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Cited by 34Immunodeficiency and Autoimmune DisordersInflammasome and immune disordersGenomics and Rare Diseases

The DOI matches its Crossref record, with a small difference in title or year; 49 of the 50 references it cites were found in a registry or an index.

When less is more: primary immunodeficiency with an autoinflammatory kick

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Giannelou, Angeliki, Zhou, Qing, Kastner, Daniel L.·2014·Current Opinion in Allergy & Clinical Immunology
DOI 10.1097/aci.0000000000000117PMC PMC4212813
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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.

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Box 1 no caption availableCC BY-NC-ND · PubMed Central
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 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.CC BY-NC-ND · PubMed Central
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.
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.CC BY-NC-ND · PubMed Central

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Research works printed but not linked: 3

  1. Van Eyck, 2014, Mutant ADA2 in vasculopathies., N Engl J Med, 371, 478, 10.1056/NEJMc1405506 · DOI
  2. Bras, 2014, Mutant ADA2 in vasculopathies., N Engl J Med, 371, 479
  3. Van Eyck, 2014, Mutant ADA2 in vasculopathies., N Engl J Med, 371, 480

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Metadata

Authors
Giannelou, A., Zhou, Q., & Kastner, D. L.
Affiliations
National Institutes of Health (US)
Corresponding author
Giannelou, Angeliki
ORCID
Venue
Current Opinion in Allergy & Clinical Immunology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2014-12
Volume
14
Issue
6
Pages
491-500
ISSN
  • 1473-6322 (ISSN-L)
  • 1528-4050
DOI
10.1097/aci.0000000000000117
PMC
PMC4212813
OpenAlex
W2023021099
Cited by
34
References
50
Citations by year
2026: 1 · 2025: 3 · 2023: 1 · 2022: 1 · 2021: 2 · 2020: 2 · 2019: 6 · 2018: 6 · 2017: 1 · 2016: 7 · 2015: 4
FWCI
0.39
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Current Opinion in Allergy and Clinical Immunology (publishedVersion)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • National Institutes of Health
  • National Human Genome Research Institute
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
Keywords
autoinflammatory disease, CECR1, ADA2, PLCγ2, germline mutations, innate immunity, M2 macrophage differentiation, cold-induced urticaria, common variable immunodeficiency, Sneddon syndrome, polyarteritis nodosa, livedo racemosa, autoinhibitory domain
MeSH terms
Adenosine Deaminase, Autoimmune Diseases, Humans, Mutation, Common Variable Immunodeficiency, Intercellular Signaling Peptides and Proteins, Phospholipase C gamma, Genome-Wide Association Study

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