Sclerosis-Associated HLA-DRB1*1501 and Predicted Epitope(s) for Multiple Encephalitogenic Epitope(s) for SJL/J Mice Encompasses the Immunodominant Major 36 - Basic Protein Region MOBP15 The Myelin-Associated Oligodendrocytic

Autoimmune response to the myelin-associated oligodendrocytic basic protein (MOBP), a CNS-specific myelin constituent, was recently suggested to play a role in the pathogenesis of multiple sclerosis (MS). The pathogenic autoimmune response to MOBP and the associated pathology in the CNS have not yet been fully investigated. In this study, we have characterized the clinical manifestations, pathology, T cell epitope-specificity, and TCRs associated with experimental autoimmune encephalomyelitis (EAE) induced in SJL/J mice with recombinant mouse MOBP (long isoform, 170 aa). Analysis of encephalitogenic MOBP-reactive T cells for reactivity to overlapping MOBP peptides defined MOBP15–36 as their major immunodominant epitope. Accordingly, MOBP15–36 was demonstrated to be the major encephalitogenic MOBP epitope for SJL/J mice, inducing severe/chronic clinical EAE associated with intense perivascular and parenchymal infiltrations, widespread demyelination, axonal loss, and remarkable optic neuritis. Molecular modeling of the interaction of I-A s with MOBP15–36, together with analysis of the MOBP15–36-specific T cell response to truncated peptides, suggests MOBP20–28 as the core sequence for I-A s -restricted recognition of the encephalitogenic region MOBP15–36. Although highly focused in their epitope specificity, the encephalitogenic MOBP-reactive T cells displayed a widespread usage of TCR V (cid:1) genes. These results would therefore favor epitope-directed, rather than TCR-targeted, approaches to therapy of MOBP-associated pathogenic autoimmunity. Localization by molecular modeling of a potential HLA-DRB1*1501-associated MOBP epitope within the encephalitogenic MOBP15–36 sequence suggests the potential relevance of T cell reactivity against MOBP15–36 to MS. The reactivity to MOBP15–36 detected in MS shown here and in another study further emphasizes the potential significance of this epitope for MS. The Journal of Immunology, 2004, 173: 1426–1435.

[1]  V. Tuohy.  Peptide determinants of myelin proteolipid protein (PLP) in autoimmune demyelinating disease: A review , 1994, Neurochemical Research.

[2]  V. Kuchroo,et al.  Minireview: Autoimmune responses to myelin proteolipid protein , 1994, Neurochemical Research.

[3]  N. Viner,et al.  Influence of a dominant cryptic epitope on autoimmune T cell tolerance , 2002, Nature Immunology.

[4]  T‐cell responses to oligodendrocyte‐specific protein in multiple sclerosis , 2001, Journal of neuroscience research.

[5]  O. Melnyk,et al.  Structural diversity of human class II histocompatibility molecules induced by peptide ligands , 2000, FEBS letters.

[6]  A. Meshorer,et al.  T-cells specific for soluble recombinant oligodendrocyte-specific protein induce severe clinical experimental autoimmune encephalomyelitis in H-2b and H-2s mice , 2000, Journal of Neuroimmunology.

[7]  Roland Martin,et al.  Myelin-Associated Oligodendrocytic Basic Protein: Identification of an Encephalitogenic Epitope and Association with Multiple Sclerosis1 , 2000, The Journal of Immunology.

[8]  J. Bronstein,et al.  Oligodendrocyte-specific protein peptides induce experimental autoimmune encephalomyelitis in SJL/J mice. , 1999, Journal of immunology.

[9]  S. Sakoda,et al.  Myelin‐associated oligodendrocytic basic protein is essential for normal arrangement of the radial component in central nervous system myelin , 1999, The European journal of neuroscience.

[10]  P. Goodfellow,et al.  Inheritance of susceptibility to multiple sclerosis. , 1998, Current opinion in immunology.

[11]  Salmi,et al.  Encephalitogenicity of myelin‐associated oligodendrocytic basic protein and 2′,3′‐cyclic nucleotide 3′‐phosphodiesterase for BALB/c and SJL mice , 1998, Immunology.

[12]  A. Rudensky,et al.  Subtle conformational changes induced in major histocompatibility complex class II molecules by binding peptides. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[13]  M. Eisenstein,et al.  The peptide-binding strategy of the MHC class II I-A molecules. , 1998, Immunology today.

[14]  W A Hendrickson,et al.  Crystal structure of I-Ak in complex with a dominant epitope of lysozyme. , 1998, Immunity.

[15]  P. A. Peterson,et al.  Crystal structures of two I-Ad-peptide complexes reveal that high affinity can be achieved without large anchor residues. , 1998, Immunity.

[16]  A. Ben-nun,et al.  Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: Reactivity to the extracellular domain of MOG is directed against three main regions , 1997, European journal of immunology.

[17]  M. Schwab,et al.  Developmental expression of the myelin gene MOBP in the rat nervous system , 1997, Journal of neurocytology.

[18]  A. Ben-nun,et al.  Delineation of the minimal encephalitogenic epitope within the immunodominant region of myelin oligodendrocyte glycoprotein: diverse Vβ gene usage by T cells recognizing the core epitope encephalitogenic for T cell receptor Vβb and T cell receptor Vβa H‐2b mice , 1996 .

[19]  A. Ben-nun,et al.  A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H‐2b mice: Fine specificity and T cell receptor Vβ expression of encephalitogenic T cells , 1995, European journal of immunology.

[20]  T. Johns,et al.  Myelin oligodendrocyte glycoprotein induces a demyelinating encephalomyelitis resembling multiple sclerosis. , 1995, Journal of immunology.

[21]  A. Ben-nun,et al.  Chronic relapsing experimental autoimmune encephalomyelitis with a delayed onset and an atypical clinical course, induced in PL/J mice by myelin oligodendrocyte glycoprotein (MOG)‐derived peptide: Preliminary analysis of MOG T cell epitopes , 1995, European journal of immunology.

[22]  V. Tuohy,et al.  Sequence 104–117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice , 1995, Journal of Neuroimmunology.

[23]  S. Sakoda,et al.  Cloning and expression of myelin-associated oligodendrocytic basic protein. A novel basic protein constituting the central nervous system myelin. , 1994, The Journal of biological chemistry.

[24]  M. Marrosu,et al.  Genetic susceptibility to multiple sclerosis , 1994, Annals of neurology.

[25]  O. Majdic,et al.  Identification of epitopes of myelin oligodendrocyte glycoprotein for the induction of experimental allergic encephalomyelitis in SJL and Biozzi AB/H mice. , 1994, Journal of immunology.

[26]  Jan Hillert,et al.  Human leukocyte antigen studies in multiple sclerosis , 1994, Annals of neurology.

[27]  R. Milo,et al.  Reactivity to myelin antigens in multiple sclerosis. Peripheral blood lymphocytes respond predominantly to myelin oligodendrocyte glycoprotein. , 1993, The Journal of clinical investigation.

[28]  P. A. Peterson,et al.  Crystal structures of two viral peptides in complex with murine MHC class I H-2Kb. , 1994, Science.

[29]  R. Germain,et al.  A role for peptide in determining MHC class II structure , 1991, Nature.

[30]  H. Weiner,et al.  T-cell recognition of an immuno-dominant myelin basic protein epitope in multiple sclerosis , 1990, Nature.

[31]  L. Steinman,et al.  The T lymphocyte in experimental allergic encephalomyelitis. , 1990, Annual review of immunology.

[32]  J. Sambrook,et al.  Molecular Cloning: A Laboratory Manual , 2001 .

[33]  A. Ben-nun,et al.  Detection of autoimmune cells proliferating to myelin basic protein and selection of T cell lines that mediate experimental autoimmune encephalomyelitis (EAE) in mice. , 1983, Journal of immunology.