ReviewThe inflammasome, autoinflammatory diseases, and gout
Introduction
Our immune system protects us from infections and other insults via its ability to differentiate between self (which is tolerated) and non-self (which is rejected). It comprises two different but complementary systems: innate immunity and adaptive immunity. Innate immunity is the oldest component of the immune system and the first to detect the presence of microorganisms or other foreign molecules. Innate immunity recognizes pathogen-associated molecular patterns, which are shared by many pathogens. Activation of the innate immune system generates alarm signals that can result in inflammation and in activation of the adaptive immune system. The adaptive immune response is a highly specific response system that emerged more recently in the evolution of vertebrates. The ability of the adaptive immune system to adjust and to refine its repertoire over time based on the pathogens that it encounters results in a high level of efficiency. Although the immune system is controlled by tight regulatory mechanisms, these occasionally fail, the result being the development of an autoimmune or autoinflammatory disease. Autoimmune diseases, such as systemic lupus erythematosus, are characterized by dysfunctional activation of B and T cells, which produce receptors and specific antibodies to self-antigens. The mechanisms and receptors involved in innate immunity were identified recently, leading to the recognition of a new category of immune-system diseases known as autoinflammatory diseases.
Section snippets
Autoinflammatory diseases
The autoinflammatory disease concept was developed in 1999 by Kastner et al. [1], [2], who were studying hereditary periodic fever syndromes. These syndromes are now considered the archetype of autoinflammatory diseases. The main difference with autoimmune diseases is that neither autoantigens nor autoantibodies are involved. Episodes of inflammation occur spontaneously, in the absence of detectable causes. Aberrant detection of bacteria or presence of micro-lesions may predispose to the
IL-1β
IL-1β belongs to a cytokine family that also includes IL-1α, IL-18, IL-33, and IL-1 receptor antagonist (IL-1RA). IL-1β is a pro-inflammatory cytokine that plays a key role in the innate immune response, defense against pathogens, and inflammation. The administration of 1–2 ng/kg of IL-1β to humans is promptly followed by a drop in blood pressure, hyperthermia, nausea, and vomiting [5], [6], [7]. The effects of IL-1β largely overlap those of TNF alpha and another pro-inflammatory cytokine.
IL-1β
NALP3 and hereditary periodic fever syndromes
Hereditary periodic fever syndromes are genetically determined diseases transmitted according to Mendelian laws. Attacks of fever and inflammation occur repeatedly, in the absence of a detectable cause. Examples include TNF-receptor-associated periodic syndrome (TRAPS), hyper IgD syndrome (HIDS), familial Mediterranean fever (FMF) and periodic syndromes associated with cryopyrin/NALP3 (CAPS) [35], [36]. FMF is probably the most common and most extensively studied periodic fever syndrome. FMF is
NALP3 and gout
Gout is a metabolic joint disease that has been known since ancient times. Gout is more common in men older than 40 years of age than in women and is associated with chronic hyperuricemia. Attacks of acute arthritis with severe pain and fever constitute the hallmark of the disease. Data collected over the last two decades suggest a steady increase in the prevalence of gout throughout the world [40]. The attacks are related to precipitation of monosodium urate within the joint tissues. In most
Conclusion
The identification of NALP3 gene mutations that cause a group of periodic fever syndromes allowed molecular studies of signaling pathways, which shed light on the mechanisms underlying inflammatory symptoms. NALP3 mutations or monosodium urate microcrystals lead to abnormal inflammasome activation. The result is dysregulation of IL-1β production, which is an early and probably initiating event in the inflammatory cascade. Daily injection of recombinant IL-1RA (anakinra) is effective in patients
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