Deficiency of caspase recruitment domain family, member 11 (CARD11), causes profound combined immunodeficiency in human subjects

被引：144

作者：

Stepensky, Polina

Keller, Baerbel ^{[1
,2
]}

Buchta, Mary ^{[1
,2
]}

Kienzler, Anne-Kathrin ^{[1
,2
]}

Elpeleg, Orly ^{[3
]}

Somech, Raz ^{[4
,5
,6
]}

Cohen, Sivan ^{[7
]}

Shachar, Idit ^{[7
]}

Miosge, Lisa A. ^{[8
]}

Schlesier, Michael ^{[1
,2
,9
]}

Fuchs, Ilka ^{[1
,2
]}

Enders, Anselm ^{[10
]}

Eibel, Hermann ^{[1
,2
]}

Grimbacher, Bodo ^{[1
,2
]}

Warnatz, Klaus ^{[1
,2
]}

机构：

[1] Univ Med Ctr Freiburg, CCI, D-79106 Freiburg, Germany

[2] Univ Freiburg, Freiburg, Germany

[3] Hebrew Univ Jerusalem, Med Ctr, Monique & Jacques Roboh Dept Genet Res, Jerusalem, Israel

[4] Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, Jeffrey Modell Fdn JMF Ctr, Dept Pediat, IL-52621 Tel Hashomer, Israel

[5] Chaim Sheba Med Ctr, Edmond & Lily Safra Childrens Hosp, Jeffrey Modell Fdn JMF Ctr, Serv Immunol, IL-52621 Tel Hashomer, Israel

[6] Tel Aviv Univ, Sackler Fac Med, IL-69978 Tel Aviv, Israel

[7] Weizmann Inst Sci, Dept Immunol, IL-76100 Rehovot, Israel

[8] Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol, Canberra, ACT 2601, Australia

[9] Univ Med Ctr Freiburg, Div Rheumatol & Clin Immunol, D-79106 Freiburg, Germany

[10] Australian Natl Univ, John Curtin Sch Med Res, Dept Immunol, Ramaciotti Immunizat Genom Lab, Canberra, ACT 2601, Australia

来源：

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY | 2013年 / 131卷 / 02期

基金：

澳大利亚国家健康与医学研究理事会;

关键词：

CARD11; human; combined immunodeficiency; hypogammaglobulinemia; profound combined immunodeficiency disorder; transitional B cell; nuclear factor kappa B; B cell-activating factor receptor; inducible T-cell costimulator; germinal center; NF-KAPPA-B; T-CELL; DIFFERENTIAL REQUIREMENT; ICOS DEFICIENCY; RECEPTOR; CARMA1; ACTIVATION; LYMPHOCYTE; MUTATION; PROLIFERATION;

D O I：

10.1016/j.jaci.2012.11.050

中图分类号：

R392 [医学免疫学];

学科分类号：

100102 ;

摘要：

Background: Profound combined immunodeficiency can present with normal numbers of T and B cells, and therefore the functional defect of the cellular and humoral immune response is often not recognized until the first severe clinical manifestation. Here we report a patient of consanguineous descent presenting at 13 months of age with hypogammaglobulinemia, Pneumocystis jirovecii pneumonia, and a suggestive family history. Objective: We sought to identify the genetic alteration in a patient with combined immunodeficiency and characterize human caspase recruitment domain family, member 11 (CARD11), deficiency. Methods: Molecular, immunologic, and functional assays were performed. Results: The immunologic characterization revealed only subtle changes in the T-cell and natural killer cell compartment, whereas B-cell differentiation, although normal in number, was distinctively blocked at the transitional stage. Genetic evaluation revealed a homozygous deletion of exon 21 in CARD11 as the underlying defect. This deletion abrogated protein expression and activation of the canonical nuclear factor kappa B (NF-kappa B) pathway in lymphocytes after antigen receptor or phorbol 12-myristate 13-acetate stimulation, whereas CD40 signaling in B cells was preserved. The abrogated activation of the canonical NF-kappa B pathway was associated with severely impaired upregulation of inducible T-cell costimulator, OX40, cytokine production, proliferation of T cells, and B cell-activating factor receptor expression on B cells. Conclusion: Thus in patients with CARD11 deficiency, the combination of impaired activation and especially upregulation of inducible T-cell costimulator on T cells, together with severely disturbed peripheral B-cell differentiation, apparently leads to a defective T-cell/B-cell cooperation and probably germinal center formation and clinically results in severe immunodeficiency. This report discloses the crucial and nonredundant role of canonical NF-kappa B activation and specifically CARD11 in the antigen-specific immune response in human subjects. (J Allergy Clin Immunol 2013;131:477-85.)

引用

页码：477 / +

页数：10