title: IL-1 receptor-associated kinase 1 regulates susceptibility to organ-specific autoimmunity.
abstract: Infections often precede the development of autoimmunity. Correlation between infection with a specific pathogen and a particular autoimmune disease ranges from moderately strong to quite weak. This lack of correspondence suggests that autoimmunity may result from microbial activation of a generic, as opposed to pathogen-specific host-defense response. The Toll-like receptors, essential to host recognition of microbial invasion, signal through a common, highly conserved pathway, activate innate immunity, and control adaptive immune responses. To determine the influence of Toll/IL-1 signaling on the development of autoimmunity, the responses of wild-type (WT) mice and IL-1R-associated kinase 1 (IRAK1)-deficient mice to induction of experimental autoimmune encephalomyelitis were compared. C57BL/6 and B6.IRAK1-deficient mice were immunized with MOG 35-55/CFA or MOG 35-55/CpG DNA/IFA. WT animals developed severe disease, whereas IRAK1-deficient mice were resistant to experimental autoimmune encephalomyelitis, exhibiting little or no CNS inflammation. IRAK1-deficient T cells also displayed impaired Th1 development, particularly during disease induction, despite normal TCR signaling. These results suggest that IRAK1 and the Toll/IL-1 pathway play an essential role in T cell priming, and demonstrate one means through which innate immunity can control subsequent development of autoimmunity. These findings may also help explain the association between antecedent infection and the development or exacerbations of some autoimmune diseases.
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Caishu
authors.initials: C
authors.lastname: Deng
authors.forename: Caius
authors.initials: C
authors.lastname: Radu
authors.forename: Asim
authors.initials: A
authors.lastname: Diab
authors.forename: May F
authors.initials: MF
authors.lastname: Tsen
authors.forename: Rehana
authors.initials: R
authors.lastname: Hussain
authors.forename: John S
authors.initials: JS
authors.lastname: Cowdery
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
authors.forename: James A
authors.initials: JA
authors.lastname: Thomas
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000502:physiology; D000818:Animals; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D018899:CpG Islands / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005620:Freund's Adjuvant / Q000008:administration & dosage / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006023:Glycoproteins / Q000276:immunology; D007113:Immunity, Innate / Q000235:genetics; D007156:Immunologic Memory / Q000235:genetics; D007279:Injections, Subcutaneous; D007371:Interferon-gamma / Q000096:biosynthesis; D053592:Interleukin-1 Receptor-Associated Kinases; D007399:Interphase / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000235:genetics; D008264:Macrophages / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein; D009838:Oligodeoxyribonucleotides / Q000008:administration & dosage / Q000276:immunology; D009928:Organ Specificity / Q000235:genetics / Q000276:immunology; D010446:Peptide Fragments / Q000276:immunology; D011494:Protein Kinases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism / Q000502:physiology; D017472:Receptors, Interleukin-1 / Q000235:genetics / Q000502:physiology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000201:enzymology / Q000276:immunology / Q000378:metabolism
chemical_list: D000276:Adjuvants, Immunologic; C408982:CPG-oligonucleotide; D006023:Glycoproteins; D063308:Myelin-Oligodendrocyte Glycoprotein; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D011948:Receptors, Antigen, T-Cell; D017472:Receptors, Interleukin-1; C445081:myelin oligodendrocyte glycoprotein (35-55); D007371:Interferon-gamma; D005620:Freund's Adjuvant; D011494:Protein Kinases; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse