title: IRAK-4- and MyD88-dependent pathways are essential for the removal of developing autoreactive B cells in humans.
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.
authors.affiliation: Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, NY 10021, USA.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Isnardi
authors.forename: Yen-Shing
authors.initials: YS
authors.lastname: Ng
authors.forename: Iva
authors.initials: I
authors.lastname: Srdanovic
authors.forename: Roja
authors.initials: R
authors.lastname: Motaghedi
authors.forename: Sergei
authors.initials: S
authors.lastname: Rudchenko
authors.forename: Horst
authors.initials: H
authors.lastname: von Bernuth
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Jouanguy
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Garty
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Camcioglu
authors.forename: Rainer
authors.initials: R
authors.lastname: Doffinger
authors.forename: Dinakantha
authors.initials: D
authors.lastname: Kumararatne
authors.forename: Graham
authors.initials: G
authors.lastname: Davies
authors.forename: John I
authors.initials: JI
authors.lastname: Gallin
authors.forename: Soichi
authors.initials: S
authors.lastname: Haraguchi
authors.forename: Noorbibi K
authors.initials: NK
authors.lastname: Day
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
mesh_terms: D000974:Antibodies, Antinuclear / Q000276:immunology / Q000378:metabolism; D001323:Autoantibodies / Q000276:immunology / Q000378:metabolism; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002648:Child; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007223:Infant; D053592:Interleukin-1 Receptor-Associated Kinases / Q000172:deficiency / Q000378:metabolism*; D008213:Lymphocyte Activation; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D011994:Recombinant Proteins / Q000276:immunology; D017634:Self Tolerance; D051193:Toll-Like Receptors / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
chemical_list: D000974:Antibodies, Antinuclear; D001323:Autoantibodies; C507779:MYD88 protein, human; D026901:Membrane Transport Proteins; D053594:Myeloid Differentiation Factor 88; D011994:Recombinant Proteins; D051193:Toll-Like Receptors; C454130:UNC93B1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases