Journal
CURRENT OPINION IN ALLERGY AND CLINICAL IMMUNOLOGY
Volume 14, Issue 6, Pages 491-500Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/ACI.0000000000000117
Keywords
autoinflammation and PLC2-associated antibody deficiency and immune dysregulation; deficiency of adenosine deaminase 2; PLC2-associated antibody deficiency and immune dysregulation; vasculitis; vasculopathy
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Funding
- National Human Genome Research Institute
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Purpose of reviewNext-generation sequencing is revolutionizing the molecular taxonomy of human disease. Recent studies of patients with unexplained autoinflammatory disorders reveal germline genetic mutations that target important regulators of innate immunity.Recent findingsWhole-exome analyses of previously undiagnosed patients have catalyzed the recognition of two new disease genes. First, a phenotypic spectrum, including livedo racemosa, fever with early-onset stroke, polyarteritis nodosa, and Sneddon syndrome, is caused by loss-of-function mutations in cat eye syndrome chromosome region, candidate 1 (CECR1), encoding adenosine deaminase 2. Adenosine deaminase 2 is a secreted protein expressed primarily in myeloid cells, and a regulator of macrophage differentiation and endothelial development. Disease-associated mutations impair anti-inflammatory M2 macrophage differentiation. Second, patients presenting with cold-induced urticaria, granulomatous rash, autoantibodies, and common variable immunodeficiency, or with blistering skin lesions, bronchiolitis, enterocolitis, ocular inflammation, and mild immunodeficiency harbor distinct mutations in phospholipase C-2, encoding a signaling molecule expressed in natural killer cells, mast cells, and B lymphocytes. These mutations inhibit the function of a phospholipase C-2 autoinhibitory domain, causing increased or constitutive signaling.SummaryThese findings underscore the power of next-generation sequencing, demonstrating how the primary deficiency of key molecular regulators or even regulatory motifs may lead to autoinflammation, and suggesting a possible role for cat eye syndrome chromosome region, candidate 1 and phospholipase C-2 in common diseases.
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