Dock8 mutations cripple B cell immunological synapses, germinal centers and long-lived antibody production

被引：216

作者：

Randall, Katrina L. ^{[1
,2
]}

Lambe, Teresa ^{[3
]}

Johnson, Andy ^{[3
,4
]}

Treanor, Bebhinn ^{[6
]}

Kucharska, Edyta ^{[1
]}

Domaschenz, Heather ^{[1
]}

Whittle, Belinda ^{[1
]}

Tze, Lina E. ^{[1
]}

Enders, Anselm ^{[1
]}

Crockford, Tanya L. ^{[3
]}

Bouriez-Jones, Tiphaine ^{[3
]}

Alston, Duncan ^{[3
]}

Cyster, Jason G. ^{[7
,8
]}

Lenardo, Michael J. ^{[5
]}

Mackay, Fabienne ^{[9
]}

Deenick, Elissa K. ^{[10
]}

Tangye, Stuart G. ^{[10
]}

Chan, Tyani D. ^{[10
]}

Camidge, Tahra ^{[10
]}

Brink, Robert ^{[10
]}

Vinuesa, Carola G. ^{[1
]}

Batista, Facundo D. ^{[6
]}

Cornall, Richard J. ^{[3
]}

Goodnow, Christopher C. ^{[1
]}

机构：

[1] Australian Natl Univ, John Curtin Sch Med Res, Canberra, ACT 0200, Australia

[2] Canberra Hosp, Dept Immunol, Garran, ACT, Australia

[3] Univ Oxford, Nuffield Dept Clin Med, Oxford, England

[4] NIAID, Cellular & Mol Immunol Lab, NIH, Bethesda, MD USA

[5] NIAID, Immunol Lab, NIH, Bethesda, MD USA

[6] Lincolns Inn Fields, London Res Inst, Canc Res UK, London, England

[7] Univ Calif San Francisco, Howard Hughes Med Inst, San Francisco, CA 94143 USA

[8] Univ Calif San Francisco, Dept Microbiol & Immunol, San Francisco, CA 94143 USA

[9] Monash Univ, Fac Med Nursing & Hlth Sci, Dept Immunol, Melbourne, Vic 3004, Australia

[10] St Vincents Hosp, Garvan Inst Med Res, Darlinghurst, NSW 2010, Australia

来源：

NATURE IMMUNOLOGY | 2009年 / 10卷 / 12期

基金：

英国医学研究理事会; 澳大利亚研究理事会; 英国惠康基金;

关键词：

COMMON VARIABLE IMMUNODEFICIENCY; HUMORAL IMMUNE-RESPONSES; MARGINAL ZONE; POSITIVE SELECTION; PHOSPHATIDYLINOSITOL; 3-KINASE; SIGNAL-TRANSDUCTION; NEGATIVE SELECTION; PLASMA-CELL; ANTIGEN; CD19;

D O I：

10.1038/ni.1820

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

To identify genes and mechanisms involved in humoral immunity, we did a mouse genetic screen for mutations that do not affect the first wave of antibody to immunization but disrupt response maturation and persistence. The first two mutants identified had loss-of-function mutations in the gene encoding a previously obscure member of a family of Rho-Rac GTP-exchange factors, DOCK8. DOCK8-mutant B cells were unable to form marginal zone B cells or to persist in germinal centers and undergo affinity maturation. Dock8 mutations disrupted accumulation of the integrin ligand ICAM-1 in the B cell immunological synapse but did not alter other aspects of B cell antigen receptor signaling. Humoral immunodeficiency due to Dock8 mutation provides evidence that organization of the immunological synapse is critical for signaling the survival of B cell subsets required for long-lasting immunity.

引用

页码：1283 / U8

页数：10

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