title: IgM+IgD+CD27+ B cells are markedly reduced in IRAK-4-, MyD88-, and TIRAP- but not UNC-93B-deficient patients.
abstract: We studied the distribution of peripheral B-cell subsets in patients deficient for key factors of the TLR-signaling pathways (MyD88, TIRAP/MAL, IL-1 receptor-associated kinase 4 [IRAK-4], TLR3, UNC-93B, TRIF). All TLRs, except TLR3, which signals through the TRIF adaptor, require MyD88 and IRAK-4 to mediate their function. TLR4 and the TLR2 heterodimers (with TLR1, TLR6, and possibly TLR10) require in addition the adaptor TIRAP, whereas UNC-93B is needed for the proper localization of intracellular TLR3, TLR7, TLR8, and TLR9. We found that IgM(+)IgD(+)CD27(+) but not switched B cells were strongly reduced in MyD88-, IRAK-4-, and TIRAP-deficient patients. This defect did not appear to be compensated with age. However, somatic hypermutation of Ig genes and heavy-chain CDR3 size distribution of IgM(+)IgD(+)CD27(+) B cells were not affected in these patients. In contrast, the numbers of IgM(+)IgD(+)CD27(+) B cells were normal in the absence of TLR3, TRIF, and UNC-93B, suggesting that UNC-93B-dependent TLRs, and notably TLR9, are dispensable for the presence of this subset in peripheral blood. Interestingly, TLR10 was found to be expressed at greater levels in IgM(+)IgD(+)CD27(+) compared with switched B cells in healthy patients. Hence, we propose a role for TIRAP-dependent TLRs, possibly TLR10 in particular, in the development and/or maintenance of IgM(+)IgD(+)CD27(+) B cells in humans.
authors.affiliation: INSERM U783, Développement du Système Immunitaire, Faculté de Médecine-Site Necker-Enfants Malades, Université Paris Descartes, Paris, France.
authors.forename: Sandra
authors.initials: S
authors.lastname: Weller
authors.forename: Mélanie
authors.initials: M
authors.lastname: Bonnet
authors.forename: Héloïse
authors.initials: H
authors.lastname: Delagreverie
authors.forename: Laura
authors.initials: L
authors.lastname: Israel
authors.forename: Maya
authors.initials: M
authors.lastname: Chrabieh
authors.forename: László
authors.initials: L
authors.lastname: Maródi
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodriguez-Gallego
authors.forename: Ben-Zion
authors.initials: BZ
authors.lastname: Garty
authors.forename: Chaim
authors.initials: C
authors.lastname: Roifman
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Issekutz
authors.forename: Simona Eva
authors.initials: SE
authors.lastname: Zitnik
authors.forename: Cyrille
authors.initials: C
authors.lastname: Hoarau
authors.forename: Yildiz
authors.initials: Y
authors.lastname: Camcioglu
authors.forename: Júlia
authors.initials: J
authors.lastname: Vasconcelos
authors.forename: Carlos
authors.initials: C
authors.lastname: Rodrigo
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Andrea
authors.initials: A
authors.lastname: Cerutti
authors.forename: Eric
authors.initials: E
authors.lastname: Meffre
authors.forename: Shen-Ying
authors.initials: SY
authors.lastname: Zhang
authors.forename: Alexandre
authors.initials: A
authors.lastname: Alcais
authors.forename: Anne
authors.initials: A
authors.lastname: Puel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Jean-Claude
authors.initials: JC
authors.lastname: Weill
authors.forename: Claude-Agnès
authors.initials: CA
authors.lastname: Reynaud
mesh_terms: D000293:Adolescent; D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000276:immunology; D006801:Humans; D007072:Immunoglobulin D / Q000032:analysis / Q000276:immunology*; D007075:Immunoglobulin M / Q000032:analysis / Q000276:immunology*; D053592:Interleukin-1 Receptor-Associated Kinases / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D026901:Membrane Transport Proteins / Q000235:genetics*; D009154:Mutation; D053594:Myeloid Differentiation Factor 88 / Q000235:genetics*; D017472:Receptors, Interleukin-1 / Q000235:genetics*; D051201:Toll-Like Receptor 10 / Q000235:genetics; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000032:analysis / Q000276:immunology*; D055815:Young Adult
chemical_list: D016207:Cytokines; D007072:Immunoglobulin D; D007075:Immunoglobulin M; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D053594:Myeloid Differentiation Factor 88; D017472:Receptors, Interleukin-1; C434984:TIRAP protein, human; C475955:TLR10 protein, human; D051201:Toll-Like Receptor 10; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; C454130:UNC93B1 protein, human; C507773:IRAK4 protein, human; D053592:Interleukin-1 Receptor-Associated Kinases