Adaptive immune response to viral infections in the central nervous system

Abstract

Historically, the central nervous system (CNS) has been considered to be an immunologically privileged site within the body (Bailey et al., 2006; Galea et al. 2007; Engelhardt, 2008; Prendergast and Anderton, 2009). By definition, immunologically privileged sites, to include the brain, cornea, testis, and pregnant uterus, have a reduced/delayed ability to reject foreign tissue grafts compared to conventional sites within the body, such as skin (Streilein, 2003; Bailey et al., 2006; Carson et al., 2006; Mrass and Weninger, 2006; Kaplan and Niederkorn, 2007). In addition and conversely, tissue grafts prepared from immunologically privileged sites have increased survival, compared to tissue grafts prepared from conventional sites, when implanted at conventional sites (Streilein, 2003). The imune privilege of the CNS has been shown to be confined to the parenchyma, whereas the immune reactivity of the meninges and the ventricles, containing the choroid plexus, cerebrospinal fluid (CSF), and the circumventricular organs, is similar to conventionalsites (Carson et al., 2006; Engelhardt, 2006; Galea et al., 2007). This confinement of the imm une privilege to the parenchyma has also been demonstrated for experimental influenza virus infection in which confinement of the infection to the brain parenchyma did not result in efficient immune system priming whereas infection of the CSF elicited a virus-specific immune response comparable to that of intranasal infection (Stevenson et al. 1997). An important functional aspect of immune privilege is that damage due to the immune response and inflammation is limited within sensitive organs containing cell types that regenerate poorly, such as neurons within the brain (Mrass and Weninger, 2006; Galea et al.. 2007; Kaplan and Niederkorn, 2007).

Keywords: adaptive immune response; cellular immunity; central nervous system; humoral immunity; immune privilege; immunopathology; neurotropic viruses; viral clearance; viral infection; viral latency; viral persistence.

Fig. 10.1

The adaptive immune response. Antigen-presenting cells (APCs) present antigen bound to the major bistocompatibility complex (MHC) class II or class I molecules to activate naïve CD4 + or CD8 + T cells, respectively, through both recognition of the bound antigen by the T-cell receptor (TCR) and costimulation. Activated CD4+T cells proliferate and differentiate into either CD4+ T-helper2 (Th2) cells which promote proliferation and differentiation of CD8+ B cells, CD4+ T-helper1 (Th1) or T-helper 17 (Thl 7) cells, which promote proliferation and differentiation of CD8 + T cells, or CD4 +cytotoxic T lymphocytes (CTL), effector cells capable of lysing virus-infected cells. Activated CD8 + T cells proliferate and differentiate into CD8+ CTL, also capable of lysing virus-infected cells. Naïve B cells are activated following interaction of surface antibody with antigen. Activated B cells can function as APCs and can proliferate and differentiate into plasma cells following interaction with CD4+ Th2 cells. Individual plasma cells secrete antibody specific for the same individual viral antigen that was recognized by the naive B cell.

Fig. 10.2

A generalized timeline of the adaptive immune response to primary infection with a virus that is nonnally cleared from the host. Virus-specific COS+ cytotoxic T lymphocytes (CTL) appear within I week, peak at 2-3 weeks, and are undetectable by 3-6 weeks after infection. Antibodies of the immunoglobulin (lg) M class appear within 1 week and are undetectable by 3 months after infection, while antibodies of the lgG class appear around 2-4 weeks, peak at 3-6 months after infection, and thereafter slowJy wane. Populations of virus-specific CD4+ and CD8 + memory T cells persist for the lifetime of the host.

Fig. 10.3

Steps and factors involved in the movement of effector cells of the adaptive immune response from the periphery, across the blood-brain barrier, and into the parenchyma of the cenlral nervous system (CNS). Effector ce11s undergo tethe ring as a result of interactions between P-selectin glycoprotc in ligandI (PSGL-1) on effector cells and P-selectin on vascular endothelial cells which in tum causes the effector cells to rol l. Chemokine receptors on the romng effector ce lls bind to chemok ine ligands on the vascular endothelial cells , wh ich results in integrin ac ti vat ion on the su rface of effector cells. Leukocyte function-associated antigen-I (LFA-1 )/intercel lular adhesion molecule-I (lCAM-1) interactions and very late antigen-4 (VLA-4)/vascular cell adhesi on molecule-I (VCAM-1) interactions serve to firmly adhere act ivated T cells to the vascular endothelial cells. The cells now arrest, fhuten, and transrn igrate/diapedes across the endotheliu m and into the perivascular space. Chemokincs and mat rix metalloproteinases (MMPs) fu nct ion to help the effector cells to cross the basement membrane of the glia limitans, thus gaining entry to the CNS parenchyma.