Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.
Cold urticaria, immunodeficiency, and autoimmunity related to PLCG2 deletions.
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DOI：
10.1056/nejmoa1102140
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发表时间：
2012-01-26
期刊：
影响因子：
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通讯作者：
Milner JD
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作者：
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
孟德尔对免疫调节紊乱的分析可以洞察与宿主防御和免疫耐受相关的分子途径。我们确定了三个家系，其主要遗传性复合体为冷性荨麻疹、抗体缺乏、感染易感性和自身免疫。免疫表型方法包括流式细胞术、血清免疫球蛋白和自身抗体分析、淋巴细胞刺激和酶分析。遗传学研究包括连锁分析、定向桑格测序和下一代全基因组测序。所有受影响的受试者都发生了寒冷性荨麻疹。其他不同的表现包括特应性、肉芽肿性皮疹、自身免疫性甲状腺炎、抗核抗体的存在、鼻窦肺部感染和常见的可变免疫缺陷。血清IgM、IgA水平及循环自然杀伤细胞和类转换型记忆B细胞水平降低。连锁分析显示，在一个家系中，染色体16q上的候选区间为7-Mb，在一个较小的家系中，与疾病相关的单倍型重叠3.5Mb。这个区间包括编码磷脂酶Cγ2(PLCγ2)的PLCG2，这是一种在B细胞、自然杀伤细胞和肥大细胞中表达的信号分子。互补DNA测序显示杂合子转录本在两个家系中缺失外显子19，在第三个家系中缺失外显子20至22。基因组测序鉴定出与疾病相关的三个不同的框内缺失。这些缺失位于编码自身抑制结构域的区域内，导致具有结构性磷脂酶活性的蛋白质产物。表达PLCG2的细胞在37℃时细胞信号转导减弱，但在亚生理温度下信号转导增强。PLCG2基因缺失导致PLCγ2功能增强，导致多个白细胞亚群的信号异常，以及包括免疫功能亢进和不足的表型。(由国立卫生研究院内部研究计划和其他机构资助。)
Mendelian analysis of disorders of immune regulation can provide insight into molecular pathways associated with host defense and immune tolerance. 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. 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 Cγ2 (PLCγ2), 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. Genomic deletions in PLCG2 cause gain of PLCγ2 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.)