Immune Surveillance of the Brain in Health and Disease

Charles A. Janeway, Jr.

Yale University School of Medicine

Funded in December, 2001: $300000 for 7 years
LAY SUMMARY . ABSTRACT . SELECTED PUBLICATIONS .

ABSTRACT

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Immune Surveillance of the Brain in Health and Disease

Our goal in the proposed studies is to analyze the effect of immune surveillance on the central nervous system (CNS), particularly the blood-cerebrospinal fluid (CSF) and blood brain endothelial barriers, during health and inflammatory disease. We hypothesize that immune surveillance of the CNS occurs predominantly through the blood-CSF barrier, rather than the blood brain endothelial barrier (BBB) and that aberrant homing of T lymphocytes through the BBB in the absence of infection or injury can initiate autoimmune, inflammatory CNS disease. We also postulate that the choroid plexus is the gating mechanism that regulates a steady state number of lymphocytes in the brain.

These issues are addressed in three Specific Aims:

1. Characterize the choroid plexus as a brain-associated lymphoid organ in immune deficient (RAG-/-) and immune competent mice.

2. Determine the homing kinetics and cellular phenotype of host-derived immune cells during bacterial (s. pneumococcus) and viral (lymphocytic choriomeningitis virus) meningitis and following the initiation of experimental autoimmune encephalomyelitis (EAE) in mice that are immune deficient (RAG-/- and irradiated) and those that are not.

3. Compare the molecular changes in the brain microenvironment during experimental meningitis and in EAE.

Our experimental approach is to combine traditional histologic methods such as immuno-histochemistry and electron microscopy with in vivo tracking of immune cells with enhanced green fluorescent protein (EGFP) and modern molecular pathologic approaches such as laser capture microdissection (LCM). We expect that the choroid plexus of immune deficient mice functionally changes to permit enhanced migration of T lymphocytes in order to maintain a steady state number of immune cells. In our animal models of meningitis and multiple sclerosis (EAE), we expect that homing of immune cells is directed predominantly to the meningeal space in LCMV and s. pneumococcus infected mice, as well as in immune competent mice that receive myelin basic protein (MBP) specific CD4 T lymphocytes. In contrast, immune deficient mice that receive MBP-specific cells will develop signs of EAE. One long term goal of these studies is to demonstrate that surveillant lymphocytes in both health and disease can functionally alter the brain. Another goal is to develop therapies that can treat brain autoimmune diseases such as multiple sclerosis but still permit normal surveillance.

SELECTED PUBLICATIONS

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Chatterjee G., Carrithers L.M., and Carrithers M.D.  Epithelial V-like antigen regulates permeability of the blood-CSF barrier.  Biochem Biophys Res Commun. 2008 Aug 1;372(3):412-7.

Carrithers M.D., Carrithers L.M., Czyzyk J., and Henegariu O.   Characterization of a severe parenchymal phenotype of experimental autoimmune encephalomyelitis in (C57BL6xB10.PL)F1 mice.  J Neuroimmunol. 2007 Jul;187(1-2):31-43.

Black J.A., Liu S., Carrithers M., Carrithers L., and Waxman S.G.  Exacerbation of experimental autoimmune encephalomyelitis after withdrawal of phenytoin. Ann Neurol. 2007 Jul;62(1):21-33.

Carrithers M.D., Dib-Hajj S., Carrithers L.M., Tokmoulina G., Pypaert M., Jonas E.A., and Waxman S.G.  Expression of the voltage-gated sodium channel, NaV1.5, in the macrophage late endosome regulates endosomal acidification. J. Immunol. 2007 Jun 15;178, 7822-7832.

Carrithers M., Tandon S., Canosa S., Michaud M., Graesser D., and Madri J.A.  Enhanced susceptibility to endotoxic shock and impaired STAT3 signaling in CD31-deficient mice.  Am J Pathol. 2005 Jan;166(1):185-96.

Carrithers M.D., Visintin I., Viret C., Janeway C.S. Jr.  Role of genetic background on P selectin-dependent immune surveillance of the central nervous system.  J Neuroimmunol. 2002 Aug;129(1-2):51-7.