Pathologic role and temporal appearance of newly emerging autoepitopes in relapsing experimental autoimmune encephalomyelitis.

Abstract

Relapsing experimental autoimmune encephalomyelitis (R-EAE) is a CD4+ T cell-mediated demyelinating disease model for multiple sclerosis. Myelin destruction during the initial relapsing phase of R-EAE in SJL mice initiated by immunization with the proteolipid protein (PLP) epitope PLP139-151 is associated with activation of T cells specific for the endogenous, non-cross-reactive PLP178-191 epitope (intramolecular epitope spreading), while relapses in R-EAE induced with the myelin basic protein (MBP) epitope MBP84-104 are associated with PLP139-151-specific responses (intermolecular epitope spreading). Here, we demonstrate that T cells specific for endogenous myelin epitopes play the major pathologic role in mediating clinical relapses. T cells specific for relapse-associated epitopes can serially transfer disease to naive recipients and are demonstrable in the CNS of mice with chronic R-EAE. More importantly, induction of myelin-specific tolerance to relapse-associated epitopes, by i.v. injection of ethylene carbodiimide-fixed peptide-pulsed APCs, either before disease initiation or during remission from acute disease effectively blocks the expression of the initial disease relapse. Further, blockade of B7-1-mediated costimulation with anti-B7-1 F(ab) during disease remission from acute PLP139-151-induced disease prevents clinical relapses by inhibiting activation of PLP178-191-specific T cells. The protective effects of anti-B7-1 F(ab) treatment are long-lasting and highly effective even when administered following the initial relapsing episode wherein spreading to a MBP epitope (MBP84-104) is inhibited. Collectively, these data indicate that epitope spreading is B7-1 dependent, plays a major pathologic role in disease progression, and follows a hierarchical order associated with the relative encephalitogenic dominance of the myelin epitopes (PLP139-151 > PLP178-191 > MBP84-104).

• Authors: C L Vanderlugt, K L Neville, K M Nikcevich, T N Eagar, J A Bluestone, S D Miller
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 164 Issue 2 Pg. 670-8 (Jan 15 2000) ISSN: 0022-1767 [Print] United States
• PMID: 10623809 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Antibodies, Monoclonal
• Autoantigens
• B7-1 Antigen
• Epitopes, T-Lymphocyte
• Immunodominant Epitopes
• Myelin Basic Protein
• Myelin Proteolipid Protein
• Peptide Fragments
• myelin basic protein 84-104
• myelin proteolipid protein (139-151)

Topics

• Adoptive Transfer
• Amino Acid Sequence
• Animals
• Antibodies, Monoclonal (administration & dosage)
• Autoantigens (administration & dosage, biosynthesis, physiology)
• B7-1 Antigen (immunology, physiology)
• Encephalomyelitis, Autoimmune, Experimental (etiology, immunology, pathology, prevention & control)
• Epitopes, T-Lymphocyte (administration & dosage, biosynthesis, physiology)
• Female
• Immune Tolerance (immunology)
• Immunodominant Epitopes (physiology)
• Lymphocyte Activation (immunology)
• Mice
• Mice, Inbred Strains
• Molecular Sequence Data
• Myelin Basic Protein (administration & dosage, immunology, physiology)
• Myelin Proteolipid Protein (administration & dosage, immunology, physiology)
• Peptide Fragments (administration & dosage, immunology, physiology)
• Recurrence
• T-Lymphocytes (transplantation)
• Time Factors