The functional significance of epitope spreading and its regulation by co-stimulatory molecules

Carol L. Vanderlugt, Wendy Smith Begolka, Katherine L. Neville, Yael Katz-Levy, Laurence M. Howard, Todd N. Eagar, Jeffrey A. Bluestone, Stephen D. Miller

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.

Original languageEnglish (US)
Pages (from-to)63-72
Number of pages10
JournalImmunological Reviews
Volume164
DOIs
StatePublished - Aug 1998

Fingerprint

Epitopes
Myelin Sheath
T-Lymphocytes
Demyelinating Diseases
Theilovirus
Viruses
Myelin Proteins
Immunodominant Epitopes
Autoimmune Experimental Encephalomyelitis
Autoimmune Diseases
Peptide T
Central Nervous System Diseases
Acute Disease
Antigen-Presenting Cells
Coinfection
Therapeutics
Central Nervous System
Antigens
Recurrence

ASJC Scopus subject areas

  • Immunology

Cite this

Vanderlugt, C. L., Begolka, W. S., Neville, K. L., Katz-Levy, Y., Howard, L. M., Eagar, T. N., ... Miller, S. D. (1998). The functional significance of epitope spreading and its regulation by co-stimulatory molecules. Immunological Reviews, 164, 63-72. https://doi.org/10.1111/j.1600-065X.1998.tb01208.x

The functional significance of epitope spreading and its regulation by co-stimulatory molecules. / Vanderlugt, Carol L.; Begolka, Wendy Smith; Neville, Katherine L.; Katz-Levy, Yael; Howard, Laurence M.; Eagar, Todd N.; Bluestone, Jeffrey A.; Miller, Stephen D.

In: Immunological Reviews, Vol. 164, 08.1998, p. 63-72.

Research output: Contribution to journalArticle

Vanderlugt, CL, Begolka, WS, Neville, KL, Katz-Levy, Y, Howard, LM, Eagar, TN, Bluestone, JA & Miller, SD 1998, 'The functional significance of epitope spreading and its regulation by co-stimulatory molecules', Immunological Reviews, vol. 164, pp. 63-72. https://doi.org/10.1111/j.1600-065X.1998.tb01208.x
Vanderlugt, Carol L. ; Begolka, Wendy Smith ; Neville, Katherine L. ; Katz-Levy, Yael ; Howard, Laurence M. ; Eagar, Todd N. ; Bluestone, Jeffrey A. ; Miller, Stephen D. / The functional significance of epitope spreading and its regulation by co-stimulatory molecules. In: Immunological Reviews. 1998 ; Vol. 164. pp. 63-72.
@article{3fc8960bc83d48ab9c179821470c3428,
title = "The functional significance of epitope spreading and its regulation by co-stimulatory molecules",
abstract = "Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.",
author = "Vanderlugt, {Carol L.} and Begolka, {Wendy Smith} and Neville, {Katherine L.} and Yael Katz-Levy and Howard, {Laurence M.} and Eagar, {Todd N.} and Bluestone, {Jeffrey A.} and Miller, {Stephen D.}",
year = "1998",
month = "8",
doi = "10.1111/j.1600-065X.1998.tb01208.x",
language = "English (US)",
volume = "164",
pages = "63--72",
journal = "Immunological Reviews",
issn = "0105-2896",
publisher = "Wiley-Blackwell",

}

TY - JOUR

T1 - The functional significance of epitope spreading and its regulation by co-stimulatory molecules

AU - Vanderlugt, Carol L.

AU - Begolka, Wendy Smith

AU - Neville, Katherine L.

AU - Katz-Levy, Yael

AU - Howard, Laurence M.

AU - Eagar, Todd N.

AU - Bluestone, Jeffrey A.

AU - Miller, Stephen D.

PY - 1998/8

Y1 - 1998/8

N2 - Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.

AB - Epitope spreading is a process whereby epitopes distinct from and non-cross-reactive with an inducing epitope become major targets of an ongoing immune response. This phenomenon has been defined in experimental and natural situations as a consequence of acute or persistent infection and secondary to chronic tissue destruction that occurs during progressive autoimmune disease. We have investigated the functional significance of this process in the chronic stages of both autoimmune and virus-induced central nervous system (CNS) demyelinating disease models in the SJL/J mouse. During the relapsing-remitting course of experimental autoimmune encephalomyelitis (R-EAE) induced with defined encephalitogenic myelin peptides, CD4+ T cells specific for endogenous epitopes on both the initiating myelin protein (intramolecular epitope spreading) and distinct myelin proteins (intermolecular epitope spreading) are primed secondary to myelin destruction during acute disease and play a major functional role in mediating disease relapses. Similarly, epitope spreading to endogenous myelin epitopes appears to play a major functional role in the chronic-progressive course of Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD), a virus-induced CD4+ T-cell-mediated immunopathology. In TMEV-IDD, myelin destruction is initiated by virus-specific CD4+ T cells which target virus epitopes persisting in CNS-derived antigen-presenting cells. However, the chronic stage of this progressive disease is associated with the activation of CD4+ T cells specific for multiple myelin epitopes. In both models, the temporal course of T-cell activation occurs in a hierarchical order of epitope dominance, spreading first to the most immunodominant epitope and progressing to lesser immunodominant epitopes. In addition, epitope spreading in R-EAE is regulated predominantly by CD28/B7-1 co-stimulatory interactions, as antagonism of B7-1-mediated co-stimulation using anti-B7-1 F(ab) fragments is an effective ameliorative therapy for ongoing disease. The process of epitope spreading has obvious important implications for the design of antigen-specific therapies for the treatment of autoimmune disease since these therapies will have to identify and target endogenous self epitopes associated with chronic tissue destruction.

UR - http://www.scopus.com/inward/record.url?scp=17344363488&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=17344363488&partnerID=8YFLogxK

U2 - 10.1111/j.1600-065X.1998.tb01208.x

DO - 10.1111/j.1600-065X.1998.tb01208.x

M3 - Article

C2 - 9795764

AN - SCOPUS:17344363488

VL - 164

SP - 63

EP - 72

JO - Immunological Reviews

JF - Immunological Reviews

SN - 0105-2896

ER -