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Deletion of the G2A receptor fails to attenuate experimental autoimmune encephalomyelitis.

Abstract
Lysophosphatidylcholine (LPC) is a chemotactic lysolipid produced during inflammation by the hydrolytic action of phospholipase A(2) enzymes. LPC stimulates chemotaxis of T cells in vitro through activation of the G protein-coupled receptor, G2A. This has led to the proposition that G2A contributes to the recruitment of T cells to sites of inflammation and thus promotes chronic inflammatory autoimmune diseases associated with the generation and subsequent tissue infiltration of auto-antigen-specific effector T cells. However, one study suggests that G2A may negatively regulate T cell proliferative responses to antigen receptor engagement and thereby attenuates autoimmunity by reducing the generation of autoreactive T cells. To address the relative contribution of these G2A-mediated effects to the pathophysiology of T cell-mediated autoimmune disease, we examined the impact of G2A inactivation on the onset and severity of murine experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). Wild type (G2A(+/+)) and G2A-deficient (G2A(-/-)) C57BL/6J mice exhibited a similar incidence and onset of disease following immunization with MOG(35-55) peptide. Disease severity was only moderately reduced in G2A(-/-) mice. Similar numbers of MOG(35-55) specific T cells were generated in secondary lymphoid organs of MOG(35-55)-immunized G2A(+/+) and G2A(-/-) mice. Comparable numbers of T cells were detected in spinal cords of G2A(+/+) and G2A(-/-) mice. We conclude that the proposed anti-proliferative and chemotactic functions of G2A are not manifested in vivo and therefore therapeutic targeting of G2A is unlikely to be beneficial in the treatment of MS.
AuthorsInga Osmers, Sherry S Smith, Brian W Parks, Shaohua Yu, Roshni Srivastava, Jillian E Wohler, Scott R Barnum, Janusz H S Kabarowski
JournalJournal of neuroimmunology (J Neuroimmunol) Vol. 207 Issue 1-2 Pg. 18-23 (Feb 15 2009) ISSN: 0165-5728 [Print] Netherlands
PMID19135725 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
Chemical References
  • Cell Cycle Proteins
  • G2A receptor
  • Glycoproteins
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • Receptors, G-Protein-Coupled
  • myelin oligodendrocyte glycoprotein (35-55)
  • Interferon-gamma
Topics
  • Animals
  • CD4-Positive T-Lymphocytes (immunology)
  • CD8-Positive T-Lymphocytes (immunology)
  • Cell Cycle Proteins (genetics, physiology)
  • Cell Proliferation (drug effects)
  • Encephalomyelitis, Autoimmune, Experimental (chemically induced, genetics, immunology)
  • Flow Cytometry (methods)
  • Gene Deletion
  • Glycoproteins (adverse effects)
  • Interferon-gamma (metabolism)
  • Lymph Nodes (drug effects, immunology, pathology)
  • Lymphocyte Activation (genetics, immunology)
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments (adverse effects)
  • Receptors, G-Protein-Coupled (deficiency, genetics, physiology)
  • Spleen (cytology, immunology, pathology)
  • T-Lymphocytes (immunology)
  • Time Factors

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