Expansion of immunoglobulin-secreting cells and defects in B cell tolerance in Rag-dependent immunodeficiency

被引：80

作者：

Walter, Jolan E. ^{[1
,2
]}

Rucci, Francesca ^{[1
,2
]}

Patrizi, Laura ^{[1
,2
]}

Recher, Mike ^{[1
,2
]}

Regenass, Stephan ^{[5
]}

Paganini, Tiziana ^{[6
]}

Keszei, Marton ^{[3
]}

Pessach, Itai ^{[1
,2
]}

Lang, Philipp A. ^{[8
]}

Poliani, Pietro Luigi ^{[7
]}

Giliani, Silvia ^{[6
]}

Al-Herz, Waleed ^{[9
]}

Cowan, Morton J. ^{[10
,11
]}

Puck, Jennifer M. ^{[10
,11
]}

Bleesing, Jack ^{[12
]}

Niehues, Tim ^{[13
]}

Schuetz, Catharina ^{[14
]}

Malech, Harry ^{[15
]}

DeRavin, Suk See ^{[15
]}

Facchetti, Fabio ^{[7
]}

Gennery, Andrew R. ^{[16
]}

Andersson, Emma ^{[1
,2
]}

Kamani, Naynesh R. ^{[17
]}

Sekiguchi, JoAnn ^{[18
]}

Alenezi, Hamid M. ^{[9
]}

Chinen, Javier ^{[19
]}

Dbaibo, Ghassan ^{[20
]}

ElGhazali, Gehad ^{[21
]}

Fontana, Adriano ^{[5
]}

Pasic, Srdjan ^{[22
]}

Detre, Cynthia ^{[3
]}

Terhorst, Cox ^{[3
]}

Alt, Frederick W. ^{[4
]}

Notarangelo, Luigi D. ^{[1
,2
]}

机构：

[1] Harvard Univ, Childrens Hosp, Div Immunol, Sch Med, Boston, MA 02115 USA

[2] Harvard Univ, Childrens Hosp, Manton Ctr Orphan Dis Res, Sch Med, Boston, MA 02115 USA

[3] Harvard Univ, Sch Med, Div Immunol, Beth Israel Deaconess Med Ctr, Boston, MA 02115 USA

[4] Harvard Univ, Sch Med, Immune Dis Inst, Boston, MA 02115 USA

[5] Univ Zurich Hosp, Div Clin Immunol, CH-8091 Zurich, Switzerland

[6] Univ Brescia, Pediat Clin, Nocivelli Inst Mol Med, I-25123 Brescia, Italy

[7] Univ Brescia, Dept Pathol, I-25123 Brescia, Italy

[8] Univ Toronto, Dept Immunol, Ontario Canc Inst, Campbell Inst Breast Canc Res, Toronto, ON M5G 2M9, Canada

[9] Al Sabah Hosp, Dept Pediat, Allergy & Clin Immunol Unit, Kuwait 70459, Kuwait

[10] Univ Calif San Francisco, Dept Pediat, Sch Med, San Francisco, CA 94143 USA

[11] UCSF Childrens Hosp, San Francisco, CA 94143 USA

[12] Childrens Hosp, Med Ctr, Cincinnati, OH 45229 USA

[13] Univ Dusseldorf, Helios Klinikum Krefeld Acad Hosp, Ctr Child Hlth & Adolescence, D-02151 Dusseldorf, Germany

[14] Univ Hosp Ulm, Dept Pediat & Adolescent Med, D-89070 Ulm, Germany

[15] NIAID, Host Def Lab, Bethesda, MD 20892 USA

[16] Newcastle Univ, Inst Cellular Med, Newcastle Upon Tyne NE2 4HH, Tyne & Wear, England

[17] Childrens Natl Med Ctr, Ctr Canc & Blood Disorders, Washington, DC 20010 USA

[18] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA

[19] Texas Childrens Hosp, Baylor Coll Med, Dept Pediat, Sect Allergy & Immunol, Houston, TX 77030 USA

[20] Amer Univ Beirut, Dept Pediat & Adolescent Med, Beirut 11072020, Lebanon

[21] King Fahad Med City, Fac Med, Dept Immunol, Riyadh 11525, Saudi Arabia

[22] Mother & Child Hlth Inst Serbia, Dept Pediat Immunol, Belgrade 11070, Serbia

来源：

JOURNAL OF EXPERIMENTAL MEDICINE | 2010年 / 207卷 / 07期

基金：

瑞士国家科学基金会; 美国国家卫生研究院;

关键词：

CLASS-SWITCH RECOMBINATION; OMENN-SYNDROME; V(D)J RECOMBINATION; BONE-MARROW; T-CELLS; HOMEOSTATIC PROLIFERATION; LYMPHOCYTE DEVELOPMENT; POSITIVE SELECTION; ESCAPE TOLERANCE; MURINE MODEL;

D O I：

10.1084/jem.20091927

中图分类号：

R392 [医学免疫学]; Q939.91 [免疫学];

学科分类号：

100102 ;

摘要：

The contribution of B cells to the pathology of Omenn syndrome and leaky severe combined immunodeficiency (SCID) has not been previously investigated. We have studied a mut/mut mouse model of leaky SCID with a homozygous Rag1 S723C mutation that impairs, but does not abrogate, V(D)J recombination activity. In spite of a severe block at the pro-B cell stage and profound B cell lymphopenia, significant serum levels of immunoglobulin (Ig) G, IgM, IgA, and IgE and a high proportion of Ig-secreting cells were detected in mut/mut mice. Antibody responses to trinitrophenyl (TNP)-Ficoll and production of high-affinity antibodies to TNP-keyhole limpet hemocyanin were severely impaired, even after adoptive transfer of wild-type CD4(+) T cells. Mut/mut mice produced high amounts of low-affinity self-reactive antibodies and showed significant lymphocytic infiltrates in peripheral tissues. Autoantibody production was associated with impaired receptor editing and increased serum B cell-activating factor (BAFF) concentrations. Autoantibodies and elevated BAFF levels were also identified in patients with Omenn syndrome and leaky SCID as a result of hypomorphic RAG mutations. These data indicate that the stochastic generation of an autoreactive B cell repertoire, which is associated with defects in central and peripheral checkpoints of B cell tolerance, is an important, previously unrecognized, aspect of immunodeficiencies associated with hypomorphic RAG mutations.

引用

页码：1541 / 1554

页数：14

共 77 条

[1] Transfer of small resting B cells into immunodeficient hosts results in the selection of a self-renewing activated B cell population [J].