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Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

ABSTRACT: BACKGROUND:Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. METHODS:We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Genetic studies included linkage analysis, targeted Sanger sequencing, and next-generation whole-genome sequencing. RESULTS:Cold urticaria occurred in all affected subjects. Other, variable manifestations included atopy, granulomatous rash, autoimmune thyroiditis, the presence of antinuclear antibodies, sinopulmonary infections, and common variable immunodeficiency. Levels of serum IgM and IgA and circulating natural killer cells and class-switched memory B cells were reduced. Linkage analysis showed a 7-Mb candidate interval on chromosome 16q in one family, overlapping by 3.5 Mb a disease-associated haplotype in a smaller family. This interval includes PLCG2, encoding phospholipase C?(2) (PLC?(2)), a signaling molecule expressed in B cells, natural killer cells, and mast cells. Sequencing of complementary DNA revealed heterozygous transcripts lacking exon 19 in two families and lacking exons 20 through 22 in a third family. Genomic sequencing identified three distinct in-frame deletions that cosegregated with disease. These deletions, located within a region encoding an autoinhibitory domain, result in protein products with constitutive phospholipase activity. PLCG2-expressing cells had diminished cellular signaling at 37°C but enhanced signaling at subphysiologic temperatures. CONCLUSIONS:Genomic deletions in PLCG2 cause gain of PLC?(2) function, leading to signaling abnormalities in multiple leukocyte subsets and a phenotype encompassing both excessive and deficient immune function. (Funded by the National Institutes of Health Intramural Research Programs and others.).

SUBMITTER: Ombrello MJ

PROVIDER: S-EPMC3298368 | biostudies-literature | 2012 Jan

REPOSITORIES: biostudies-literature

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Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

Ombrello Michael J MJ Remmers Elaine F EF Sun Guangping G Freeman Alexandra F AF Datta Shrimati S Torabi-Parizi Parizad P Subramanian Naeha N Bunney Tom D TD Baxendale Rhona W RW Martins Marta S MS Romberg Neil N Komarow Hirsh H Aksentijevich Ivona I Kim Hun Sik HS Ho Jason J Cruse Glenn G Jung Mi-Yeon MY Gilfillan Alasdair M AM Metcalfe Dean D DD Nelson Celeste C O'Brien Michelle M Wisch Laura L Stone Kelly K Douek Daniel C DC Gandhi Chhavi C Wanderer Alan A AA Lee Hane H Nelson Stanley F SF Shianna Kevin V KV Cirulli Elizabeth T ET Goldstein David B DB Long Eric O EO Moir Susan S Meffre Eric E Holland Steven M SM Kastner Daniel L DL Katan Matilda M Hoffman Hal M HM Milner Joshua D JD

The New England journal of medicine 20120111 4

<h4>Background</h4>Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance.<h4>Methods</h4>We identified three families with a dominantly inherited complex of cold-induced urticaria, antibody deficiency, and susceptibility to infection and autoimmunity. Immunophenotyping methods included flow cytometry, analysis of serum immunoglobulins and autoantibodies, lymphocyte stimulation, and enzymatic assays. Gene ...[more]

PMID: 22236196

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Project description:IntroductionAutoimmune disorders, IgA deficiency, and allergies seem to be common among individuals with 18q deletion syndrome [OMIM 601808]. We aimed to determine the prevalence, mechanism, and genetic background of autoimmunity, immune deficiency, and allergy in a cohort of patients with 18q deletions.Material and methodsMedical registries and social media were used to recruit the patients. Microarray oligonucleotide comparative genomic hybridization (aCGH) (Agilent, Santa Clara, CA, USA) was performed in all patients to identify size and location of chromosome 18 deletion. Clinical evaluation and medical record collection were performed in each of the study participants. The history of autoimmune disorders, severe and/or recurrent infections, and symptoms of allergy were noted. Total immunoglobulin IgG, IgA, IgM, IgE, and IgG1-4 serum levels were measured using nephelometry and ELISA methods. Lymphocyte T subset phenotyping was performed in 24 subjects from 18q del cohort. To predict the most promising candidate genes, we used the ENDEAVOUR-a free web resource for gene prioritization.Results18q deletion was confirmed by means of array CGH analysis in 27 individuals, 15 (55.6%) females and 12 males, referred to the project by specialists in medical genetics, diabetology, or pediatric endocrinology between May 2015 and December 2019. The mean age at examination was 11.8 years (min-max: 4.0-33.5). Autoimmune disorders were present in 14/27 (51.8%) of the cohort. In eight of patients, symptoms of immune deficiency coexisted with autoimmunity. Allergy was reported in nine of 27 (33.4%) patients. Over 89% of patients presented with at list one type of immunoglobulin (IgA, IgM, IgG, IgE, and IgG1-4) deficiency and eight of 25 (32%) had abnormalities in at least two major immunoglobulin (IgG, IgA, IgM) measurements (CVID-like phenotype). Patients with 18q del exhibited a significantly decreased CD4, Treg FOXP3+, TregFOXP3+Helios+, and TemCD4 cell numbers in comparison with the control groups of 24 T1DM patients and 28 healthy controls.ConclusionsPatients with 18q deletions frequently suffer from autoimmune disorders, recurrent infections, and allergy due to immune dysregulation presenting with variable antibody deficiencies and T-regulatory cell deficiency (CD4+CD25+CD127lowFOXP3+). The spectrum of speculations regarding which gene might be responsible for such phenotype ranges from single gene haploinsufficiency to deletion of a cluster of immunogenes located distally to 18q21.

Dataset Information

Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

Publications

Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.

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