Neuropsychiatric (NP) lupus is a major contributor to the morbidity and mortality in SLE. Although the etiology of central nervous system (CMS) dysfunction in lupus is incompletely understood, recent work has shown that anti-double stranded DNA antibodies can induce brain injury in normal mice via cross-reactivity with N-methyl-D-aspartate (NMDA) receptors with neuronal injury. More recent evidence using a peptide-induced murine model of SLE indicates that entry of such autoantibodies into the CNS occurs upon breach of the blood-brain barrier (BBB). In preliminary studies, TLR activation caused opening of the BBB with enhanced immunoglobulin (Ig) deposition in the brain in the MRL mouse model of SLE. These findings suggest the hypothesis that BBB disruption is the likely mechanism for Ig entry into the brain in lupus, and that stimulation of Toll-like receptors (TLRs) initiates and/or promotes this disruption, leading to deposition of Ig and subsequent CNS injury. This hypothesis is supported by evidence that TLR engagement, including TLR9, and most likely TLRsS, 7 and/or 8, plays a critical role in disease initiation and/or disease propagation in lupus. The goal of this proposal is to explore the role of TLR activation in CNS lupus, and in particular key TLRs that are likely involved in disease genesis using MRL mice and MRL mice with genetic deficiencies in selected TLRs. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21NS052560-02
Application #
7140311
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Utz, Ursula
Project Start
2005-09-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2008-06-30
Support Year
2
Fiscal Year
2006
Total Cost
$183,707
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520