Purpose of review: To review the remarkable recent progress in our understanding of a range of inflammatory conditions in humans that until recently appeared unrelated. The term autoinflammatory disease has been proposed to describe a group of disorders characterized by attacks of seemingly unprovoked inflammation without significant levels of autoantibodies and autoreactive T cells.

Recent findings: As the link between the innate immune response and disease susceptibility has become more apparent, some remarkable associations have emerged. The majority of hereditary periodic fevers are due to mutations in the pyrin and tumour necrosis factor receptor superfamilies of molecules, both of which are intimately involved in innate immunity. Pyrin/marenostrin protein is mutated in familial Mediterranean fever, while mutations in a related protein, cryopyrin, are associated with Muckle-Wells/familial cold urticaria and chronic infantile neurologic cutaneous and articular syndrome. Both of these proteins interact with the apoptotic speck-like protein involved in caspase-1 activation and regulation of nuclear factor kappa B transcription; furthermore cryopyrin contains regions of homology with the nucleotide-binding oligomerization domain 2 protein, which is associated with susceptibility to Crohn's disease. Variants in the leucine-rich repeat domain of nucleotide-binding oligomerization domain are found in approximately 20% of patients with Crohn's disease, depending on ethnic background, while mutations in the NACHT domain are associated with a rare dominant granulomatous disease called Blau syndrome.

Summary: The study of autoinflammatory disease has progressed from genetics to definition of the functional defects in these patients. Although a direct association between defective innate immune responses to bacterial components and these diseases has not been formally established, much ongoing research is aimed towards confirmation of that hypothesis.