When less is more: primary immunodeficiency with an autoinflammatory kick

Abstract

Purpose of review: Next-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 findings: Whole-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 Cγ₂, encoding a signaling molecule expressed in natural killer cells, mast cells, and B lymphocytes. These mutations inhibit the function of a phospholipase Cγ₂ autoinhibitory domain, causing increased or constitutive signaling.

Summary: These 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 Cγ₂ in common diseases.

Box 1

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FIGURE 1

Effect of adenosine deaminase 2 deficiency on endothelial and inflammatory cells. In the absence of ADA2, endothelial cells appear damaged and express activation markers, such as E-selectin, with an overall loss of endothelial integrity. In the tissue, skewing toward proinflammatory M1 macrophages leads to accumulation of proinflammatory cytokines and tissue injury. ADA2, adenosine deaminase 2.

FIGURE 2

Schematic diagrams of the function of the phospholipase Cγ₂ enzyme under normal conditions, in PLAID and in APLAID. (a) In normal unstimulated cells, PLCγ₂ is in a state of autoinhibition, with the cSH2 domain blocking the catalytic site. Upon stimulation of receptor tyrosine kinases (RTKs) by various ligands, PLCγ₂ is recruited to the cell membrane. Through a chain of interactions PLCγ₂ becomes phosphorylated at tyrosine residue 783, causing conformational changes that lead to exposure of the catalytic site to its substrate, phosphatidylinositol 4,5-bisphosphate (PIP2). The active PLCγ₂ enzyme then catalyzes the formation of IP₃ and diacylglycerol (DAG) from PIP2, which leads to the downstream effects of increased intracellular calcium (Ca²⁺) and extracellular signal-regulated kinase (ERK) phosphorylation. (b) In PLAID, genomic deletions affecting the autoinhibitory cSH2 domain cause constitutive activation of PLCγ₂ even in the absence of RTK ligands, leading either to substrate depletion or to activation of inhibitory pathways. Cellular activation is therefore not observed under physiologic conditions but only upon exposure to cold. (c) In APLAID, the missense mutation p.Ser707Tyr may either create an additional tyrosine residue available for phosphorylation or may disrupt the interaction of the catalytic domain with the autoinhibitory cSH2 domain. In either case, the net effect is an increase in the PLCγ₂ enzymatic activity and an increase in inducible cellular activation at physiologic temperatures.