treatment with the IL-1 receptor antagonist anakinra drives down not only the manifestations of the disease but also gene expression for IL-1α, IL-1β, TNFα, IL-6 and caspase-1 [4]. The most compelling evidence for the importance of IL-1 in inflammation comes from persons born with a mutation in the gene that codes for the IL-1 receptor antagonist. The syndrome is called DIRA for deficiency of the IL-1 receptor antagonist [5], [6]. At birth, these patients develop lethal inflammation with massive numbers of neutrophils in the skin and high levels of IL-17.

Interleukin-1 and the Treatment of Auto-inflammatory Diseases

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