Identification of an embryonic isoform of myelin basic protein that is expressed widely in the mouse embryo.

Mathisen, Peter M.; Pease, S; Garvey, James E.; Hood, Leroy; Readhead, Carol

doi:10.1073/pnas.90.21.10125

Cited by 102 publications

(55 citation statements)

References 25 publications

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“…Furthermore, myelin Ags are expressed in peripheral lymphoid tissues and are most likely accessible to local APCs for presentation to peripheral T cells (7)(8)(9)(10)(11)(12). Paradoxically, recent studies suggest that these conditions might serve to inhibit, rather than promote, the development of autoimmune demyelinating disease.…”

Section: Discussionmentioning

confidence: 99%

“…This includes CD4 ϩ T cells specific for myelin Ags, the mediators of experimental autoimmune encephalomyelitis (EAE) 3 and presumably of multiple sclerosis (MS) (1)(2)(3)(4)(5)(6). Furthermore, candidate autoantigens, including isoforms of myelin basic protein and proteolipid protein (PLP), have been detected in secondary lymphoid tissues, where they might be accessible for processing and presentation by professional APCs (7)(8)(9)(10)(11)(12). Nonetheless, autoimmune diseases, including MS, are relatively rare.…”

Section: Activation Of Apcsmentioning

confidence: 99%

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Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Ichikawa

Williams

Segal

2002

The Journal of Immunology

131

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Some autoreactive T cells normally escape thymic selection and persist in the periphery. This is true of myelin-reactive CD4+ T cells, the effectors of experimental autoimmune encephalomyelitis (EAE) in laboratory animals and the presumed mediators of multiple sclerosis in humans. Nonetheless, most individuals do not succumb to autoimmune disease. There is growing evidence that while peripheral APCs stimulate immune responses against foreign Ags in the setting of tissue destruction and “danger,” they actually maintain tolerance against self Ags under steady state conditions. We hypothesized that tolerance against candidate autoantigens could be reversed by activation of APCs via CD40 or Toll-like receptor 9 signaling. Adult SJL mice injected i.p. with a peptide fragment of proteolipid protein (a candidate autoantigen in multiple sclerosis) emulsified in IFA fail to mount lymphoproliferative or cytokine responses and are protected from EAE upon subsequent challenge with the Ag combined with adjuvants. Here we report that tolerized proteolipid protein-specific lymph node cells regain the ability to divide, differentiate along a Th1 lineage, and transfer EAE when reactivated in the presence of agonistic Abs against CD40 or CpG oligonucleotides. The effects of both anti-CD40 and CpG oligonucleotides are dependent upon induction of IL-12. Our findings suggest two mechanisms to explain the well-documented association between infectious illnesses and flare-ups of multiple sclerosis. Microbial pathogens could 1) release molecules that bind Toll-like receptors, and/or 2) stimulate microbe-specific T cells to express CD40 ligand, thereby licensing APCs that bear both microbial and autoantigens to break tolerance.

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Section: Discussionmentioning

confidence: 99%

Section: Activation Of Apcsmentioning

confidence: 99%

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Ichikawa

Williams

Segal

2002

The Journal of Immunology

131

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“…At least five isoforms of MBP were identified with molecular weights ranging from 14 to 21 kDa. (57). Again, this is not likely the SHBG receptor, but it could be a component of it.…”

Section: ------------------------------------------------mentioning

confidence: 99%

Identification of sex hormone binding globulin-interacting proteins in the brain using phage display screening

Gnanasekar¹

2009

Int J Mol Med

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Abstract. The present study reports the identification of human sex hormone binding globulin (SHBG)-interacting proteins in the brain using a phage display-based screening technology. Phage display is a system in which a foreign protein is displayed on the surface of a bacteriophage as a fusion protein with one of the coat proteins of the bacteriophage. T7 phage clones expressing normal human brain proteins (human normal brain phage-display cDNA expression library) were screened using SHBG as bait. The bound phage clones were then identified by DNA sequencing and by BLAST search analysis. Of the twenty binding proteins analyzed, three were found to be membrane-associated proteins: synaptosomal associated protein 25 (SNAP25), Thy-1 cell surface antigen and zonadhesin. Further studies will determine if the interactions of SHBG with these proteins have any role in the internalization and cell signaling events or whether they contribute to steroid delivery to specific cells.

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“…Our findings with T cell-DC clustering and naïve T-cell activation suggested that the shift in thymic selection of Tconv and Treg cells in the absence of CTLA-4 resulted from an altered affinity of TCRs using endogenous α-chains, because TCRs using the transgenic chain cannot change their affinity for the cognate peptide. It is important to note that MBP is expressed in the thymus, but because of its unstable binding to I-A u MHC II, MBP Ac1-9 expression does not lead to negative selection of all cells with specific TCRs (40)(41)(42). The main site of peptide recognition in the TCRα is the CDR3, created by the combination of TRAV and TRAJ gene segments.…”

Section: Ctla-4 Affects the Diversity And Sequence Of Endogenous Cdr3αmentioning

confidence: 99%

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

Verhagen

Genolet

Britton

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4; CD152) is of pivotal importance for self-tolerance, with deficiency or unfavorable polymorphisms leading to autoimmune disease. Tolerance to self-antigens is achieved through thymic deletion of highly autoreactive conventional T (Tconv) cells and generation of FoxP3 + regulatory T (Treg) cells. The main costimulatory molecule, CD28, augments the negative selection of Tconv cells and promotes the generation of FoxP3 + Treg cells. The role of its antagonistic homolog CTLA-4, however, remains a topic of debate. To address this topic, we investigated the thymic development of T cells in the presence and absence of CTLA-4 in a T-cell receptor (TCR) transgenic mouse model specific for the myelin basic protein peptide Ac1-9. We reveal that CTLA-4 is expressed in the corticomedullary region of the thymus. Its absence alters the response of CD4 + CD8 − thymocytes to self-antigen recognition, which affects the quantity of the Treg cells generated and broadens the repertoire of peripheral Tconv cells. T-cell repertoire alteration after deletion of CTLA-4 results from changes in TCR Vα and Jα segment selection as well as CDR3α composition in Tconv and Treg cells. CTLA-4, therefore, regulates the early development of self-reactive T cells in the thymus and plays a key role in central tolerance.costimulation | immune regulation | experimental autoimmune encephalomyelitis

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Identification of an embryonic isoform of myelin basic protein that is expressed widely in the mouse embryo.

Cited by 102 publications

References 25 publications

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Activation of APCs Through CD40 or Toll-Like Receptor 9 Overcomes Tolerance and Precipitates Autoimmune Disease

Identification of sex hormone binding globulin-interacting proteins in the brain using phage display screening

CTLA-4 controls the thymic development of both conventional and regulatory T cells through modulation of the TCR repertoire

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