2015
DOI: 10.1001/jamadermatol.2014.5641
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Distinct Cutaneous Manifestations and Cold-Induced Leukocyte Activation Associated WithPLCG2Mutations

Abstract: IMPORTANCE PLCG2-associated antibody deficiency and immune dysregulation (PLAID) is a newly characterized immunodeficiency syndrome associated with distinct cutaneous features. Awareness of the cutaneous skin findings associated with PLAID may facilitate diagnosis and improve patient care. OBJECTIVES To characterize the cutaneous manifestations of PLAID and identify potential cellular mechanisms of the disease. DESIGN, SETTING, AND PARTICIPANTS In this retrospective analysis of patients with PLAID and PLAI… Show more

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Cited by 59 publications
(64 citation statements)
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“…Gain-of-function mutations in PLCG2 in PLAID causes paradoxically decreased receptor-mediated intracellular signaling in NK cells and B-cells at physiologic temperatures, leading to autoimmunity and humoral immune deficiency. [39] However, at subphysiologic temperatures, B-cells, neutrophils, monocytes and mast cells have increased cellular activity, even in the absence of receptor crosslinking, leading to granulomatous skin lesions [40], and a form of cold urticaria [39,40]. A tendency toward a Th2 phenotype is also seen in patients with Loeys–Dietz syndrome (LDS), a connective tissue disorder commonly caused by mutations in TGFBR1 or TGFBR2 that result in upregulation of TGFβ signaling [41••,42]; this increased signaling alone appears sufficient to drive naïve T-cells toward a Th2 phenotype [41••].…”
Section: Introductionmentioning
confidence: 99%
“…Gain-of-function mutations in PLCG2 in PLAID causes paradoxically decreased receptor-mediated intracellular signaling in NK cells and B-cells at physiologic temperatures, leading to autoimmunity and humoral immune deficiency. [39] However, at subphysiologic temperatures, B-cells, neutrophils, monocytes and mast cells have increased cellular activity, even in the absence of receptor crosslinking, leading to granulomatous skin lesions [40], and a form of cold urticaria [39,40]. A tendency toward a Th2 phenotype is also seen in patients with Loeys–Dietz syndrome (LDS), a connective tissue disorder commonly caused by mutations in TGFBR1 or TGFBR2 that result in upregulation of TGFβ signaling [41••,42]; this increased signaling alone appears sufficient to drive naïve T-cells toward a Th2 phenotype [41••].…”
Section: Introductionmentioning
confidence: 99%
“…Furthermore it was not clear that neutrophils could produce superoxide in response to stimulation over and above the basal activation seen, making it possible that other neutrophil defects, in addition to cold-induced activation, could contribute to granuloma formation. It should be noted, however that the cold-induced activation of neutrophils and monocytes, as well as B-cells, was present in all patients, whether a granuloma was present or not 5, 6 . Additional factors must modify the risk for granuloma formation, be they external temperature exposure variation, other intrinsic environmental exposures, or genetic modifiers.…”
mentioning
confidence: 76%
“…Histopathological examination led to the diagnosis of sarcoidosis in at least one patient due to the presence of non-caseating granulomatous dermatitis, but there was little evidence suggest a clear etiology. ACE levels were all normal in PLAID patients, with and without granulomata 6 .…”
mentioning
confidence: 86%
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