myelin-basic-protein and myelin-proteolipid-protein-(178-191)

Studies of MS histopathology are largely dependent on suitable animal models. While light microscopic analysis gives an overview of tissue pathology, it falls short in evaluating detailed changes in nerve fiber morphology. The ultrastructural data presented here and obtained from studies of myelin oligodendrocyte glycoprotein (MOG):35-55-induced experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice delineate that axonal damage and myelin pathology follow different kinetics in the disease course. While myelin pathology accumulated with disease progression, axonal damage coincided with the initial clinical disease symptoms and remained stable over time. This pattern applied both to irreversible axolysis and early axonal pathology. Notably, these histopathological patterns were reflected by the normal-appearing white matter (NAWM), suggesting that the NAWM is also in an active neurodegenerative state. The data underline the need for neuroprotection in MS and suggest the MOG model as a highly valuable tool for the assessment of different therapeutic strategies.

Topics: Animals; Axons; Encephalomyelitis, Autoimmune, Experimental; Female; Kinetics; Lumbar Vertebrae; Mice; Mice, Inbred C57BL; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteolipid Protein; Myelin Sheath; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Recombinant Fusion Proteins; Spinal Cord

In this study we demonstrate that experimental autoimmune encephalomyelitis (EAE) induced by the MBP-PLP fusion protein MP4, MOG peptide 35-55, or PLP peptide 178-191 in C57BL/6 mice, respectively, displays distinct features of CNS pathology. Major differences between the three models resided in (i) the region-/tract-specificity and disseminated nature of spinal cord degeneration, (ii) the extent and kinetics of demyelination, and (iii) the involvement of motoneurons in the disease. In contrast, axonal damage was present in all models and to a similar extent, proposing this feature as a possible morphological correlate for the comparable chronic clinical course of the disease induced by the three antigens. The data suggest that the antigen targeted in autoimmune encephalomyelitis is crucial to the induction of differential histopathological disease manifestations. The use of MP4-, MOG:35-55-, and PLP:178-191-induced EAE on the C57BL/6 background can be a valuable tool when it comes to reproducing and studying the structural-morphological diversity of multiple sclerosis.

Topics: Animals; Encephalomyelitis, Autoimmune, Experimental; Female; Mice; Mice, Inbred C57BL; Motor Neuron Disease; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Phenotype; Recombinant Fusion Proteins; Spinal Cord

T cell receptor engagement and the B7-CD28 / CTLA-4 signaling pathways play critical roles in T cell activation and regulation. CD28 engagement results in T cell activation, differentiation and survival while CTLA-4 signals block IL-2 production, cell cycle progression and T cell differentiation. We explored the role of CTLA-4 in peripheral tolerance induced by intravenous administration of ethylene carbodiimide-fixed, antigen-coupled splenocytes in the PLP139 - 151-induced relapsing experimental autoimmune encephalomyelitis system. Tolerance induction with PLP139 - 151-coupled splenocytes correlates with low B7 expression on the fixed antigen-presenting cells, conditions that would favor CTLA-4-mediated inhibition. Administration of CTLA-4Ig or anti-CTLA-4 concomitant with the 'tolerogenic' stimulus, however, failed to reverse tolerance induction. In contrast, blocking CTLA-4 at the time of secondary 'immunogenic' encounter with antigen reversed the tolerant state. These findings indicate that CTLA-4 is required to maintain the unresponsive state of the tolerized T cells upon antigenic stimulation under inflammatory conditions and, therefore, have important implications for therapeutic regulation of autoimmune disease.

Topics: Abatacept; Amino Acid Sequence; Animals; Antigens, CD; Antigens, Differentiation; Autoantigens; Autoimmune Diseases; B7-1 Antigen; B7-2 Antigen; Capsid; Capsid Proteins; Cells, Cultured; Clonal Anergy; CTLA-4 Antigen; Encephalomyelitis, Autoimmune, Experimental; Female; Hypersensitivity, Delayed; Immune Tolerance; Immunization; Immunoconjugates; Inflammation; Lymphocyte Activation; Membrane Glycoproteins; Mice; Mice, Mutant Strains; Molecular Sequence Data; Myelin Basic Protein; Myelin Proteolipid Protein; Ovalbumin; Peptide Fragments; Receptors, Antigen, T-Cell; Specific Pathogen-Free Organisms; T-Lymphocyte Subsets; Thymectomy

The synthetic amino acid copolymer, copolymer 1 (Cop 1) induces T suppressor (Ts) lines/clones, which are confined to the Th2 pathway, cross react with myelin basic protein (MBP), but not with other myelin antigens on the level of Th2 cytokine secretion. Nevertheless, Cop 1 Ts cells inhibited the IL-2 response of a proteolipid protein (PLP) specific line. Furthermore, Cop 1 Ts cells ameliorated EAE induced by two unrelated encephalitogenic epitopes of PLP: p139-151 and p178-191, that produced different forms of disease. This bystander suppression demonstrated by the Cop 1 Ts cells may explain the therapeutic effect of Cop 1 in EAE and MS.

Topics: Animals; Clone Cells; Cross Reactions; Cytokines; Encephalomyelitis, Autoimmune, Experimental; Epitopes; Female; Glatiramer Acetate; Immunosuppressive Agents; Mice; Mice, Inbred BALB C; Multiple Sclerosis; Myelin Basic Protein; Myelin Proteolipid Protein; Peptide Fragments; Peptides; Th2 Cells

The role of epitope spreading in the pathology of relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE) was examined. Using peripherally induced immunologic tolerance as a probe to analyze the neuropathologic T cell repertoire, we show that the majority of the immunopathologic reactivity during the acute phase of R-EAE in SJL/J mice induced by active immunization with the intact proteolipid (PLP) molecule is directed at the PLP139-151 epitope and that responses to secondary encephalitogenic PLP epitopes may contribute to the later relapsing phases of disease. Intermolecular epitope spreading was demonstrated by showing the development of T cell responses to PLP139-151 after acute disease in mice in which R-EAE was initiated by the transfer of T cells specific for the non-cross-reactive MBP84-104 determinant. Intramolecular epitope spreading was demonstrated by showing that endogenous host T cells specific for a secondary encephalitogenic PLP epitope (PLP178-191) are demonstrable by both splenic T cell proliferative and in vivo delayed-type hypersensitivity responses in mice in which acute central nervous system damage was initiated by T cells reactive with the immunodominant, non-cross-reactive PLP139-151 sequence. The PLP178-191-specific responses are activated as a result of and correlate with the degree of acute tissue damage, since they do not develop in mice tolerized to the initiating epitope before expression of acute disease. Most importantly, we show that the PLP178-191-specific responses are capable of mediating R-EAE upon adoptive secondary transfer to naive recipient mice. Furthermore, induction of tolerance to intact PLP (which inhibits responses to both the initiating PLP139-151 epitope and to the PLP178-191 epitope) after the acute disease episode is sufficient to prevent relapsing disease. These results strongly support a contributory role of T cell responses to epitopes released as a result of acute tissue damage to the immunopathogenesis of relapsing clinical episodes and have important implications for the design of antigen-specific immunotherapies for the treatment of chronic autoimmune disorders in humans.

Topics: Acute Disease; Amino Acid Sequence; Animals; Autoimmune Diseases; Cross Reactions; Desensitization, Immunologic; Encephalomyelitis, Autoimmune, Experimental; Female; Immunodominant Epitopes; Immunotherapy, Adoptive; Lymphocyte Activation; Mice; Mice, Inbred Strains; Molecular Sequence Data; Myelin Basic Protein; Myelin Proteins; Myelin Proteolipid Protein; Peptide Fragments; Recurrence; Th1 Cells