Immune Regulation of CNS Viral Recrudescence

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DESCRIPTION (provided by applicant): The major cell types responsible for maintaining humoral immunity are antibody secreting cells (ASC). Following peripheral infections, ASC preferentially migrate to bone marrow (BM), where they differentiate into long lived sessile plasma cells (PC) dedicated to immunoglobubulin (Ig) secretion. However, ASC are also drawn to inflammatory sites, where they can persist for prolonged periods similar to the BM. Intrathecal antibody (Ab) synthesis is well documented in humans during infections associated with neurological complications and the demyelinating disease multiple sclerosis (MS). Although antibody may contribute to pathology, local secretion within the central nervous system (CNS) may also be protective in controlling neurotropic viruses. However, B cell migration to the CNS, and local survival are poorly understood. The overall goal of this proposal is to identify factors mediating ASC homing, differentiation and maintenance in the CNS following acute encephalomyelitis induced by neurotropic coronavirus. We have shown that virus specific ASC (vASC) peak in the CNS after infectious virus is cleared and their retention at high frequencies prevents viral recrudescence. The Specific Aims are to 1) characterize differentiation and specificities of ASC within the CNS; 2) identify signals regulating preferential vASC migration into the CNS; 3) determine the relative role of CNS localized Ag versus chemokines in regulating ASC retention and 4) demonstrate that BAFF is the major survival factor for ASC within the CNS. Using a novel transgenic mouse, termed Blimpgfp/+, a combination of flow cytometry and ELISPOT techniques will characterize GFP+ ASC populations unique to the CNS and their potential to differentiate into sessile PC. The role of virus induced chemokines as major signals for CNS ASC recruitment into the CNS are assessed using partial bone marrow chimeras as well as chemokine inhibition. Immunization with a tracer Ag will monitor recruitment and retention of 'bystander' ASC to the CNS following viral infection. Understanding the regulation of humoral immunity associated with persistent CNS infection will reveal novel insights into intrathecal ASC survival during persistent infections of the human CNS, i.e. measles virus, rubella virus, JC virus, and HIV. Their protective role in a model of viral persistence associated with limited ongoing inflammation may distinguish them from detrimental events prevailing during chronic inflammatory autoimmune diseases.