文献：Ombrello MJ et al.Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions.January 11, 2012 (10.1056/NEJMoa1102140).
寒冷蕁麻疹、免疫不全などの優性遺伝を持った3家族を対象に、免疫表現型検査を実施。参加者すべてに寒冷蕁麻疹の発症が見られた。PLCG2遺伝子領域を含む染色体の欠失が、2家族では19番、もう1家族では20-22番に見られた。PLCG2の欠損はホスホリパーゼCγ2機能を獲得し、免疫機能の過剰と不全を生じると示唆された。
Cold Urticaria, Immunodeficiency, and Autoimmunity Related to PLCG2 Deletions
Michael J. Ombrello, M.D., Elaine F. Remmers, Ph.D., Guangping Sun, M.D., Alexandra F. Freeman, M.D., Shrimati Datta, Ph.D., Parizad Torabi-Parizi, M.D., Naeha Subramanian, Ph.D., Tom D. Bunney, Ph.D., Rhona W. Baxendale, Ph.D., Marta S. Martins, Ph.D., Neil Romberg, M.D., Hirsh Komarow, M.D., Ivona Aksentijevich, M.D., Hun Sik Kim, Ph.D., Jason Ho, Ph.D., Glenn Cruse, Ph.D., Mi-Yeon Jung, Ph.D., Alasdair M. Gilfillan, Ph.D., Dean D. Metcalfe, M.D., Celeste Nelson, C.R.N.P., Michelle O'Brien, B.S.N., Laura Wisch, M.S.N., Kelly Stone, M.D., Ph.D., Daniel C. Douek, M.D., Ph.D., Chhavi Gandhi, M.D., Alan A. Wanderer, M.D., Hane Lee, Ph.D., Stanley F. Nelson, M.D., Kevin V. Shianna, Ph.D., Elizabeth T. Cirulli, Ph.D., David B. Goldstein, Ph.D., Eric O. Long, Ph.D., Susan Moir, Ph.D., Eric Meffre, Ph.D., Steven M. Holland, M.D., Daniel L. Kastner, M.D., Ph.D., Matilda Katan, Ph.D., Hal M. Hoffman, M.D., and Joshua D. Milner, M.D.
January 11, 2012 (10.1056/NEJMoa1102140)
Abstract
Article
References
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 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.
Conclusions
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.)
