Relapsing and remitting experimental allergic encephalomyelitis: a focused response to the encephalitogenic peptide rather than epitope spread.
The progression of experimental allergic encephalomyelitis (EAE) in certain mouse strains has been reported to involve a broadening of the response to myelin antigens, apparently resulting from priming to endogenous determinants of the myelin sheath. The phenomenon has been termed determinant spread. Interest in this effect has centered on the mechanism it offers to explain the progressive, relapsing and remitting course of EAE and indeed of multiple sclerosis. We have conducted a systematic, longitudinal study in SJL mice to look for determinant spread during relapsing and remitting EAE, correlating epitope recognition and cytokine production with disease severity. Disease was induced using three of the four encephalitogenic proteolipid protein or myelin basic protein epitopes, and responses to each of four epitopes recognized by SJL T cells were tracked through acute disease, remission and relapse. The responses of lymph node cells, splenocytes and central nervous system (CNS)-infiltrating T cells were analyzed. While marginal, transient responses to secondary epitopes were detectable in splenocytes, CNS-infiltrating cells showed a dominant response to the original disease-inducing epitope without evidence of a shift to other determinants during relapse. Disease relapse was correlated with an increase in CNS-infiltrating cells and a high proliferative and interferon (IFN)-gamma response to the disease-inducing peptide. During remission, there was a decrease in numbers of cells infiltrating the CNS. These cells were down-regulated, showing low if any response to the myelin peptides tested as measured by proliferation, production of IFN-gamma or production of IL-4. Our findings argue strongly against a causal role for determinant spread in disease relapse as observed in these models of EAE.
Takács
K
K
Clinical Sciences Centre, Royal Postgraduate Medical School, Hammersmith Hospital, London, GB.
Chandler
P
P
Altmann
D M
DM
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000276:immunology* / Q000473:pathology; D005260:Female; D016056:Immunodominant Epitopes / Q000032:analysis / Q000276:immunology*; D008198:Lymph Nodes / Q000276:immunology / Q000473:pathology; D051379:Mice; D008815:Mice, Inbred Strains; D008969:Molecular Sequence Data; D004676:Myelin Basic Protein / Q000276:immunology*; D018991:Myelin Proteolipid Protein / Q000276:immunology*; D010446:Peptide Fragments / Q000276:immunology*; D012008:Recurrence; D013116:Spinal Cord / Q000276:immunology / Q000378:metabolism; D013154:Spleen / Q000276:immunology / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D013997:Time Factors
D016207:Cytokines; D016056:Immunodominant Epitopes; D004676:Myelin Basic Protein; D018991:Myelin Proteolipid Protein; D010446:Peptide Fragments; C435023:myelin proteolipid protein (139-151)