title: MyD88- and Bruton's tyrosine kinase-mediated signals are essential for T cell-independent pathogen-specific IgM responses.
abstract: Bacteremia is one of the leading causes of death by infectious disease. To understand the immune mechanisms required for the rapid control of bacteremia, we studied Borrelia hermsii, a bacterial pathogen that colonizes the blood stream of humans and rodents to an extremely high density. A T cell-independent IgM response is essential and sufficient for controlling B. hermsii bacteremia. Mice deficient in Bruton's tyrosine kinase (Btk), despite their known defect in BCR signaling, generated B. hermsii-specific IgM and resolved bacteremia, suggesting that an alternative activation or costimulatory pathway remained functional for T cell-independent B cells in Btk(-/-) mice. B. hermsii contains putative ligands for TLRs, and we found that mice deficient in TLR1, TLR2, or the TLR adaptor MyD88 generated anti-B. hermsii IgM with delayed kinetics and suffered more severe episodes of bacteremia. In striking contrast to the anti-B. hermsii IgM response in mice deficient only in Btk, mice deficient in both Btk and MyD88 were entirely incapable of generating B. hermsii-specific Ab or resolving bacteremia. The response to a T cell-dependent model Ag was unaffected in Btk(-/-) x MyD88(-/-) mice. These results suggest that MyD88 specifically promotes T cell-independent BCR signaling and that, in the absence of Btk, this TLR-mediated stimulation is a required component of this signal.
authors.affiliation: Department of Microbiology and Immunology and Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA. kishore.alugupalli@mail.jci.tju.edu
authors.forename: Kishore R
authors.initials: KR
authors.lastname: Alugupalli
authors.forename: Shizuo
authors.initials: S
authors.lastname: Akira
authors.forename: Egil
authors.initials: E
authors.lastname: Lien
authors.forename: John M
authors.initials: JM
authors.lastname: Leong
mesh_terms: D000077329:Agammaglobulinaemia Tyrosine Kinase; D000818:Animals; D000907:Antibodies, Bacterial / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D001898:Borrelia / Q000276:immunology; D001899:Borrelia Infections / Q000235:genetics / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology*; D007375:Interleukin-1; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000276:immunology*; D011505:Protein-Tyrosine Kinases / Q000172:deficiency / Q000276:immunology*; D011947:Receptors, Antigen, B-Cell / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D051194:Toll-Like Receptor 1 / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology
chemical_list: D000907:Antibodies, Bacterial; D007075:Immunoglobulin M; D007375:Interleukin-1; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D011947:Receptors, Antigen, B-Cell; C493486:Tlr2 protein, mouse; D051194:Toll-Like Receptor 1; D051195:Toll-Like Receptor 2; D011505:Protein-Tyrosine Kinases; D000077329:Agammaglobulinaemia Tyrosine Kinase; C000625949:BTK protein, human; C000625951:Btk protein, mouse