Loss-of-function mutations in the IL-21 receptor gene cause a primary immunodeficiency syndrome

被引：156

作者：

Kotlarz, Daniel ^{[1
,6
]}

Zietara, Natalia ^{[1
,6
]}

Uzel, Gulbu ^{[7
]}

Weidemann, Thomas ^{[11
]}

Braun, Christian J. ^{[1
,6
]}

Diestelhorst, Jana ^{[1
,6
]}

Krawitz, Peter M. ^{[12
,13
,14
]}

Robinson, Peter N. ^{[12
,13
,14
]}

Hecht, Jochen ^{[12
,13
,14
]}

Puchalka, Jacek ^{[6
]}

Gertz, E. Michael

Schaeffer, Alejandro A.

Lawrence, Monica G. ^{[8
]}

Kardava, Lela ^{[9
]}

Pfeifer, Dietmar ^{[15
]}

Baumann, Ulrich ^{[2
]}

Pfister, Eva-Doreen ^{[2
]}

Hanson, Eric P. ^{[10
]}

Schambach, Axel ^{[3
]}

Jacobs, Roland ^{[4
]}

Kreipe, Hans ^{[5
]}

Moir, Susan ^{[9
]}

Milner, Joshua D. ^{[8
]}

Schwille, Petra ^{[11
]}

Mundlos, Stefan ^{[12
,13
,14
]}

Klein, Christoph ^{[1
,6
]}

机构：

[1] Hannover Med Sch, Dept Pediat Hematol Oncol, D-30625 Hannover, Germany

[2] Hannover Med Sch, Dept Pediat Kidney Liver & Metab Dis, D-30625 Hannover, Germany

[3] Hannover Med Sch, Dept Expt Hematol, D-30625 Hannover, Germany

[4] Hannover Med Sch, Dept Clin Immunol & Rheumatol, D-30625 Hannover, Germany

[5] Hannover Med Sch, Dept Pathol, D-30625 Hannover, Germany

[6] Univ Munich, Dr von Hauner Childrens Hosp, Dept Pediat, D-80539 Munich, Germany

[7] NIAID, Immunopathogenesis Sect, Lab Clin Infect Dis, Bethesda, MD USA

[8] NIAID, Lab Allerg Dis, Bethesda, MD USA

[9] NIAID, Lab Immunoregulat, Bethesda, MD USA

[10] NIAMSD, NIH, Bethesda, MD 20892 USA

[11] Tech Univ Dresden, Biophys Res Grp, D-01062 Dresden, Germany

[12] Max Planck Inst Mol Genet, D-14195 Berlin, Germany

[13] Charite, Inst Med Genet & Human Genet, D-10117 Berlin, Germany

[14] Charite, Berlin Brandenburg Ctr Regenerat Therapies BCRT, D-10117 Berlin, Germany

[15] Univ Med Ctr Freiburg, Genom Core Lab, Dept Hematol Oncol, D-79095 Freiburg, Germany

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2013年 / 210卷 / 03期

关键词：

CELL RESPONSES; WSXWS MOTIF; T-CELLS; DIFFERENTIATION; INTERLEUKIN-21; CHAIN; DEFICIENCY; ACTIVATION; GENERATION; INFECTION;

D O I：

10.1084/jem.20111229

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

Primary immunodeficiencies (PIDs) represent exquisite models for studying mechanisms of human host defense. In this study, we report on two unrelated kindreds, with two patients each, who had cryptosporidial infections associated with chronic cholangitis and liver disease. Using exome and candidate gene sequencing, we identified two distinct homozygous loss-of-function mutations in the interleukin-21 receptor gene (IL21R; c.G602T, p.Arg201Leu and c.240_245delCTGCCA, p.C81_H82del). The IL-21R(Arg201Leu) mutation causes aberrant trafficking of the IL-21R to the plasma membrane, abrogates IL-21 ligand binding, and leads to defective phosphorylation of signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5. We observed impaired IL-21-induced proliferation and immunoglobulin class-switching in B cells, cytokine production in T cells, and NK cell cytotoxicity. Our study indicates that human IL-21R deficiency causes an immunodeficiency and highlights the need for early diagnosis and allogeneic hematopoietic stem cell transplantation in affected children.

引用

页码：433 / 443

页数：11

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