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

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PART III

Elucidating Infl ammatory

Mediators of Disease

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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 medi￾ated by autoreactive major histocompatibility com￾plex (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

292 ELUCIDATING INFLAMMATORY MEDIATORS OF DISEASE

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 neurode￾generation promotes irreversible disability.

Keywords: central nervous system, immune surveil￾lance, infl ammation, tissue damage, multiple sclerosis.

IMMUNE RESPONSES WITHIN THE

CENTRAL NERVOUS SYSTEM

The central nervous system (CNS) has tra￾ditionally been considered as an immu￾nologically privileged site in which the

immune surveillance is lacking and where

the development of an immune response is more lim￾ited 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 immu￾nologically 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 media￾tors, 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 histocom￾patibility 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 modifi 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

fi 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 traffi cking

across the BBB in the noninfl amed CNS (Hickey,

Hsu, Kimura 1991); (c) brain antigens are effi 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 leptomenin￾ges 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 infl 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 demyelina￾tion 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 fl uid (CSF)

across the choroid plexus; (b) from blood to suba￾rachnoid space; and (c) from blood to parenchyma.

In the fi rst pathway, which is currently believed to be

the main route by which T cells infi 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 suba￾rachnoid and perivascular spaces. In the third path￾way, 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 traffi c into

the brain across the blood–brain

barrier (BBB) in the noninfl 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 infl 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 pres￾ent such antigens to naïve T cells at the level of local

lymph nodes (Galea, Bechmann, Perry 2007). In nor￾mal brain, a constitutive expression of MHC antigens

is present on endothelial cells, perivascular, men￾ingeal, 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 infl 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 infl 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 infl 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 pro￾teins can be transported to local peripheral lymph

nodes where they can trigger priming and activa￾tion of naïve T lymphocytes. Nevertheless, these

interactions require local APCs capable of express￾ing specifi 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 chor￾oid plexus macrophages and dendritic cells (Aloisi,

Ria, Adorini 2000; Ransohoff, Kivisäkk, Kidd 2003;

Engelhardt, Ransohoff 2005). Moreover, also micro￾glial cells acquire APC properties in the course of

CNS infl ammation (Aloisi, Ria, Adorini 2000; Carson,

Doose, Melchior et al. 2006). In this regard, the pres￾ence 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 fl 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