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PMID: 19006693 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans.

Immunity ·Vol. 29 ·No. 5 ·2008-11-14 ·Pages 746-57

Isnardi I, Ng YS, Srdanovic I, Motaghedi R, Rudchenko S, von Bernuth H, Zhang SY, Puel A, Jouanguy E, Picard C, Garty BZ, Camcioglu Y, Doffinger R, Kumararatne D, Davies G, Gallin JI, Haraguchi S, Day NK, Casanova JL, Meffre E

Abstract

Most autoreactive B cells are normally counterselected during early B cell development. To determine whether Toll-like receptors (TLRs) regulate the removal of autoreactive B lymphocytes, we tested the reactivity of recombinant antibodies from single B cells isolated from patients deficient for interleukin-1 receptor-associated kinase 4 (IRAK-4), myeloid differentiation factor 88 (MyD88), and UNC-93B. Indeed, all TLRs except TLR3 require IRAK-4 and MyD88 to signal, and UNC-93B-deficient cells are unresponsive to TLR3, TLR7, TLR8, and TLR9. All patients suffered from defective central and peripheral B cell tolerance checkpoints, resulting in the accumulation of large numbers of autoreactive mature naive B cells in their blood. Hence, TLR7, TLR8, and TLR9 may prevent the recruitment of developing autoreactive B cells in healthy donors. Paradoxically, IRAK-4-, MyD88-, and UNC-93B-deficient patients did not display autoreactive antibodies in their serum or develop autoimmune diseases, suggesting that IRAK-4, MyD88, and UNC-93B pathway blockade may thwart autoimmunity in humans.

MeSH Terms
Antibodies, Antinuclear/immunology,metabolism Autoantibodies/immunology,metabolism Autoimmunity B-Lymphocytes/immunology,metabolism Child Female Gene Expression Profiling Humans Infant Interleukin-1 Receptor-Associated Kinases/deficiency,metabolism Lymphocyte Activation Male Membrane Transport Proteins/deficiency,metabolism Myeloid Differentiation Factor 88/deficiency,metabolism Oligonucleotide Array Sequence Analysis Recombinant Proteins/immunology Self Tolerance Toll-Like Receptors/immunology,metabolism Young Adult
Chemicals
Antibodies, Antinuclear Autoantibodies MYD88 protein, human Membrane Transport Proteins Myeloid Differentiation Factor 88 Recombinant Proteins Toll-Like Receptors UNC93B1 protein, human IRAK4 protein, human Interleukin-1 Receptor-Associated Kinases
Authors & Affiliations
20 authors, click to expand affiliations / ORCID
Isnardi Isabelle
Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, NY 10021, USA.
Ng Yen-Shing
Srdanovic Iva
Motaghedi Roja
Rudchenko Sergei
von Bernuth Horst
Zhang Shen-Ying
Puel Anne
Jouanguy Emmanuelle
Picard Capucine
Garty Ben-Zion
Camcioglu Yildiz
Doffinger Rainer
Kumararatne Dinakantha
Davies Graham
Gallin John I
Haraguchi Soichi
Day Noorbibi K
Casanova Jean-Laurent
Meffre Eric
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Article Info
Journal
Immunity
Abbr.
Immunity
ISSN
1097-4180
DOI
10.1016/j.immuni.2008.09.015
Published
2008-11-14
Pages
746-57
Language
English
Region
United States
NLM ID
9432918
PMCID
PMC2666307
Subset
IM
Grants
NIAID NIH HHS · R01 AI071087-03 · United States
NIAID NIH HHS · R01 AI071087 · United States
NIAID NIH HHS · AI071087 · United States
NIAID NIH HHS · P01 AI061093 · United States
NIAID NIH HHS · P01 AI061093-050004 · United States
NCRR NIH HHS · C06-RR12538-01 · United States
NCRR NIH HHS · C06 RR012538 · United States
NIAID NIH HHS · R21 AI095848 · United States
NIAID NIH HHS · AI061093 · United States
Databases
GEO
GSE13300
Corrections
CommentIn
PMID: 19006689
External Links
PubMed source DOI: 10.1016/j.immuni.2008.09.015 PMC Full Text View journal details
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