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. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI047249-07A1
Application #
7266595
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Park, Eun-Chung
Project Start
2000-04-01
Project End
2011-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
7
Fiscal Year
2007
Total Cost
$386,250
Indirect Cost
Name
Cleveland Clinic Lerner
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
135781701
City
Cleveland
State
OH
Country
United States
Zip Code
44195
Phares, Timothy W; DiSano, Krista D; Stohlman, Stephen A et al. (2014) Progression from IgD+ IgM+ to isotype-switched B cells is site specific during coronavirus-induced encephalomyelitis. J Virol 88:8853-67
Phares, Timothy W; DiSano, Krista D; Hinton, David R et al. (2013) IL-21 optimizes T cell and humoral responses in the central nervous system during viral encephalitis. J Neuroimmunol 263:43-54
Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2013) Astrocyte-derived CXCL10 drives accumulation of antibody-secreting cells in the central nervous system during viral encephalomyelitis. J Virol 87:3382-92
Phares, Timothy W; Stohlman, Stephen A; Bergmann, Cornelia C (2013) Intrathecal humoral immunity to encephalitic RNA viruses. Viruses 5:732-52
Phares, Timothy W; Stohlman, Stephen A; Hwang, Mihyun et al. (2012) CD4 T cells promote CD8 T cell immunity at the priming and effector site during viral encephalitis. J Virol 86:2416-27
Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2012) Enhanced CD8 T-cell anti-viral function and clinical disease in B7-H1-deficient mice requires CD4 T cells during encephalomyelitis. J Neuroinflammation 9:269
Phares, Timothy W; Marques, Cristina P; Stohlman, Stephen A et al. (2011) Factors supporting intrathecal humoral responses following viral encephalomyelitis. J Virol 85:2589-98
Marques, Cristina P; Kapil, Parul; Hinton, David R et al. (2011) CXCR3-dependent plasma blast migration to the central nervous system during viral encephalomyelitis. J Virol 85:6136-47
Parra, Gabriel I; Bergmann, Cornelia C; Phares, Timothy W et al. (2010) Gamma interferon signaling in oligodendrocytes is critical for protection from neurotropic coronavirus infection. J Virol 84:3111-5
Phares, Timothy W; Stohlman, Stephen A; Hinton, David R et al. (2010) Enhanced antiviral T cell function in the absence of B7-H1 is insufficient to prevent persistence but exacerbates axonal bystander damage during viral encephalomyelitis. J Immunol 185:5607-18

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