Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Immunization of animals with myelin proteolipid protein (PLP) causes experimental autoimmune encephalomyelitis (EAE), a disease model that shares many features with human multiple sclerosis (MS). The SJL/J (H-2s) mouse is widely used in EAE studies because of its high disease susceptibility. Previous studies have shown that sequences 139-151 HCLGKWLGHPDKF and 178-191 NTWTTCQSIAFPSK represent distinct co-immunodominant encephalitogenic determinants of PLP for SJL/J mice. In the present study, we identify a third distinct PLP encephalitogenic peptide for SJL/J mice. Following immunization with PLP 104-117 KTTICGKGLSATVT, 10/14 SJL/J mice developed clinical and histological EAE with a mean time of onset of 38 days (18-65 days). T cell lines generated from SJL/J mice immunized with p104-117 were predominantly (> 90%) CD3+, CD4+, alpha beta TCR+, CD8dim, gamma delta TCRdim T cells and responded in an Ag-specific, I-A(s)-restricted manner to p104-117. Upon adoptive transfer of 16-40 x 10(6) T line cells, EAE was produced in naive SJL/J recipients 20-34 days after transfer. The delayed onset of both active and passive disease may be related to the non-immunodominant, cryptic nature of p104-117 in SJL/J mice. Lymph node cells from SJL/J mice immunized with either whole PLP or with pooled encephalitogenic PLP peptides responded to challenge with the immunodominant PLP determinants p139-151 and p178-191 but did not respond to p104-117. The existence of three distinct PLP encephalitogenic T cell determinants for SJL/J mice suggests that susceptibility to EAE and perhaps MS may be related to promiscuous T cell recognition of multiple myelin protein determinants.
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PMID:Sequence 104-117 of myelin proteolipid protein is a cryptic encephalitogenic T cell determinant for SJL/J mice. 753 82

In the present study we address the question of whether distinct self-determinants can target alternative autoimmune disease patterns in experimental autoimmune encephalomyelitis (EAE), an animal model widely used for studying multiple sclerosis. We have found that the clinical course of EAE can be determined by the target peptide selected for induction of disease. In SJL/J mice, actively induced and passively transferred EAE mediated by the immunodominant PLP determinants p139-151 and p178-191 consistently produced a rapid onset of severe clinical signs. In contrast, a delayed onset of both active and passive EAE is associated with the nondominant cryptic PLP determinant p104-117. The delayed disease induced with p104-117 is not associated with any unusual peptide feature, with bystander immunoregulation, with inept class II MHC binding, or with failure to induce T cell expression of CD44, VLA-4, or IL-2 receptor upon activation. However, delayed disease is associated with innate qualities of the T cell repertoire responding to the p104-117 determinant. T cell lines responding to the cryptic p104-117 show limited TCR-V beta utilization compared to the diverse repertoire responding to the dominant p139-151 determinant. The repertoire deletions are accompanied by low level production of pathogenic Th1 cytokines (IFN gamma; IL-2) and increased production of regulatory Th2 (IL-4) cytokine in activated p104-117 primed T cells. Thus, the delayed encephalitogenicity of p104-117 may be due to TCR-V beta deletions and activation defects in the responding T cell repertoire. The development of "slow disease" mediated by autoreactivity against hidden self-determinants may have important implications in the pathogenesis of both relapsing and chronic autoimmune demyelinating disease.
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PMID:Determinant-regulated onset of experimental autoimmune encephalomyelitis: distinct epitopes of myelin proteolipid protein mediate either acute or delayed disease in SJL/J mice. 882 78

SJL/J mice were infected with a recombinant vaccinia virus encoding myelin proteolipid protein (PLP) (VVplp). Antibody responses to whole PLP and to encephalitogenic peptides, p139-151, p178-191 or p104-117 were measured after vaccination and following challenge with these three PLP peptides. Competitive ELISAs showed that antibodies to p139-151 and p178-191 represented the majority of antibodies in the anti-PLP antibody response following VVplp vaccination, since the antibodies to intact PLP could be inhibited 56, 35 and 1%, respectively, by p139-151, p178-191 and p104-117. After peptide challenge, epitope specific anti-peptide antibodies were enhanced. These anti-peptide antibodies also reacted with the intact PLP molecule. Interestingly, the mean titer of anti-p139-151 antibody in p139-151 challenged mice was significantly higher than that observed for anti-p178-191 in p178-191 and for anti-p104-117 in p104-117 challenged mice. Following peptide challenge, the anti-PLP IgG response shifted from an IgG1 to an IgG2a and 2b phenotype. In these mice, both the clinical disease and histological pattern of experimental allergic encephalomyelitis (EAE) were enhanced. The enhancement was most pronounced in the pathologic scores in the p139-151 challenged group followed by p104-117 challenged mice. Thus, humoral immune responses to PLP encephalitogenic peptides can be generated with virus encoding a self central nervous system (CNS) protein.
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PMID:Enhancement of EAE and induction of autoantibodies to T-cell epitopes in mice infected with a recombinant vaccinia virus encoding myelin proteolipid protein. 914 40

Recent reports indicate that autoreactive T cells may produce neurotrophic factors capable of mediating repair and regeneration of damaged neurons. By using semiquantitative RT-PCR, we examined gene expression of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3), and the trkB BDNF receptor in autoreactive T cells from SWXJ mice immunized with the p104-117 encephalitogen of myelin proteolipid protein (PLP 104-117). We observed antigen-inducible expression of NGF and BDNF, but not NT-3 and trkB, in lymph node cells activated with PLP 104-117. To determine which leukocyte subpopulation expressed neurotrophins, CD4(+), CD8(+), B220(+), CD11b(+), and NK1.1(+) cells were purified from activated primary cultures, and their mRNAs were analyzed. Neurotrophin expression was also measured in CD3(+) T cells purified from mouse CNS during acute onset of experimental autoimmune encephalomyelitis as well as in resting and activated human T cells and B cells purified from peripheral blood of normal subjects. In all cases, we found that neurotrophin expression was confined exclusively to B cells (B220(+)) in both mouse and human. CD3(+), CD4(+), and CD8(+) T cells as well as NK1.1(+) cells and CD11b(+) monocytes and macrophages did not express any detectable BDNF, NGF, NT-3, or trkB under any conditions. Our data indicate that B cells rather than T cells are the predominant if not the only source of leukocyte-derived neurotrophins and as such may provide "protective autoimmunity" in repair and regeneration of the injured nervous system.
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PMID:Human and murine lymphocyte neurotrophin expression is confined to B cells. 1535 17