Editors' ChoiceAUTOINFLAMMATORY DISEASE

Too Much of a Good Thing

See allHide authors and affiliations

Science Translational Medicine  01 Oct 2014:
Vol. 6, Issue 256, pp. 256ec168
DOI: 10.1126/scitranslmed.3010417

The immune system is trained to recognize pathogens and protect the host from disease. However, our body’s first line of defense—the inborn innate immune response—is relatively non-specific. It provides immediate protection against infection and is conserved across species, but even the innate immune response can go wrong if left unfettered. When this happens, people develop autoinflammatory disorders, which are characterized by intense episodes of inflammation. The innate immune response reacts even though it has never encountered antigens, with potentially disastrous effects.

In two studies, Romberg et al. and Canna et al.—using careful clinical, genetic, and molecular detective work—separately identified patients with a new syndrome of recurrent fevers, gastrointestinal inflammation, and evidence of systemic autoinflammation. Both groups identified de novo gain of function mutations in NLRC4, an important inflammasome protein with caspase-activating and recruitment domains. Typically, NLRC4 is activated in the presence of flagellin-associated pathogens such as Pseudomonas and Salmonella. These NLRC4 mutations, without any obvious microbial activation, resulted in spontaneous and increased production of caspase-1 cleavage products, inflammasome complex formation, and interleukin-1 family cytokines (IL-1β and IL-18) with evidence of pyroptosis, a proinflammatory form of cell death. These studies also identified a subset of life-threatening autoinflammatory diseases that could be treated with existing IL-1-blocking therapeutics.

The discoveries of these patients with features of autoinflammation involving NLRC4 highlight the importance of regulating the complex interactions of the immune pathways, and how abnormal activation can lead to pathology. The exact contribution of NLRC4 mutations to heightened inflammasome activation needs to be further explored. The next generation sequencing technologies used in these studies will continue to be instrumental in discovering disease-causing mutations in otherwise unknown and uncharacterized diseases, especially when combined with astute clinical acumen to identify these cases.

N. Romberg et al., Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation, Nat. Genet. 10.1038/ng.3066 (2014). [Abstract]

S. W. Canna et al., An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 10.1038/ng.3089 (2014). [Abstract]

Navigate This Article