NEUROVASCULAR MEDICINE - Pursuing Cellular Longevity for Healthy Aging Part 6 ppt

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PART III Elucidating Infl ammatory Mediators of Disease This page intentionally left blank 291 Chapter 12 NEUROIMMUNE INTERACTIONS THAT OPERATE IN THE DEVELOPMENT AND PROGRESSION OF INFLAMMATORY DEMYELINATING DISEASES: LESSONS FROM PATHOGENESIS OF MULTIPLE SCLEROSIS Enrico Fainardi and Massimiliano Castellazzi ABSTRACT Multiple sclerosis (MS) is considered an autoimmune chronic infl ammatory disease of the central nervous system (CNS) characterized by demyelination and axonal damage. It is widely accepted that MS immune response compartmentalized within the CNS is mediated by autoreactive major histocompatibility complex (MHC) class II–restricted CD4 + T cells traffi cking across the blood–brain barrier (BBB) after activation and secreting T helper 1 (Th1)-type pro-infl ammatory cytokines. These cells seem to regulate a combined attack of both innate and acquired immune responses directed against myelin proteins, which includes macrophages, MHC class I–restricted CD8 + T cells, B cells, natural killer (NK) cells, and γδ T cells. This coordinated assault is also directed toward neurons and results in axonal loss. However, although the understanding of the mechanisms that orchestrate the development and the progression of the disease has recently received increasing attention, the sequence of events leading to myelin and axonal injury currently remains uncertain. Failure of peripheral immunologic tolerance is hypothesized to play a crucial role in the initiation of MS, but evidence for a single triggering factor is lacking. In addition, the different theories proposed to explain this crucial step, suggesting the involvement of an infectious agent, a dysfunction of regulatory pathways in the periphery and a primary neurodegeneration, are diffi cult to reconcile. On the other hand, the view of MS as a “two-stage disease,” with a predominant infl ammatory demyelination in the early phase (relapsing–remitting MS form) and ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 292 a subsequent secondary neurodegeneration in the late phase (secondary or primary progressive MS) of the disease, is now challenged by the demonstration that axonal destruction may occur independently of infl ammation and may also produce it. Therefore, as CNS infl ammation and degeneration can coexist throughout the course of the disease, MS may be a “simultaneous two-component disease,” in which the combination of neuroinfl ammation and neurodegeneration promotes irreversible disability. Keywords: central nervous system, immune surveillance, infl ammation, tissue damage, multiple sclerosis. IMMUNE RESPONSES WITHIN THE CENTRAL NERVOUS SYSTEM T he central nervous system (CNS) has tra- ditionally been considered as an immunologically privileged site in which the immune surveillance is lacking and where the development of an immune response is more limited compared to other non-CNS organs. This view was based on the results obtained in earlier transplan- tation studies demonstrating that a relative tolerance to grafts is present in the brain (Medawar 1948; Barker, Billingham 1977). In addition, the immunologically privileged status of the CNS was further supported by the following complementary observa- tions (Ransohoff, Kivisäkk, Kidd 2003; Engelhardt, Ransohoff 2005; Bechmann 2005; Carson, Doose, Melchior et al. 2006): (a) the existence of a blood– brain barrier (BBB), a mechanical diffusion barrier for hydrophilic molecules, immune cells, and mediators, which is formed by specialized endothelial cells with tight junctions located at the level of brain capillar- ies and by the surrounding basement membrane and astroglial end-feet (glia limitans); (b) the absence of a lymphatic drainage of the brain parenchyma; (c) the lack of a constitutive expression of major histocompatibility complex (MHC) class I and class II antigens on neural cells; and (d) no occurrence of professional antigen-presenting cells (APCs) in the CNS. However, a growing body of evidence coming from experimen- tal and human investigations now suggests that this paradigm should be modi ed. CNS as an Immunologically Specialized Site As indicated in Table 12.1, the immune privilege of the CNS has recently been challenged by several  ndings showing that (a) rejection of tissue grafts (Mason, Charlton, Jones et al. 1986) and delayed type hypersensitivity reactions (Matyszak, Perry 1996a) can be observed in the CNS; (b) activated lymphocytes are able to enter the brain traf cking across the BBB in the nonin amed CNS (Hickey, Hsu, Kimura 1991); (c) brain antigens are ef ciently drained into cervical lymph nodes via the cribroid plate and perineural sheaths of cranial nerves (Cserr, Knopf 1992; Kida, Pantazis, Weller 1993); (d) CNS- associated cells acting as APCs are detectable in the Virchow-Robin perivascular spaces, the leptomeninges and the choroid plexus (Matyszak, Perry 1996b; McMenamin 1999); and (e) all brain cell types can express MHC class I and II molecules after activation in the in amed CNS (Hemmer, Cepok, Zhou et al. 2004). In particular, it has been documented that foreign tissue grafts are rejected when injected into the ventricular system, whereas bystander demyelination and axonal loss are triggered by a delayed type hypersensitivity response after intraventricular bac- terial injection (Galea, Bechmann, Perry 2007). In addition, migration of activated T cells from the intra- vascular compartment into the CNS can occur using different routes of entry (Ransohoff, Kivisäkk, Kidd 2003): (a) from blood to cerebrospinal  uid (CSF) across the choroid plexus; (b) from blood to subarachnoid space; and (c) from blood to parenchyma. In the  rst pathway, which is currently believed to be the main route by which T cells in ltrate the CNS under normal conditions, T cells penetrate fenes- trated endothelial cells and specialized epithelial cells with tight junctions of the choroid plexus stroma and then move into the CSF. In the second pathway, T cells extravasate through the postcapillary venules at the pial surface of the brain and then arrive in the subarachnoid and perivascular spaces. In the third pathway, T cells traverse the postcapillary venules, pass into the subarachnoid and perivascular spaces, cross Table 12.1 Data Supporting the View of the Central Nervous System (CNS) as Immunospecialized Site Evidence References Occurrence of tissue graft rejection and delayed type hypersensitivity responses in the CNS Mason et al. 1986 Matyszac, Perry 1996a Existence of a lymphocyte traf c into the brain across the blood–brain barrier (BBB) in the nonin amed normal CNS Hickey et al. 1991 Drainage of brain antigens into cervical lymph nodes through the CSF Cserr, Knopf 1992 Kida et al. 1993 Detection of CNS-associated cells acting as resident antigen- presenting cells (APC) in the Virchow-Robin perivascular spaces, the leptomeninges, and the choroid plexus Matyszac, Perry 1996b McMenamin 1999 Expression of MHC class I and II molecules on all brain cell types after activation in the in amed CNS Hemmer et al. 2004 Chapter 12: Neuroimmune Interactions in Demyelinating Diseases 293 responses, is of relevance. In fact, these cells could capture CSF soluble proteins coming from brain parenchyma and transport them to draining cervical lymph nodes. Furthermore, dendritic cells may present such antigens to naïve T cells at the level of local lymph nodes (Galea, Bechmann, Perry 2007). In normal brain, a constitutive expression of MHC antigens is present on endothelial cells, perivascular, meningeal, and choroid plexus macrophages, and some microglial cells for MHC class I molecules (Hoftberger, Aboul-Enein, Brueck et al. 2004). Conversely, MHC class II molecules result constitutively expressed only on perivascular, meningeal, and choroid plexus cells since their expression on resting microglia still remains a controversial issue (Becher, Prat, Antel 2000; Aloisi, Ria, Adorini 2000; Aloisi 2001; Hemmer, Cepok, Zhou et al. 2004; Becher, Beckmann, Greter 2006). During intrathecal in ammatory responses, microglial cells and astrocytes become MHC-I and MHC-II positive, whereas oligodendrocytes and neurons upregulate MHC class I molecules (Dong, Benveniste 2001; Aloisi 2001; Neumann, Medana, Bauer 2002). Notably, while CD4 + T cells recognize antigens bound to MHC class II molecules, CD8 + T cells respond to peptides associated to MHC class I molecules. Therefore, in in amed CNS, all brain cell types are theoretically susceptible to attack by CD8 + T cells, whereas only microglial cells and astrocytes react with CD4 + T cells (Hemmer, Cepok, Zhou et al. 2004). As given in Table 12.2, these data indicate that an immune reaction can take place in the CNS because both the afferent and the efferent arms of this response exist there (Harling-Berg, Park, Knopf the BBB, and then gain direct access to brain tissue. In this setting, it is important to note that, in absence of ongoing CNS in ammation only activated T cells travel into the brain since resting T lymphocytes fail to transit across the BBB. On the other hand, the subarachnoid and perivascular spaces of the nasal olfactory artery are connected, via the cribriform plate, with nasal lymphatics and cervical lymph nodes, thus allowing CSF drainage into the cervical lymphatics (Harling-Berg, Park, Knopf 1999; Aloisi, Ria, Adorini 2000; Ransohoff, Kivisäkk, Kidd 2003; Engelhardt, Ransohoff 2005; Galea, Bechmann, Perry 2007). In this way, after their migration in CSF from white matter through the ependyma and from grey matter along perivascular spaces, brain-soluble proteins can be transported to local peripheral lymph nodes where they can trigger priming and activation of naïve T lymphocytes. Nevertheless, these interactions require local APCs capable of express- ing speci c antigens associated to MHC molecules on cell surface after engulfment. Resident APCs of the CNS include a variety of myeloid-lineage cells such as perivascular cells (macrophages), meningeal macrophages and dendritic cells, intraventricular macrophages (epiplexus or Kolmer cells), and choroid plexus macrophages and dendritic cells (Aloisi, Ria, Adorini 2000; Ransohoff, Kivisäkk, Kidd 2003; Engelhardt, Ransohoff 2005). Moreover, also microglial cells acquire APC properties in the course of CNS in ammation (Aloisi, Ria, Adorini 2000; Carson, Doose, Melchior et al. 2006). In this regard, the presence of meningeal and choroid plexus dendritic cells, which are the most effective APCs for initiating T-cell Table 12.2 Afferent and Efferent Arms of Immune Responses of the Central Nervous System (CNS) Pathway Features References Afferent arm Migration of brain-soluble antigens from parenchyma to cerebrospinal  uid (CSF) through the ependyma for white matter and along perivascular spaces for grey matter Harling-Berg et al. 1999 Ransohoff et al. 2003 Engelhardt, Ransohoff 2005 Galea et al. 2007 Capture and transport of CSF brain-soluble antigens to draining cervical lymph nodes operated by meningeal and choroid plexus dendritic cells Efferent arm Presentation of brain soluble antigens released from the CNS to naive T cells performed by dendritic cells at the level of cervical lymph nodes Harling-Berg et al. 1999 Ransohoff et al. 2003 Engelhardt, Ransohoff 2005 Galea et al. 2007 Priming and activation of naive T cells in cervical lymph nodes Migration of activated T cells from blood to CSF across the choroid plexus Presentation of cognate antigen to activated T cells carried out by perivascular macrophages ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 294 where they interact with the corresponding local APCs. At this point, if perivascular cells do not present the cognate antigen to T lymphocytes, these activated immunocompetent cells do not progress across the glia limitans and recirculate into the blood stream or undergo apoptotic death. On the contrary, if T cells recognize the related antigen presented by perivascular macrophages, they cross the glia limitans, invade the CNS parenchyma, and promote the acti vation of microglial cells that release several soluble factors, leading to the development of an in ammatory response. In both these cases, the mechanisms of lymphocyte recruitment are largely unknown, although it has been hypothesized that the egress of T cells into the CSF is regulated by chemokines and adhesion molecules such as selectins (Rebenko-Moll, Liu, Cardona et al. 2006), whereas the migration of T cells into the brain could be due to proteolytic enzymatic activity of matrix metalloproteinases (MMPs) (Bechmann, Galea, Perry 2007). The occurrence of a CNS immune surveillance in the CSF of the subarachnoid spaces seems to be con rmed by the demonstration that, in patients with nonin ammatory neurological mani- festations, central memory CD4 + T lymphocytes traf cking into the CSF across choroid plexus and meninges (Kivisäkk, Mahad, Callahan et al. 2003) are present in identical amounts within ventricular and lumbar CSF (Provencio, Kivisäkk, Tucky et al. 2005). This concept is reinforced by the data coming from animal studies in which the induction of a monopha- sic brain in ammation in immunocompetent trans- genic mice after transfer of CD8 + T cells suggest the potential role of these lymphocytes in CNS immune surveillance (Cabarrocas, Bauer, Piaggio et al. 2003). The fact that not only T cells but also B cells can contribute to CNS immune surveillance since their entry into the CSF has been described (Uccelli, Aloisi, Pistoia 2005). The presence of immune mechanisms that provide a continuous monitoring of CNS micro- environment plays a fundamental role in protecting the brain. In fact, immune responses contribute to host defense against pathogens and preservation of tissue homeostasis since they aim to eliminate dangerous infectious agents invading the CNS, remove irreversible damaged cells and their products, and promote tissue repair (Becher, Prat, Antel 2000; Hickey 2001; Becher, Beckmann, Greter 2006). Moreover, immune reactions to foreign antigens are self-limited because, after the eradication of the antigens, the immune system returns to its basal resting state because of apoptotic deletion of activated T cells (Jiang, Chess 2006). However, when the antigen is dif cult to clear from the CNS or a self–brain protein is recognized as non-self, there is a persistent antigenic stimulation of the immune system that favors the development of a chronic intrathecal in ammatory response leading 1999; Ransohoff, Kivisäkk, Kidd 2003; Engelhardt, Ransohoff 2005; Galea, Bechmann, Perry 2007). The afferent limb is provided by the circulation of brain antigens from parenchyma to CSF where dendritic cells associated to meninges and choroid plexus provide for the transfer of these proteins to the cervical lymph nodes. Priming of immunocompetent cells in the peripheral lymphoid tissue due to the presentation of neural proteins released from the CNS by dendritic cells, the migration of activated immune cells into the CSF, and the presentation of cognate antigen operated by resident APCs constitute the efferent limb. Thus, it is reasonable to assume that the CNS could represent an immunospecialized site, rather than an organ with an immune privilege status, in which neural antigens are not segregated and the events related to immune surveillance can occur (Hickey 2001; Becher, Beckmann, Greter 2006). However, rejection of tissue grafts and delayed type hypersensitivity reactions do not arise when injection of the material is performed in the brain parenchyma (Mason, Charlton, Jones et al. 1986; Matyszak, Perry 1996a; Galea, Bechmann, Perry 2007). In addition, in normal CNS, activated T cells are retained in the CSF after entry because they do not traverse glia limitans (Becher, Beckmann, Greter 2006; Bechmann, Galea, Perry 2007) and the cellular route of the afferent arm of immune responses is lacking in the brain parenchyma since dendritic cells are con ned within the CSF (Galea, Bechmann, Perry 2007). Therefore, in absence of pathologic conditions, the interactions between the immune system and the CNS occur within the CSF, whereas brain parenchyma main- tains a relative immune privilege. For this reason, the immune specialization of the CNS should be assumed to be a dynamic process regulated by func- tional characteristics of the intrathecal compartment (Becher, Beckmann, Greter 2006; Galea, Bechmann, Perry 2007). Immune Surveillance in the CNS Under physiologic circumstances, it is widely accepted that immune surveillance is performed at the level of perivascular spaces (Becher, Prat, Antel 2000; Hickey 2001; Ransohoff, Kivisäkk, Kidd 2003; Engelhardt, Ransohoff 2005; Becher, Beckmann, Greter 2006; Bechmann, Galea, Perry 2007). In fact, the intrathecal compartment is constantly patrolled by T cells that have already been activated by the primary encounter with neural antigens in cervical lymph nodes. These cells penetrate the CSF across the choroid plexus and, to a lesser extent, the vessel wall of postcapillary venules located in Virchow-Robin spaces and then accumulate principally in the perivascular spaces Chapter 12: Neuroimmune Interactions in Demyelinating Diseases 295 by co-receptors that bind their matching ligands (signal 2). In absence of costimulation, T lymphocytes do not respond to antigen presentation and are either eliminated by apoptosis or enter a state of unre- sponsiveness called anergy. The co- stimulatory pathways include (a) CD4 and CD8 molecules expressed by T cells that bind MHC class I (CD8) and class II (CD4) molecules positioned on APCs; (b) CD40 ligand (CD40L) expressed by T cells that engages CD40 expressed by APCs; (c) CD28 molecule expressed by T cells that reacts with CD80 (B7–1) and CD86 (B7–2) on the surface of APCs; (d) leukocyte function– associated antigen 1 (LFA-1) expressed by T cells that interacts with intercellular adhesion molecule 1 (ICAM-1) expressed by APCs; (e) very late activation-4 (VLA-4) antigen expressed by T cells that binds vascular cell adhesion molecule 1 (VCAM-1) on APCs; and (f) CD2 molecule expressed by T cells that binds leukocyte function-associated antigen 3 (LFA-3) expressed by APCs. In particular, the engagement of T-cell co-receptor CD28 with its ligand CD80 (B7–1)/CD86 (B7–2) on APCs, stimu- lated by CD40L-CD40 interactions, induces the full activation of T lymphocytes that acquire effector functions. Therefore, in the course of CNS immune surveillance, two distinct phases can be identi-  ed (Bechmann, Galea, Perry 2007). The  rst step implies the migration of activated T cells from blood to perivascular spaces through choroid plexus and postcapillary vessels, which is not necessarily associated to pathological conditions involving the brain since it can occur when the appearance of a strong immune response in the body promotes the priming of T cells at the level of the secondary lymphoid organs (Hickey 2001). The second step is characterized by the penetration of activated T cells from perivascular spaces to brain parenchyma across the glia limitans, which is a restricted phenomenon because it depends on antigen presentation performed by perivascular cells. In fact, activated T cells are able to invade the CNS only when they re-encounter their cognate antigen in the context of appropriate MHC molecules associated to perivascular APCs. Conversely, activated T cells monitor the subarachnoid space and rapidly leave the CNS. Table 12.3 summa- rizes the mechanisms of CNS immune surveillance. Immune Sentinels of the CNS Given their ability to act as resident APCs for T cells in normal brain, perivascular cells can be viewed as sentinels at the gate of the CNS parenchyma (Becher, Beckmann, Greter 2006). Under in ammatory conditions, the same role can be imagined for the other CNS-associated cells, such as meningeal to tissue destruction. Thus, immune surveillance can exert not only bene cial but also detrimental effects (Becher, Prat, Antel 2000; Hickey 2001; Becher, Beckmann, Greter 2006). In this scenario, it becomes clear that the recognition of the cognate antigens on APCs by activated T cells in ltrating the perivascular spaces is the fundamental prerequisite for CNS immune surveillance (Becher, Beckmann, Greter 2006; Bechmann, Galea, Perry 2007). More precisely, as depicted in Figure 12.1, in the process of antigen presentation two types of signal are needed (Hart, Fabry 1995; Becher, Prat, Antel 2000). Initially, the T lymphocyte–associated T-cell receptor (TCR) speci c for a brain peptide can identify the related antigen only when it is presented in the context of MHC molecules expressed by perivascular APCs and in presence of associated molecules such as CD3 (signal 1). Subsequently, T cells and APCs express accessory molecules that provide co-stimulatory signals for T-cell activation and that are represented VCAM-1 VLA-4 B7 CD40 MHC-II CD3 TCR CD4 LFA-1ICAM-1 LFA-3 Ag CD40L CD28 CD2 VCAM-1 VLA-4 B7 CD40 MHC-I CD3 APC APC A B CD8 + CD4 + TCR CD8 LFA-1ICAM-1 LFA-3 Ag CD40L CD28 CD2 Figure 12.1 Signals implicated in antigen presentation: (A) recognition of the cognate antigen (Ag) by specifi c-T lymphocyte- associated T-cell receptor (TCR) after presentation in the context of major histocompatibility complex (MHC) molecules (class I for CD8 + T cells and class II for CD4 + T cells) expressed by perivascular antigen-presenting cells (APC) and in presence of associated molecules such as CD3; (B) co-stimulatory signals for T-cell activation provided by binding between accessory molecules expressed by T cells and APC. ICAM, intercellular adhesion molecule; LFA, leukocyte function–associated antigen; VCAM, vascular cell adhesion molecule. ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE 296 factors, and regulate neuronal functions by pro- viding metabolic support and uptake of neu- rotransmitters (Dong, Benveniste 2001). During in ammation, astroglia become MHC class I-positive and can express low levels of MHC class II and co-stim ulatory molecules (Becher, Prat, Antel 2000; Aloisi, Ria, Adorini 2000; Dong, Benveniste 2001; Hemmer, Cepok, Zhou et al. 2004; Becher, Beckmann, Greter 2006). Therefore, the effective involvement of these cells in intrathecal antigen presentation still remains uncertain and, at present, is believed to be restricted to CD4 + T helper with Th2 phenotype (Aloisi, Ria, Adorini 2000). On the other hand, the activation of microglia and astrocytes due to the presence of an in ammatory response within the brain is associated to increased cellular expression of pattern recognition receptors (PRPs) that can identify a broad spectrum of microbial proteins and pathogenic insults (Farina, Aloisi, Meinl 2007). Toll-like receptors (TLRs), dsRNA-dependent protein kinase (PKR), CD14, nucleotide-binding oligomeriza- tion domain (NOD) proteins, complement, mannose receptor (MR), and scavenger receptors (SRs) mediate an innate immune response that represents a trigger factor aimed at informing the immune system about brain tissue injury formation. Intriguingly, evidence for the constitutive expression of PRPs in meningeal, choroid plexus, and perivascular macrophages under normal circumstances indicate a potential role of these molecules as a  rst-line defense against dan- ger signals (Aloisi 2001; Farina, Aloisi, Meinl 2007). In addition, microglial cells and astroglia share with neurons and endothelial cells the ability to eliminate T cells invading the CNS through Fas (CD95)/Fas ligand (FasL or CD95L)-dependent apoptosis under both physiologic and pathologic circumstances. In fact, while the expression of FasL on these cells is constitutive in the normal brain and is enhanced in the in amed CNS, in ltrating T cells exhibit the receptor Fas on their surface (Bechmann, Mor, Nilsen et al 1999; Pender, Rist 2001; Choi, Benveniste 2004). The and choroid plexus macrophages and dendritic cells, which increase in number and exhibit APC properties in the in amed brain (Hickey 2001; Becher, Beckmann, Greter 2006). Considering their impor- tance in CNS immune surveillance, perivascular cells and other resident APCs are persistently repopu- lated by bone marrow– derived monocytes (Becher, Beckmann, Greter 2006). Although this peculiarity is absent in microglial cells and astrocytes, during intrathecal in ammation these cells may exert APC functions and can, therefore, be considered as sentinels within the CNS parenchyma (Aloisi, Ria, Adorini 2000; Dong, Benveniste 2001; Aloisi 2001; Becher, Beckmann, Greter 2006). Microglia is composed of cells of hematopoietic lineage that derive from mesodermal precursor cells and likely originate from monocytes entering the brain parenchyma from the blood compartment (Becher, Beckmann, Greter 2006). In the in amed CNS, there is an activation of microglial cells that upregulate MHC class I and class II molecules and co-stimulatory molecules at their cell surface and then acquire the ability to present antigen to previously primed CD8 + and CD4 + T lymphocytes. Therefore, like meningeal and choroid plexus dendritic cells and perivascular cells, microglial cells also are resident APCs. However, while dendritic cells are professional APCs that are able to initiate a primary immune response by the presentation of brain antigens to naïve T cells in the secondary lymphoid organs, perivascular and microglial cells are nonprofessional APCs that trigger a secondary immune reaction by the presentation of neural antigens to already activated T cells in the Virchow-Robin space and within the brain, respectively (Aloisi, Ria, Aloisi 2001; Adorini 2000; Becher, Prat, Antel 2000; Becher, Beckmann, Greter 2006). Astrocytes are cells of neuroectodermal origin, which are fundamental for brain homeostasis and neuronal function since they contribute to the induction and maintenance of BBB by their foot processes, induce scar formation and tissue repair by astrogliosis, produce neurotrophic Table 12.3 The Biphasic Nature of Immune Surveillance in the Central Nervous System (CNS) Phases Location Mechanisms References Migration of activated T cells from blood to perivascular spaces (step 1) Choroid plexus and postcapillary vessel wall Activation of T cells in the secondary lymphoid organs due to a strong immune response in the body Becher et al. 2000 Hickey 2001 Ransohoff et al. 2003 Engelhardt, Ransohoff 2005 Becher et al. 2006 Bechmann et al. 2007 Migration of activated T cells from perivascular spaces to brain parenchyma (step 2) Glia limitans (astroglial end-feet) Recognition of the cognate antigens by activated T cells after presentation in the context of appropriate MHC molecules expressed on perivascular cells Becher et al. 2000 Hickey 2001 Becher et al. 2006 Bechmann et al. 2007 MHC, major histocompatability complex. Chapter 12: Neuroimmune Interactions in Demyelinating Diseases 297 of epithelial barriers, monocytes, macrophages, NK cells, complement pathways, and cytokines and pro- vides an early immune response directed against foreign antigens, which is characterized by low speci city and no memory. Conversely, the acquired immune system consists of humoral immunity mediated by B cells and cell-mediated immunity driven by MHC class I–restricted CD8 + T cells and MHC class II–restricted CD4 + T cells and triggers a late immune reaction targeting foreign antigens, which is able to respond more vigorously to repeated expo- sures to the same antigen because of its high speci - city and memory (Medzhitov, Janeway 1997). Among the cellular players of adaptive immunity, CD4 + T helper (Th) cells can be divided into two different populations with two distinct cytokine pro les and effector functions (Mosmann, Sad 1996). Th1 subset secreting interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ (Th1-type cytokines) are implicated in macrophage activation, production of opsonizing and complement- xing antibodies, and delayed hypersensitivity. Th2 cells producing IL-4, IL-5, IL-10, and IL-13 (Th2-type cytokines) antagonize Th1-mediated reaction and are involved in the production of neutralizing antibodies and allergic conditions. For these reasons, Th1 and Th2 polarized responses are believed to have opposite functions. Th1 response is judged as a pro- in ammatory reaction promoting cell-mediated immunity, whereas Th2 response is regarded as an anti-in ammatory reaction that mediates humoral immunity. Microglia and astroglia can release pro-in ammatory chemokines of the CXC or α-family chemokines, such as IL-8 (CXCL8) and IP-10 (CXCL10), and of the CC or β-family, including MIP-1α (CCL3), MIP-1β (CCL4), MCP-1 (CCL2), and RANTES (CCL5), which facili- tate the intracerebral recruitment of additional interaction between FasL expressed by resident brain cells and Fas expressed by immune cells traf cking across the BBB can induce apoptotic deletion of T cells migrating into the CNS. Apoptosis is an active suicide program leading to cell death in response to external stimuli (Krammer 2000). This process appears particularly ef cient in astrocytes, neurons, and endothelial cells in which the low expression of co-stimulatory molecules activates the Fas/FasL pathway (Pender, Rist 2001; Dietrich, Walker, Saas 2003). Therefore, resident CNS cells, by using Fas/FasL-mediated mechanisms, are able to limit the penetration of immune cells into the brain at two different sites: at the BBB and within the brain parenchyma. Consequently, microglia, astroglia, neurons, and endothelial cells form an immunological brain barrier that preserves the brain against the in ltra- tion of immunocompetent cells by the maintenance of a state of immune suppression within the CNS (Bechmann, Mor, Nilsen et al. 1999; Choi, Benveniste 2004). The characteristics of CNS immune sentinels are reported in Table 12.4. Regulation of Immune Responses in the Infl amed CNS In the course of brain in ammation, after the interactions with activated T cells entering the CNS parenchyma, microglial cells and astrocytes produce a series of pro-in ammatory and anti-in ammatory soluble mediators, such as cytokines and chemokines, which in uence both innate and acquired (or adaptive) immune responses within the CNS (Becher, Prat, Antel 2000; Aloisi, Ria, Adorini 2000; Dong, Benveniste 2001; Aloisi 2001; Becher, Beckmann, Greter 2006). The innate immune system comprises Table 12.4 Features of Central Nervous System (CNS) Cells acting as Immune Sentinels in the Normal and Infl amed Brain Cell Type Functions Mechanisms References CNS-associated cells (meningeal and choroid plexus macrophages and dendritic cells, perivascular cells) Immune sentinels at the gate of the CNS parenchyma Expression of MHC class I and II antigens, co-stimulatory molecules and pattern recognition receptors Becher et al. 2000 Aloisi 2001 Becher et al. 2006 Farina et al. 2007 Microglia Immune sentinels within the CNS parenchyma Expression of MHC class I and II antigens, co-stimulatory molecules, pattern recognition receptors and, along with neurons and endothelial cells, Fas ligand Bechmann et al 1999 Aloisi 2000 Aloisi 2001 Choi, Benveniste 2004 Farina et al. 2007 Astroglia Immune sentinels within the CNS parenchyma Expression of MHC class I and II antigens, co-stimulatory molecules at low levels, pattern-recognition receptors and, along with neurons and endothelial cells, Fas ligand Bechmann et al 1999 Aloisi 2000 Dong, Benveniste 2001 Choi, Benveniste 2004 Farina et al. 2007 [...]... space Glia limitans ↑ MHC-II ↑ Pro-inflammatory cytokines Ectopic follicles Demyelination IL-12 IL-23 Infiltrating cells MMPs TNF-α IFN-γ MMPs IFN-γ TNF-β IL-10 Apoptosis IL-4 Perivascular cells Axonal damage ROS NO Recruitment and activation via Fas/FasL TGF-β IL-10 IL-12 Microglia Neuron Myelin Axon Astrocyte APC Th-1 Th-2 CD8+ B-cells NK T-reg Macrophage Antibody MHC-I/TCR MHC-II/TCR Promotion Inhibition... Beckmann, Greter 20 06) IL-1 and TNF-α contribute to leukocyte extravasation into the CNS, IL -6 stimulates growth of B cells and their differentiation into antibody-secreting plasma cells, IL-15 activates NK and CD8+ T cells, and IL-18 promotes the synthesis of IFN-γ by NK and T cells Nevertheless, the key inducers of CNS inflammation are IL-12 and IL-23 IL-12 elicits the secretion of IFN-γ by NK cells and... cells by the release of IL-10 and TGF-β, respectively (Jiang, Chess 20 06; Baecher-Allan, Hafler 20 06) The activity of invading CD4+ Th1 cells is also downregulated by NK T cells through the liberation of IL-4, IL-10, and TGF-β (Jiang, Chess 20 06) and by NK2 cells through the delivery of IL-10 and TGF-β and the cytolysis of APCs (Johansson, Berg, Hall et al 2005; Shi, Van Kaer 20 06) The protective functions... Nervous System (CNS) Cellular Players Principal Functions Soluble Mediators References Pro-inflammatory chemokines: MIP-1α (CCL3) Aloisi 2000 Dong, Benveniste 2001 Aloisi 2001 Pro-inflammatory cytokines: IL-12/ IFN-γ Aloisi 2000 Becher et al 2000 Aloisi 2001 Becher et al 20 06 Immune deviation toward Th17-mediated immune responses Pro-inflammatory cytokines: IL-23/IL-17 Becher et al 20 06 Recruitment of... F-D 2005 Differential effects of IL-21 during initiation and progression of autoimmunity against neuroantigen J Immunol 174: 269 6–2701 Wiendl H 2007 HLA-G in the nervous system Hum Immunol 68 :2 86 293 Wiendl H, Feger U, Mittelbronn M et al 2005 Expression of the immune-tolerogenic major histocompatibility molecule HLA-G in multiple sclerosis: implications for CNS immunity Brain 128: 268 9–2704 Xiao B-G,... induced by IL-23 (McKenzie, Kastelein, Cua 20 06) Accordingly, it is currently presumed that the development of brain inflammation is critically dependent on the IL-23/IL-17 axis rather than on the IL-12/ IFN-γ circuit, which probably exerts immunoregulatory functions (Iwakura, Ishigame 20 06) Microglial cells and astrocytes are also producers of anti-inflammatory cytokines such as IL-10 and transforming... al 20 06 Frohman et al 20 06 Myelin damage and axonal loss mediated by toxic factors (TNF-α, IFN-γ, reactive oxygen species, NO and MMPs) for microglial cells and CD4+ Th1 cell-activated macrophages, antibodies for B cells, and cytolysis for CD8+ T cells, γδ T cells and NK1 cells Becher et al 2000 Archelos, Hartung 2000 Hemmer et al 2004 Friese, Fugger 2005 Hauser, Oksenberg 20 06 Shi, Van Kaer 20 06 Presentation... located on the top of astrocytic end-feet For this reason, extravasating immune cells release 300 ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE Activation Tethering/Rolling Adhesion Diapedesis Perivascular space Glia limitans Selectins (E, L-ligands/E-ligands, L) Integrins/Immunoglobulins (LFA-1, MAC-1/ICAM-1) (VLA-4/VCAM-1) (PECAM, others) MMPs, a family of zinc-containing and calciumrequiring endopeptidases,... T-cell responses by CNS antigen-presenting cells: different roles for microglia and astrocytes Immunol Today 21:141–147 Aloisi F, Pujol-Borrell R 20 06 Lymphoid neogenesis in chronic inflammatory diseases Nat Rev Immunol 6: 205–217 Aranami T, Miyake S, Yamamura T 20 06 Differential expression of CD11c by peripheral blood NK cells reflects temporal activity of multiple sclerosis J Immunol 177: 565 9– 566 7... the central nervous system FASEB J 20:8 96 905 Hunt JS, Petroff MG, McIntire RH, Ober C 2005 HLA-G and immune tolerance in pregnancy FASEB J 19 :68 1 69 3 Imitola J, Chitnis T, Khuory AJ 20 06 Insights into molecular pathogenesis of progression in multiple sclerosis Arch Neurol 63 :25–33 Iwakura Y, Ishigame H 20 06 The IL-23/IL-17 axis in inflammation J Clin Invest 1 16: 1218–1222 Jacobsen M, Cepok S, Quak E . provide co-stimulatory signals for T-cell activation and that are represented VCAM-1 VLA-4 B7 CD40 MHC-II CD3 TCR CD4 LFA-1ICAM-1 LFA-3 Ag CD40L CD28 CD2 VCAM-1 VLA-4 B7 CD40 MHC-I CD3 APC APC A B CD8 + CD4 + TCR CD8 LFA-1ICAM-1 LFA-3 Ag CD40L CD28 CD2 Figure. interaction Macrophage APC Th-1 Antibody Perivascular cells Perivascular space Endothelium Glia limitans ↑ MHC-II ↑ Pro-inflammatory cytokines IL-12 IL-23 Ectopic follicles TNF-α IFN-γ MMPs TNF-β IL-10 TGF-β IL-10 Apoptosis via. macrophage activation. Therefore, IL-12 and IL-23 promote two different immunological pathways that play separate but complementary roles. However, IL-23 but not IL-12 is essential for

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