Differential abilities of central nervous system resident endothelial cells and astrocytes to serve as inducible antigen-presenting cells

Abstract

IntroductionThe brain has been considered an immune-privileged site in the presence of an intact blood-brain barrier (BBB). The BBB consists of tight junctions between cerebrovascular endothelial cells (CVEs), and it serves as a physical barrier limiting T-cell and antibody passage into the central nervous system (CNS). 1 Few unactivated T cells are capable of extravasating through the BBB, regardless of their antigen specificity, but low numbers of T cells can be found in the CNS of healthy humans and rats, so there appears to be a role for T-cell surveillance of the CNS in the absence of inflammation. Under these conditions, the low expression of major histocompatibility complex (MHC) class II and T-cell costimulation/adhesion molecules on CNS-resident cells renders the CNS an unsuitable site for T-cell priming. However, during an inflammatory immune response, the BBB is disrupted and all T cells and mononuclear cells have the ability to traffic into the brain and spinal cord and to recognize target antigens within the CNS. [2][3][4] Under these conditions, potential antigen-presenting cells (APCs) residing in the CNS are likely to play a major role in T-cell responses and may contribute to the propagation or regulation of inflammatory immune responses in the CNS, as they do in multiple sclerosis (MS).The BBB is damaged by demyelinating diseases such as MS and its animal model, experimental autoimmune encephalomyelitis (EAE). MS and EAE are characterized by CNS infiltration of myelin protein-specific Th1 cells, pro-inflammatory cytokine production of interferon-␥ (IFN-␥) and tumor necrosis factor-␣ (TNF-␣), mononuclear cell accumulation, and destruction of myelin. 5,6 CNS-resident cells, particularly microglia, pericytes, astrocytes, and CVEs, have the potential to affect the immune response by serving as APCs in the target organ. To serve as an APC, a cell must be able to express the requisite molecules to deliver the 2 signals necessary to activate a T cell. 7 Signal 1 is the antigen-specific signal delivered by antigen in MHC class II binding to the T-cell receptor (TCR). Signal 2, the costimulatory signal, is potently delivered by the B7 family of molecules binding to CD28 on the surface of the T cell. 8 Other costimulatory/adhesion molecules (ie, CD40, CD152, CD106) can deliver or enhance signal 2. 9-11 Professional APCs, such as B lymphocytes, macrophages, and dendritic cells, have been reported to constitutively express MHC class II and B7-1/2. Nonprofessional APCs must up-regulate MHC class II and B7 family members in response to an inflammatory stimulus. The class II transactivator (CIITA), which is absent in the human disease bare-lymphocyte syndrome, 12 has been found to be essential for the inducible and constitutive expression of MHC class II, 13,14 and it is the master switch for MHC class II expression. Moreover, the CIITA has a significant effect on the expression of other proteins associated with class II antigen processing and presentation, including H-2M and invariant chain (Ii). 15 CIITA pr...

Microarray analysis of IFN-γ response genes in astrocytes

“…This is partly due to discrepancies from both in vitro and in vivo studies about the ability of astrocytes to express the accessory molecules, CD80 and CD86 (B7.1 and B7.2 respectively in mice). Some in vitro studies in mice for example, have found that IFN-γ stimulated astrocytes expressed both B7.1 and B7.2 while other studies found IFN-γ stimulated astrocytes expressed neither B7.1 or B7.2 (Aloisi et al, 1998;Girvin et al, 2002;Nikcevich et al, 1997;Soos et al, 1998). Likewise some in vivo studies have found IFN-γ induces B7.2 expression on astrocytes while others found expression of neither B7.1 nor B7.2 on astrocytes (Issazadeh et al, 1998;Cross and Ku, 2000).…”

Infection with Theiler's Murine Encephalomyelitis Virus Directly Induces Proinflammatory Cytokines in Primary Astrocytes via NF-κB Activation: Potential Role for the Initiation of Demyelinating Disease

“…In addition, the different immune components specific for TMEV have been extensively studied in order to understand the pathogenic mechanisms involved in this apparently immunemediated demyelinating disease (21). We and others have shown the ability of astrocytes to process and present viral antigens resulting in Fas-mediated lysis thereby compromising the BBB (12,39). Many previous studies have also demonstrated the predominant expression of proinflammatory cytokines (IL-12, IL-1, IFN-␥, TNF-␣, and IL-6) in the CNS of TMEV-infected animals both at the early (prior to T-cell infiltration) and late (clinical) stages of disease (5,6,21,44,49).…”

B7-1 Costimulatory Molecule Is Critical for the Development of Experimental Autoimmune Myasthenia Gravis

“…B7-1 and B7-2 molecules have been shown to have different expression kinetics (31,33,34). B7-2 seemed to be the dominant B7 molecule in the early stages of immunological response, whereas B7-1 had a more significant role in the continuation and preservation of the T cell response to immunogens (35). Accordingly, administration of anti-B7-2 Ab prevented experimental diabetes only when they were given in the earlier stages of autoimmune disease (32).…”

“…Accordingly, administration of anti-B7-2 Ab prevented experimental diabetes only when they were given in the earlier stages of autoimmune disease (32). Moreover B7-1 production was not restricted to immunological cells, and various different tissues, including endothelial cells, expressed this molecule (35). Other than lymphocyte interactions, B7-1 expression might also play a role in tissue response (from Ag presentation with MHC molecules to inflammatory events) (35,36).…”