Inflammatory Disease Section, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, USA.
N Engl J Med. 2012 Jan 26;366(4):330-8. doi: 10.1056/NEJMoa1102140. Epub 2012 Jan 11.
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 Cγ(2) (PLCγ(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.
Genomic deletions in PLCG2 cause gain of PLCγ(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.).
免疫调节障碍的孟德尔分析可以深入了解与宿主防御和免疫耐受相关的分子途径。
我们鉴定了三个家族，它们具有冷诱导性荨麻疹、抗体缺陷和易感染及自身免疫的显性遗传复合物。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、淋巴细胞刺激和酶测定。遗传研究包括连锁分析、靶向 Sanger 测序和下一代全基因组测序。
所有受影响的患者均出现冷性荨麻疹。其他可变表现包括特应性、肉芽肿性皮疹、自身免疫性甲状腺炎、抗核抗体阳性、鼻肺感染和常见可变免疫缺陷。血清 IgM 和 IgA 水平以及循环自然杀伤细胞和类别转换记忆 B 细胞减少。连锁分析显示一个家族的 16q 染色体上有一个 7-Mb 候选间隔，与一个较小家族中疾病相关的单倍型重叠 3.5Mb。该间隔包括 PLCG2，其编码在 B 细胞、自然杀伤细胞和肥大细胞中表达的信号分子磷脂酶 Cγ(2)（PLCγ(2)）。互补 DNA 的测序显示两个家族存在缺失外显子 19 的杂合转录本，第三个家族缺失外显子 20 到 22。基因组测序鉴定了三个与疾病共分离的框内缺失。这些缺失位于编码自身抑制域的区域内，导致具有组成型磷酸酶活性的蛋白质产物。PLCG2 表达细胞在 37°C 时细胞信号减弱，但在亚生理温度下信号增强。
PLCG2 中的基因组缺失导致 PLCγ(2)功能获得，导致多个白细胞亚群的信号异常，并表现出过度和缺陷免疫功能。（由美国国立卫生研究院内部研究计划和其他机构资助）。
