Generation of autonomously pathogenic neo-autoreactive Th1 cells during the development of the determinant spreading cascade in murine autoimmune encephalomyelitis.
Chronic progression of autoimmune disease is accompanied by the acquisition of autoreactivity to new self-determinants. Recent evidence indicates that this process, commonly referred to as determinant spreading, may be pathogenic for chronicity. Our studies on experimental autoimmune encephalomyelitis (EAE), a murine model widely used in multiple sclerosis (MS) studies, have shown that determinant spreading develops as a predictable sequential cascade of neo-autoimmunity during progression to chronic disease. By 7-8 weeks after immunization of (SWR x SJL)F1 mice with the immunodominant myelin proteolipid protein determinant (PLP 139-151), splenocytes consistently respond to the immunodominant myelin basic protein determinant (MBP 87-99). In the present study, we directly address the pathogenicity of neo-autoimmunity resulting from endogenous self-priming during the course of disease. Our results indicate that T cells responding to the spreading MBP 87-99 determinant produce a proinflammatory cytokine profile consistent with type 1 helper T cells (Th1) cells. In addition, splenocytes activated to the spreading MBP 87-99 determinant consistently transfer acute EAE in naive recipients even when T cells reactive to the priming PLP 139-151 immunogen are eliminated by bromodeoxyuridine (BUdR)-mediated photolysis. Our data indicate that endogenous neo-autoantigen priming during chronic autoimmune disease generates type 1 helper T cells (Th1) cells that are autonomously pathogenic. These results provide further evidence supporting the view that determinant spreading is a pathogenic process that leads to chronic progression of autoimmune disease.
Yu
M
M
Cleveland Clinic Foundation, Department of Immunology, OH 44195, USA.
Johnson
J M
JM
Tuohy
V K
VK
D019264:Adoptive Transfer; D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D000963:Antimetabolites / Q000494:pharmacology; D001324:Autoantigens / Q000276:immunology / Q000494:pharmacology; D006690:Bisbenzimidazole / Q000494:pharmacology; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002493:Central Nervous System Diseases / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000276:immunology / Q000378:metabolism; D003711:Demyelinating Diseases / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000517:prevention & control; D000939:Epitopes / Q000276:immunology / Q000494:pharmacology; D005260:Female; D005456:Fluorescent Dyes / Q000494:pharmacology; D007114:Immunization; D051379:Mice; D008815:Mice, Inbred Strains; D004676:Myelin Basic Protein / Q000276:immunology / Q000494:pharmacology; D009185:Myelin Proteins / Q000276:immunology / Q000494:pharmacology; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments / Q000276:immunology / Q000494:pharmacology; D010777:Photochemistry; D013154:Spleen / Q000166:cytology / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
D000963:Antimetabolites; D001324:Autoantigens; D016207:Cytokines; D000939:Epitopes; D005456:Fluorescent Dyes; D004676:Myelin Basic Protein; D009185:Myelin Proteins; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151); D001973:Bromodeoxyuridine; D006690:Bisbenzimidazole