The mammalian immune system has evolved to protect the host against microbial infections and cellular waste that accumulates when cells are damaged or die. Two types of immune defense systems have emerged. Recognition of exogenous and endogenous “danger” by the innate immune system is mediated through pattern recognition receptors, which are germline coded; they bind invariant microbial molecules such as microbial cell wall components. Recognition of danger by the adaptive or acquired immune system is mediated by receptors on T and B cells that undergo somatic mutation, leading to fine tuning of the receptor specificity in response to antigen contact. This mechanism allows the development of a highly diverse receptor repertoire, and enables the development of immunologic memory [67•
(the gene causing CAPS) and its structurally related cousin NOD2
(the gene involved in PGA and Crohn’s disease) are members of the newly discovered NOD-like receptors that have structural homology with plant resistance proteins, which play a role in host-parasite interaction. This family consists of 14 NALP and five NOD receptors [68•
]. NLRs have been shown to form active multimolecular complexes called inflammasomes that, in the case of the most often studied NALP3 inflammasome, result in increased caspase-1–mediated IL-1β processing and secretion. Whether the inflammasome is activated through direct interaction of a trigger with the LRR domain, or whether NLRs function as “guards” that interact with host proteins targeted by microbial or stress signals [69
], is a topic of active research.
The unraveling of the central role of the NLR inflammasomes in immune recognition and autoinflammatory disease has been paralleled by successful clinical investigations exploring the role of blocking IL-1. Mutations of several genes that may modulate the IL-1β–producing inflammasome—such as pyrin (protein mutated in FMF), PSTPIP1 (protein mutated in PAPA), and likely PSTPIP2 (protein mutated in mouse CRMO)—have provided the conceptual framework to use IL-1 blockade in other autoinflammatory diseases and point to a central role of IL-1β regulation in their pathogenesis.
Although considerable insight has been gained into the regulatory function of pyrin on the inflammasome, the role of pyrin mutations in the B30.2 domain (or SPRY domain, a protein domain recently shown to target retroviruses and prevent their replication [70•
]) on altered sensing of danger signals has yet to be explored.
Other systemic inflammatory diseases with presumed more complex modes of inheritance, such as systemic-onset juvenile idiopathic arthritis, adult-onset Still’s disease, and Behcet’s disease, have been added to the group of autoinflammatory diseases. The recent discovery that gout is caused by increased activation of the NALP3 inflammasome by uric acid crystals has illustrated the role of the NALP3 inflammasome in a common disease. Evidence is emerging that the innate immune system may play a role in other common rheumatic diseases (rheumatoid arthritis, dermatomyositis, and systemic lupus erythematosus).