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Review
. 2017 Dec;17(6):398-404.
doi: 10.1097/ACI.0000000000000396.

NLRC4 inflammasomopathies

Neil Romberg  1 , Tiphanie P Vogel, Scott W Canna
Affiliations
Review

NLRC4 inflammasomopathies

Neil Romberg et al. Curr Opin Allergy Clin Immunol. 2017 Dec.

Abstract

Purpose of review: The purpose of the review is to highlight developments in autoinflammatory diseases associated with gain-of-function mutations in the gene encoding NLR-family CARD-containing protein 4 (NLRC4), the NLRC4-inflammasomopathies.

Recent findings: Three years since the identification of the first autoinflammation with infantile enterocolitis (AIFEC) patients, there is an improved understanding of how the NLRC4 inflammasome and interleukin 18 (IL-18) contribute to gut inflammation in myeloid and also intestinal epithelial cells. This information has opened new therapeutic avenues to treat AIFEC patients with targeted agents like recombinant IL-18 binding protein and antiinterferon-γ antibodies. Additional phenotypes traditionally associated with NLRP3 mutations like familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), have now also been associated with gain-of-function NLRC4 mutations. Finally, NLRC4 somatic mosaicism has now been identified in a NOMID and an AIFEC patient, a finding emphasizing nontraditional modes of inheritance in autoinflammatory diseases.

Summary: The NLRC4 inflammasomopathies constitute a growing autoinflammatory disease category that spans a broad clinical spectrum from cold urticaria to NOMID and the often fatal disease AIFEC. Rapid case identification with biomarkers like elevated serum IL-18 concentrations and early intervention with targeted immunomodulatory therapies are key strategies to improving outcomes for AIFEC patients.

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Conflict of interest statement

Conflicts of interest

S.W.C. is a paid consultant for AB2Bio, Ltd and T.P.V. attended their clinical trial investigator meeting. For the remaining author, no conflicts were declared.

Figures

Figure 1
Figure 1
Disease-associated NLRC4 variants cluster near the ADP-binding site. A) The functional domains of NLRC4 are depicted and color coded: CARD domain black; NBD=purple; HD1=pink; WHD=yellow; HD2=green; LRR=gray. Variants associated with predominantly skin phenotypes are marked by *, the NOMID-associated variant is marked by ‡, and AIFEC mutations by #. B) A color coded NLRC4 crystal structure without a CARD is displayed per Ref. . ADP (red) is depicted within its binding pocket (inset, right). Disease associated residues (white) are labeled.
See this image and copyright information in PMC

References

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