- 作者：Haifa H. Jabara ; Toshiro Ohsumi ; Janet Chou ; Michel J. Massaad ; Halli Benson ; Andre Megarbane ; Eliane Chouery ; Raymond Mikhael ; Oliver Gorka ; Andreas Gewies ; Pierre Portales ; Toshinori Nakayama ; Hiroyuki Hosokawa ; Patrick Revy ; Henry Herrod ; Francoise Le Deist ; Gerard Lefranc ; J¨¹rgen Rul ; Raif S. Geha
- 关键词：MALT1 ; combined immunodeficiency (CID) ; NF-¦ÊB
- 刊名：Journal of Allergy and Clinical Immunology
- 出版年：2013
- 出版时间：July, 2013
- 年：2013
- 卷：132
- 期：1
- 页码：151-158
- 全文大小：1019 K
Background
Combined immunodeficiency (CID) is characterized by severe recurrent infections with normal numbers of T and B lymphocytes but with deficient cellular and humoral immunity. Most cases are sporadic, but autosomal recessive inheritance has been described. In most cases, the cause of CID remains unknown.Objective
We wanted to identify the genetic cause of CID in 2 siblings, the products of a first-cousin marriage, who experienced recurrent bacterial and candidal infections with bronchiectasis, growth delay, and early death.
Methods
We performed immunologic, genetic, and biochemical studies in the 2 siblings, their family members, and healthy controls. Reconstitution studies were performed with T cells from mucosa-associated lymphoid tissue lymphoma-translocation gene 1-deficient (Malt1?/?) mice.
Results
The numbers of circulating T and B lymphocytes were normal, but T-cell proliferation to antigens and antibody responses to vaccination were severely impaired in both patients. Whole genome sequencing of 1 patient and her parents, followed by DNA sequencing of family members and healthy controls, showed the presence in both patients of a homozygous missense mutation in MALT1 that resulted in loss of protein expression. Analysis of T cells that were available on one of the patients showed severely impaired I¦ÊB¦Á degradation and IL-2 production after activation, 2 events that depend on MALT1. In contrast to wild-type human MALT1, the patients' MALT1 mutant failed to correct defective nuclear factor-¦ÊB activation and IL-2 production in MALT1-deficient mouse T cells.
Conclusions
An autosomal recessive form of CID is associated with homozygous mutations in MALT1. If future patients are found to be similarly affected, they should be considered as candidates for allogeneic hematopoietic cell transplantation.