myelin-oligodendrocyte-glycoprotein-(35-55) and Brain-Injuries

Studies with multiple sclerosis patients and animal models of experimental autoimmune encephalomyelitis (EAE) implicate adenosine and adenosine receptors in modulation of neuroinflammation and brain injury. Although the involvement of the A(1) receptor has been recently demonstrated, the role of the adenosine A(2A) receptor (A(2A)R) in development of EAE pathology is largely unknown. Using mice with genetic inactivation of the A(2A) receptor, we provide direct evidence that loss of the A(2A)R exacerbates EAE pathology in mice. Compared with wild-type mice, A(2A)R knockout mice injected with myelin oligodendroglia glycoprotein peptide had a higher incidence of EAE and exhibited higher neurological deficit scores and greater decrease in body weight. A(2A)R knockout mice displayed increased inflammatory cell infiltration and enhanced microglial cell activation in cortex, brainstem, and spinal cord. In addition, demyelination and axonal damage in brainstem were exacerbated, levels of Th1 cytokines increased, and Th2 cytokines decreased. Collectively, these findings suggest that extracellular adenosine acting at A(2A)Rs triggers an important neuroprotective mechanism. Thus, the A(2A) receptor is a potential target for therapeutic approaches to multiple sclerosis.

Topics: Adenosine A1 Receptor Antagonists; Animals; Astrocytes; Axons; Brain Injuries; Cell Proliferation; Cells, Cultured; Cerebral Cortex; Cytokines; Demyelinating Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Enzyme-Linked Immunosorbent Assay; Female; Filtration; Flow Cytometry; Freund's Adjuvant; Gene Expression Regulation; Mice; Mice, Inbred C57BL; Mice, Knockout; Microglia; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Protein Binding; Receptor, Adenosine A2A; RNA, Messenger; Spinal Cord; Spleen; Statistics, Nonparametric; Tritium; Xanthines

In general, autoimmune responses are considered harmful to the host. In the best-defined model of autoimmune disease, murine experimental allergic encephalomyelitis (EAE), for example, brain-protein-specific autoimmune responses of both major classes, type-1 and type-2, have been implicated in causing brain pathology. We induced type-1 and type-2 autoimmunity to myelin oligodendrocyte protein (MOG) in C57.BL/6 mice. Instead of using pertussis toxin (PTX) to open the blood-brain barrier (BBB), which is the classic procedure, we set an aseptic cerebral injury (ACI) to see what the consequences of pre-primed, autoreactive type-1 and type-2 memory T cells gaining access to the brain in the course of sterile tissue injury would be. Neither of these autoimmune response types induced pathology; on the contrary, both accelerated re-vascularization and post-traumatic healing. The data suggest that induction of either type-1 or type-2 autoimmune responses is not inherently noxious to the host, but can have beneficial effects on tissue repair. Autoimmune pathology may develop only if molecules of microbial origin such as pertussis toxin additionally induce the "infectious nonself/danger" reaction in the antigen-presenting cells (APC) of the target organ itself.

Topics: Animals; Autoimmunity; Blood-Brain Barrier; Brain Injuries; CD4-Positive T-Lymphocytes; Encephalomyelitis, Autoimmune, Experimental; Female; Freund's Adjuvant; Glycoproteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myelin-Oligodendrocyte Glycoprotein; Peptide Fragments; Pertussis Toxin; Th1 Cells; Th2 Cells; Wound Healing