Immunoregulation and immunogenetics of monophasic and relapsing experimental autoimmune encephalomyelitis with emphasis on cytokines
Author: Issazadeh, Shohreh
Date: 1996-05-21
Location: Barnklinikens föreläsningssal, Q3:01 Karolinska sjukhuset
Time: 09.00
Department: Inst för medicin, Solna / Dept of Medicine, Solna
Abstract
Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell mediated autoimmune disease of the central nervous system (CNS) that resembles multiple sclerosis (MS). An MS-like histopathology and disease course can be provoked by immunization of susceptible animals with inoculum containing CNS antigens. The pathogenesis of EAE involves (1) presentation of encephalitogenic antigens to T cells, (2) proliferation and polarization of T cells upon recognition of antigens in contexts of self-major histocompatibility molecules (MHC), (3) migration of activated T cells and other immunocompetent cells to the target organ CNS, (4) elicitation of neuroinflammation and in some models even demyelination.
Different EAE models facilitate investigation of different pathogenetic aspects of autoimmune neuroinflammation which may have relevance for its human counterpart. Some strains of rats, for instance Lewis rats upon active immunization with whole guinea pig spinal cord in complete Freund's adjuvant exhibit a monophasic EAE, with brief neurological deficits as a result of neuroinflammation with no or sparse demyelination. DA rats manifest a severe relapsing-remitting type of EAE (SPR-EAE) with extensive demyelination. The present study aimed to delineate the immunoregulatory factors responsible for self-limiting autoimmunity versus factors involved in chronic autoaggressive tissue destruction. Our hypothesis was that cytokines produced by immunocompetent cells might be involved in shaping the outcome of immune responses and thus might play a decisive role in autoimmunity. We investigated how cytokines in the peripheral lymphoid system and in the CNS can influence the type of autoimmune attack and clinical manifestations of the disease.
In acute monophasic EAE in Lewis rats, we identified an ordered appearance of putative disease-promoting and -limiting cytokines in the CNS; (i) IL-12, TNF-beta, IL-lbeta and cytolysin appeared early and before onset of clinical signs of EAE, (ii) IFN-gamma, TNF-alpha and IL-lbeta peaked at height of clinical signs of EAE, (iii) TGF-beta appeared shortly before onset and during clinical recovery, IL-10 elevated significantly during recovery phase. However, in SPR-EAE in the DA strain, the cytokine pattern was distinctly different from that of M-EAE in Lewis rats. We observed (i) IL- 12, TNF-beta, IL- 1beta, IFN-gamma, TNF-alpha and cytolysin before and during first attack. These cytokines were long-lasting and were elevated even during second and third attacks, (ii) TGF-beta, IL-10 and IL-4 were undetectable or present in minute levels.
Our results suggest (1) a disease-promoting role for proinflammatory cytokines (IL-12, TNF-beta, IL-lbeta, IFN-gamma, TNF-alpha and cytolysin), in initiation and effector phases of autoaggressive neuroinflammation in both strains, (2) a disease-limiting role for TGF-beta and IL-10 in M-EAE, which implicates that these immuno downmodulatory cytokines are associated with disease recovery in monophasic EAE in LEW rats, (3) the MS-like protracted and relapsing EAE in DA rats is associated with a genetically determined prolonged production of proinflammatory cytokines and/or absence of immuno downmodulatory cytokines. Thus, the balance in cytokine profile might be crucial for determining if an autoimmune reaction will be noxious. We were further interested in investigating how MHC genes influence susceptibility to MBP-peptide induced EAE by affecting polarization of T cells, cytokine production and thus the quality of immune response. We immunized Lewis congenics (Lewis background genome, different MHC haplotypes) and Lewis intra-MHC recombinants strains with MBP 63-88, 89-101 and 87-110 peptides.
Our observations revealed the following: (1) MHC-control of EAE is peptide-specific, (2) the MBP 87-110 peptide contains a major MHC associated encephalitogenic peptide in rat, (3) MHC class II control of EAE-permissiveness is associated with induction of Thl type immune responses indicated by IFN-gamma production, (4) Both MHC class I and class II exert protective influences on EAE development by production of MHC class I dependent TGF-beta and MHC class II dependent IL-4 and IL-10, (5) the protective influence of MHC class I and class II is peptide-specific and is dependent on recognition of certain combinations of MHC-MBP peptide.
Different EAE models facilitate investigation of different pathogenetic aspects of autoimmune neuroinflammation which may have relevance for its human counterpart. Some strains of rats, for instance Lewis rats upon active immunization with whole guinea pig spinal cord in complete Freund's adjuvant exhibit a monophasic EAE, with brief neurological deficits as a result of neuroinflammation with no or sparse demyelination. DA rats manifest a severe relapsing-remitting type of EAE (SPR-EAE) with extensive demyelination. The present study aimed to delineate the immunoregulatory factors responsible for self-limiting autoimmunity versus factors involved in chronic autoaggressive tissue destruction. Our hypothesis was that cytokines produced by immunocompetent cells might be involved in shaping the outcome of immune responses and thus might play a decisive role in autoimmunity. We investigated how cytokines in the peripheral lymphoid system and in the CNS can influence the type of autoimmune attack and clinical manifestations of the disease.
In acute monophasic EAE in Lewis rats, we identified an ordered appearance of putative disease-promoting and -limiting cytokines in the CNS; (i) IL-12, TNF-beta, IL-lbeta and cytolysin appeared early and before onset of clinical signs of EAE, (ii) IFN-gamma, TNF-alpha and IL-lbeta peaked at height of clinical signs of EAE, (iii) TGF-beta appeared shortly before onset and during clinical recovery, IL-10 elevated significantly during recovery phase. However, in SPR-EAE in the DA strain, the cytokine pattern was distinctly different from that of M-EAE in Lewis rats. We observed (i) IL- 12, TNF-beta, IL- 1beta, IFN-gamma, TNF-alpha and cytolysin before and during first attack. These cytokines were long-lasting and were elevated even during second and third attacks, (ii) TGF-beta, IL-10 and IL-4 were undetectable or present in minute levels.
Our results suggest (1) a disease-promoting role for proinflammatory cytokines (IL-12, TNF-beta, IL-lbeta, IFN-gamma, TNF-alpha and cytolysin), in initiation and effector phases of autoaggressive neuroinflammation in both strains, (2) a disease-limiting role for TGF-beta and IL-10 in M-EAE, which implicates that these immuno downmodulatory cytokines are associated with disease recovery in monophasic EAE in LEW rats, (3) the MS-like protracted and relapsing EAE in DA rats is associated with a genetically determined prolonged production of proinflammatory cytokines and/or absence of immuno downmodulatory cytokines. Thus, the balance in cytokine profile might be crucial for determining if an autoimmune reaction will be noxious. We were further interested in investigating how MHC genes influence susceptibility to MBP-peptide induced EAE by affecting polarization of T cells, cytokine production and thus the quality of immune response. We immunized Lewis congenics (Lewis background genome, different MHC haplotypes) and Lewis intra-MHC recombinants strains with MBP 63-88, 89-101 and 87-110 peptides.
Our observations revealed the following: (1) MHC-control of EAE is peptide-specific, (2) the MBP 87-110 peptide contains a major MHC associated encephalitogenic peptide in rat, (3) MHC class II control of EAE-permissiveness is associated with induction of Thl type immune responses indicated by IFN-gamma production, (4) Both MHC class I and class II exert protective influences on EAE development by production of MHC class I dependent TGF-beta and MHC class II dependent IL-4 and IL-10, (5) the protective influence of MHC class I and class II is peptide-specific and is dependent on recognition of certain combinations of MHC-MBP peptide.
Issue date: 1996-04-30
Publication year: 1996
ISBN: 91-628-2002-8
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