Skip to main page content
Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
, 14 (6), 491-500

When Less Is More: Primary Immunodeficiency With an Autoinflammatory Kick


When Less Is More: Primary Immunodeficiency With an Autoinflammatory Kick

Angeliki Giannelou et al. Curr Opin Allergy Clin Immunol.


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
Box 1
no caption available
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.
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.

Similar articles

  • Monogenic polyarteritis: the lesson of ADA2 deficiency.
    Caorsi R, Penco F, Schena F, Gattorno M. Caorsi R, et al. Pediatr Rheumatol Online J. 2016 Sep 8;14(1):51. doi: 10.1186/s12969-016-0111-7. Pediatr Rheumatol Online J. 2016. PMID: 27609179 Free PMC article. Review.
  • Deficiency of Adenosine Deaminase 2 (DADA2), an Inherited Cause of Polyarteritis Nodosa and a Mimic of Other Systemic Rheumatologic Disorders.
    Hashem H, Kelly SJ, Ganson NJ, Hershfield MS. Hashem H, et al. Curr Rheumatol Rep. 2017 Oct 5;19(11):70. doi: 10.1007/s11926-017-0699-8. Curr Rheumatol Rep. 2017. PMID: 28983775 Review.
  • Early-onset stroke and vasculopathy associated with mutations in ADA2.
    Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C, Zavialov AV, Stone DL, Chae JJ, Rosenzweig SD, Bishop K, Barron KS, Kuehn HS, Hoffmann P, Negro A, Tsai WL, Cowen EW, Pei W, Milner JD, Silvin C, Heller T, Chin DT, Patronas NJ, Barber JS, Lee CC, Wood GM, Ling A, Kelly SJ, Kleiner DE, Mullikin JC, Ganson NJ, Kong HH, Hambleton S, Candotti F, Quezado MM, Calvo KR, Alao H, Barham BK, Jones A, Meschia JF, Worrall BB, Kasner SE, Rich SS, Goldbach-Mansky R, Abinun M, Chalom E, Gotte AC, Punaro M, Pascual V, Verbsky JW, Torgerson TR, Singer NG, Gershon TR, Ozen S, Karadag O, Fleisher TA, Remmers EF, Burgess SM, Moir SL, Gadina M, Sood R, Hershfield MS, Boehm M, Kastner DL, Aksentijevich I. Zhou Q, et al. N Engl J Med. 2014 Mar 6;370(10):911-20. doi: 10.1056/NEJMoa1307361. Epub 2014 Feb 19. N Engl J Med. 2014. PMID: 24552284 Free PMC article.
  • Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.
    Ombrello MJ, Remmers EF, Sun G, Freeman AF, Datta S, Torabi-Parizi P, Subramanian N, Bunney TD, Baxendale RW, Martins MS, Romberg N, Komarow H, Aksentijevich I, Kim HS, Ho J, Cruse G, Jung MY, Gilfillan AM, Metcalfe DD, Nelson C, O'Brien M, Wisch L, Stone K, Douek DC, Gandhi C, Wanderer AA, Lee H, Nelson SF, Shianna KV, Cirulli ET, Goldstein DB, Long EO, Moir S, Meffre E, Holland SM, Kastner DL, Katan M, Hoffman HM, Milner JD. Ombrello MJ, et al. N Engl J Med. 2012 Jan 26;366(4):330-8. doi: 10.1056/NEJMoa1102140. Epub 2012 Jan 11. N Engl J Med. 2012. PMID: 22236196 Free PMC article.
  • Autoimmune phenotype with type I interferon signature in two brothers with ADA2 deficiency carrying a novel CECR1 mutation.
    Skrabl-Baumgartner A, Plecko B, Schmidt WM, König N, Hershfield M, Gruber-Sedlmayr U, Lee-Kirsch MA. Skrabl-Baumgartner A, et al. Pediatr Rheumatol Online J. 2017 Aug 22;15(1):67. doi: 10.1186/s12969-017-0193-x. Pediatr Rheumatol Online J. 2017. PMID: 28830446 Free PMC article.
See all similar articles

Cited by 10 articles

See all "Cited by" articles


    1. International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997; 90:797–807 - PubMed
    1. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17:25–31 - PubMed
    1. McDermott MF, Aksentijevich I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 1999; 97:133–144 - PubMed
    1. Hoffman HM, Mueller JL, Broide DH, et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 2001; 29:301–305 - PMC - PubMed
    1. Feldmann J, Prieur AM, Quartier P, et al. Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 2002; 71:198–203 - PMC - PubMed

Publication types

MeSH terms