Project 2: Regulation of immune responses in the central nervous system Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (NS) that is thought to be mediated by an autoimmune tack directed against CNS myelin. Although the etiology and pathogenesis of MS is unknown, disease expression is considered to reflect a loss of tolerance for self-reactive lymphocytes. The pathways involved in regulation of immune responses remain rather poorly understood, but in MS may reflect an imbalance between pro- and anti- inflammatory activities. In the coming granting period we propose to dissect out the contribution of some of the regulatory pathways involved as they relate to CNS inflammation. Two major areas of research will be investigated. The first will address the potential contribution of altered chemokine receptor expression to the generation of a highly polarized immune response. We have identified two previously undocumented point mutations in the chemokine receptors CCR3 and CCR1b in the SJL mice. We will investigate how these mutations affect the functional properties of different subsets of leukocytes, alter susceptibility to experimental allergic encephalomyelitis (the animal model for MS), and determine whether similar mutations are present in patients with MS. The second area is directed at determining regulatory pathways involved in NF-kappaB activation that result in differential regulation of genes dependent upon NF-kappaB for transcription. In preliminary studies we have shown that signaling via purinergic receptors modulates NF-kappaB expression by specifically targeting activation of IkappaBbeta, proving us with a tool to dissect out potential mechanisms involved in the regulation of stimulus-specific and cell-type specific responses. The hypothesis to be tested is that the inflammatory response is regulated at many different levels, resulting in a response that shows factor-specific, cell-type specific, and species-specific regulatory events, even though common initiating pathways are activated. To test the hypothesis we propose: 1) to define the contribution of mutations in chemokine receptors to the establishment of an immune response that is biased towards a Th1 response. 2) to assess whether patients with MS demonstrate point mutations in these chemokine receptors and show altered migratory responses to specific ligands. 3) to determine the regulatory pathways involved in NF-kappaB activation that may lead to differential activation of specific components of the inflammatory cascade. 4) to investigate whether the functional activity of NF-kappaB is regulated by species-specific and/or the stimulus-specific signals. 5) to study MS plaques And animals with EAE for expressing of members of the NF-kappaB signaling cascade, and relate this expression to lesion activity. The overall objective of this proposal is to identify novel targets for specific therapies directed at inhibiting the induction and/or persistence of an inflammatory cascade within the CNS.
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