Loss-of-function of the protein kinase C δ (PKCδ) causes a B-cell lymphoproliferative syndrome in humans

被引:101
作者
Kuehn, Hye Sun [1 ]
Niemela, Julie E. [1 ]
Rangel-Santos, Andreia [1 ]
Zhang, Mingchang [1 ]
Pittaluga, Stefania [2 ]
Stoddard, Jennifer L. [1 ]
Hussey, Ashleigh A. [3 ]
Evbuomwan, Moses O. [2 ]
Priel, Debra A. Long [4 ]
Kuhns, Douglas B. [4 ]
Park, C. Lucy [5 ]
Fleisher, Thomas A. [1 ]
Uzel, Gulbu [3 ]
Oliveira, Joao B. [1 ]
机构
[1] NIH, Dept Lab Med, Ctr Clin, Bethesda, MD 20892 USA
[2] NCI, Pathol Lab, Bethesda, MD 20892 USA
[3] NIAID, Lab Clin Infect Dis, NIH, Bethesda, MD 20892 USA
[4] SAIC Frederick Inc, NCI Frederick, Clin Serv Program, Frederick, MD USA
[5] Univ Illinois, Div Pediat Allergy & Immunol & Pulmonol, Childrens Hosp, Chicago, IL USA
基金
美国国家卫生研究院;
关键词
PHORBOL ESTER; ACTIVATION; APOPTOSIS; MECHANISMS;
D O I
10.1182/blood-2012-12-469544
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Defective lymphocyte apoptosis results in chronic lymphadenopathy and/or splenomegaly associated with autoimmune phenomena. The prototype for human apoptosis disorders is the autoimmune lymphoproliferative syndrome (ALPS), which is caused by mutations in the FAS apoptotic pathway. Recently, patients with an ALPS-like disease called RAS-associated autoimmune leukoproliferative disorder, in which somatic mutations in NRAS or KRAS are found, also were described. Despite this progress, many patients with ALPS-like disease remain undefined genetically. We identified a homozygous, loss-of-function mutation in PRKCD (PKC delta) in a patient who presented with chronic lymphadenopathy, splenomegaly, autoantibodies, elevated immunoglobulins and natural killer dysfunction associated with chronic, low-grade Epstein-Barr virus infection. This mutation markedly decreased protein expression and resulted in ex vivo B-cell hyperproliferation, a phenotype similar to that of the PKCd knockout mouse. Lymph nodes showed intense follicular hyperplasia, also mirroring the mouse model. Immunophenotyping of circulating lymphocytes demonstrated expansion of CD5+CD20+ B cells. Knockdown of PKC delta in normal mononuclear cells recapitulated the B-cell hyperproliferative phenotype in vitro. Reconstitution of PKC delta in patient-derived EBV-transformed B-cell lines partially restored phorbol-12-myristate-13-acetate-induced cell death. In summary, homozygous PRKCD mutation results in B-cell hyperproliferation and defective apoptosis with consequent lymphocyte accumulation and autoantibody production in humans, and disrupts natural killer cell function.
引用
收藏
页码:3117 / 3125
页数:9
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