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The CD1 protein family present lipid antigens to the immune system. CD1d has been observed in the CNS of MS patients, yet no studies have quantitatively characterized this expression and related it to inflammatory demyelinative activity in MS plaques. In this study, we set out to localize and quantify the presence of CD1d expression by astrocytes in MS brain tissue lesions. Formalin‐fixed, paraffin‐embedded MS and control brain tissues were examined. Lesions were classified as active, chronic active or chronic silent. Using immunofluorescence, the density of CD1d‐positive cells was determined in active lesions, chronic active lesion edges and chronic active lesion centers. The percentage of CD1d‐positive cells that were GFAP‐positive was also determined in each of these regions. CD1d immunoreactivity was significantly increased in MS compared to control tissue, was significantly more prevalent in areas of active demyelination, and colocalized with GFAP‐positive reactive astrocytes. Increases of CD1d immunoreactivity in the CNS of MS patients being greatest in areas of active demyelination and localized to GFAP‐positive astrocytes lend support to the hypothesis of a lipid‐targeted autoimmune process contributing to the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Mucosal tolerance to E-selectin prevents stroke and protects against ischemic brain damage in experimental models of stroke studying healthy animals or spontaneously hypertensive stroke-prone rats. A reduction in inflammation and neural damage was associated with immunomodulatory or "tolerogenic" responses to E-selectin. The purpose of the current study on ApoE deficient mice is to assess the capacity of this stroke prevention innovation to influence atherosclerosis, a major underlying cause for ischemic strokes; human E-selectin is being translated as a potential clinical prevention strategy for secondary stroke. Female ApoE-/- mice received intranasal delivery of E-selectin prior to (pre-tolerization) or simultaneously with initiation of a high-fat diet. After 7 weeks on the high-fat diet, lipid lesions in the aorta, serum triglycerides, and total cholesterol were assessed as markers of atherosclerosis development. We also assessed E-selectinspecific antibodies and cytokine responses, in addition to inflammatory responses that included macrophage infiltration of the aorta and altered gene expression profiles of aortic mRNA. Intranasal delivery of E-selectin prior to initiation of high-fat chow decreased atherosclerosis, serum total cholesterol, and expression of the leucocyte chemoattractant CCL21 that is typically upregulated in atherosclerotic lesions of ApoE-/- mice. This response was associated with the induction of Eselectin specific cells producing the immunomodulatory cytokine IL-10 and immunosuppressive antibody isotypes. Intranasal administration of E-selectin generates E-selectin specific immune responses that are immunosuppressive in nature and can ameliorate atherosclerosis, a major risk factor for ischemic stroke. These results provide additional preclinical support for the potential of induction of mucosal tolerance to E-selectin to prevent stroke. [ABSTRACT FROM AUTHOR]

Multiple sclerosis is mediated by T-cell responses to central nervous system antigens such as myelin basic protein (MBP). To investigate self-peptide/major histocompatibility complex (MHC) recognition and T-cell receptor (TCR) degeneracy, we determined the crystal structure, at 2.8 Å resolution, of an autoimmune TCR (3A6) bound to an MBP self-peptide and the multiple sclerosis-associated MHC class II molecule, human leukocyte antigen (HLA)-DR2a. The complex reveals that 3A6 primarily recognizes the N-terminal portion of MBP, in contrast with antimicrobial and alloreactive TCRs, which focus on the peptide center. Moreover, this binding mode, which may be frequent among autoimmune TCRs, is compatible with a wide range of orientation angles of TCR to peptide/MHC. The interface is characterized by a scarcity of hydrogen bonds between TCR and peptide, and TCR-induced conformational changes in MBP/HLA-DR2a, which likely explain the low observed affinity. Degeneracy of 3A6, manifested by recognition of superagonist peptides bearing substitutions at nearly all TCR-contacting positions, results from the few specific interactions between 3A6 and MBP, allowing optimization of interface complementarity through variations in the peptide. [ABSTRACT FROM AUTHOR]

Limited success with antigen-specific immunotherapies has led to the identification of novel approaches which consider the degeneracy of the T cell response, i.e. their ability to respond to multiple antigenic peptides. Random complex mixtures of polypeptides such as glatiramer acetate (GA) were among the first to be applied as immunodulators that take into account T cell degeneracy. While the mechanisms of action are not completely understood, the immunogenicity of GA, its strong major histocompatability complex (MHC) binding, immune deviation and bystander suppression all appear to be important. In the present study we have designed peptidic complex mixtures (CM) of varied lengths and compositions to test their potential as immunomodulating agents. CM were synthesized that had defined lengths and contained aa corresponding to binding motifs of MHC class II molecules relevant in multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE), specifically HLA-DRB1*1501 and HLA-DRB5*0101, which are related to MS, and H2-IAs associated with EAE in SJL mice. Additional CM were designed based on specificity profiles derived from positional scanning synthetic combinatorial library (PS-SCL) testing of a GA-specific T cell clone (TCC). Several mixtures were strongly stimulatory for peripheral blood mononuclear cells (PBMC) from MS patients and healthy donors suggesting a high degree of cross-reactivity with other peptide antigens. A subset of these mixtures exhibited cross-reactivity to myelin antigens and prophylactic efficacy in reducing the severity of EAE. Based on these observations we envision mixture-based peptidic compounds can be developed not only for immunotherapeutic purposes in autoimmune diseases and cancer, but also in vaccine development. [Copyright &y& Elsevier]