Immunoregulation and immunogenetics of monophasic and relapsing experimental autoimmune encephalomyelitis with emphasis on cytokines

Experimental autoimmune encephalomyelitis (EAE) is a CD4+ T cell mediated autoimmune disease ofthe central nervous system (CNS) that resembles multiple sclerosis (MS). An MS-like histopathologyand disease course can be provoked by immunization of susceptible animals with inoculum containingCNS antigens. The pathogenesis of EAE involves (1) presentation of encephalitogenic antigens to Tcells, (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 otherimmunocompetent cells to the target organ CNS, (4) elicitation of neuroinflammation and in somemodels even demyelination. Different EAE models facilitate investigation of different pathogeneticaspects 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 spinalcord in complete Freund's adjuvant exhibit a monophasic EAE, with brief neurological deficits as aresult 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 delineatethe immunoregulatory factors responsible for self-limiting autoimmunity versus factors involved inchronic autoaggressive tissue destruction. Our hypothesis was that cytokines produced byimmunocompetent cells might be involved in shaping the outcome of immune responses and thusmight play a decisive role in autoimmunity. We investigated how cytokines in the peripheral lymphoidsystem and in the CNS can influence the type of autoimmune attack and clinical manifestations of thedisease.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 earlyand before onset of clinical signs of EAE, (ii) IFN-gamma, TNF-alpha and IL-lbeta peaked at height of clinicalsigns of EAE, (iii) TGF-beta appeared shortly before onset and during clinical recovery, IL-10 elevatedsignificantly during recovery phase. However, in SPR-EAE in the DA strain, the cytokine pattern wasdistinctly 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 wereelevated even during second and third attacks, (ii) TGF-beta, IL-10 and IL-4 were undetectable orpresent in minute levels. Our results suggest (1) a disease-promoting role for proinflammatorycytokines (IL-12, TNF-beta, IL-lbeta, IFN-gamma, TNF-alpha and cytolysin), in initiation and effector phases ofautoaggressive neuroinflammation in both strains, (2) a disease-limiting role for TGF-beta and IL-10 inM-EAE, which implicates that these immunodownmodulatory cytokines are associated with diseaserecovery in monophasic EAE in LEW rats, (3) the MS-like protracted and relapsing EAE in DA rats isassociated with a genetically determined prolonged production of proinflammatory cytokines and/orabsence of immunodownmodulatory cytokines. Thus, the balance in cytokine profile might be crucialfor determining if an autoimmune reaction will be noxious.We were further interested in investigating how MHC genes influence susceptibility to MBP-peptideinduced EAE by affecting polarization of T cells, cytokine production and thus the quality of immuneresponse. 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. Ourobservations 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 IIcontrol of EAE-permissiveness is associated with induction of Thl type immune responsesindicated by IFN-gamma production, (4) Both MHC class I and class II exert protective influences onEAE development by production of MHC class I dependent TGF-beta and MHC class II dependent IL-4and IL-10, (5) the protective influence of MHC class I and class II is peptide-specific and isdependent on recognition of certain combinations of MHC-MBP peptide. ISBN 91-628-2002-