Activation of APCs through CD40 or Toll-like receptor 9 overcomes tolerance and precipitates autoimmune disease.
Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4(+) T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals do not succumb to autoimmune disease. There is growing evidence that while peripheral APCs stimulate immune responses against foreign Ags in the setting of tissue destruction and "danger," they actually maintain tolerance against self Ags under steady state conditions. We hypothesized that tolerance against candidate autoantigens could be reversed by activation of APCs via CD40 or Toll-like receptor 9 signaling. Adult SJL mice injected i.p. with a peptide fragment of proteolipid protein (a candidate autoantigen in multiple sclerosis) emulsified in IFA fail to mount lymphoproliferative or cytokine responses and are protected from EAE upon subsequent challenge with the Ag combined with adjuvants. Here we report that tolerized proteolipid protein-specific lymph node cells regain the ability to divide, differentiate along a Th1 lineage, and transfer EAE when reactivated in the presence of agonistic Abs against CD40 or CpG oligonucleotides. The effects of both anti-CD40 and CpG oligonucleotides are dependent upon induction of IL-12. Our findings suggest two mechanisms to explain the well-documented association between infectious illnesses and flare-ups of multiple sclerosis. Microbial pathogens could 1) release molecules that bind Toll-like receptors, and/or 2) stimulate microbe-specific T cells to express CD40 ligand, thereby licensing APCs that bear both microbial and autoantigens to break tolerance.
Department of Neurology, University of Rochester School of Medicine and Dentistry, NY 14642, USA.
Hiroshi T
HT
Ichikawa
Lucas P
LP
Williams
Benjamin M
BM
Segal
D000069594:Abatacept; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000378:metabolism*; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology / Q000502:physiology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology / Q000502:physiology*; D060908:CTLA-4 Antigen; D018899:CpG Islands / Q000276:immunology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D004198:Disease Susceptibility / Q000209:etiology / Q000276:immunology; D004306:Dose-Response Relationship, Immunologic; D004338:Drug Combinations; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology*; D005260:Female; D005620:Freund's Adjuvant / Q000008:administration & dosage; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate; D018796:Immunoconjugates; D016056:Immunodominant Epitopes / Q000008:administration & dosage / Q000276:immunology; D007274:Injections, Intraperitoneal; D008055:Lipids; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008213:Lymphocyte Activation; D051379:Mice; D008815:Mice, Inbred Strains; D018991:Myelin Proteolipid Protein / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology* / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000037:antagonists & inhibitors / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology; D051217:Toll-Like Receptor 9
D000276:Adjuvants, Immunologic; D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D019013:CD40 Antigens; C408982:CPG-oligonucleotide; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D004268:DNA-Binding Proteins; D004338:Drug Combinations; D018796:Immunoconjugates; D016056:Immunodominant Epitopes; D008055:Lipids; D018991:Myelin Proteolipid Protein; D009838:Oligodeoxyribonucleotides; D010446:Peptide Fragments; D011956:Receptors, Cell Surface; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; C114843:incomplete Freund's adjuvant; C435023:myelin proteolipid protein (139-151); D000069594:Abatacept; D005620:Freund's Adjuvant