Invited Review
Central nervous system: A modified immune surveillance circuit?

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Abstract

Immune surveillance in the central nervous system (CNS) was considered impossible because: (i) the brain parenchyma is separated from the blood circulation by the blood–brain barrier (BBB); (ii) the brain lacks lymphatic drainage and (iii) the brain displays low major histocompatibility complex class II (MHCII) expression. In this context, the BBB prevents entry of immune molecules and effector cells to the CNS. The absence of lymphatic vessels avoids CNS antigens from reaching the lymph nodes for lymphocyte presentation and activation. Finally, the low MHCII expression hinders effective antigen presentation and re-activation of T cells for a competent immune response. All these factors limit the effectiveness of the afferent and efferent arms necessary to carry out immune surveillance. Nevertheless, recent evidence supports that CNS is monitored by the immune system through a modified surveillance circuit; this work reviews these findings.

Highlight

► Despite its own anatomical and structural properties CNS presents a modified circuit of immune surveillance allowing its constant immune monitoring.

Introduction

The immune system protects the organism by constant monitoring by specialized cells. These cells freely circulate between the lymphoid organs and other tissues searching for all kinds of potentially damaging agents of internal or external origin through a process known as immune surveillance (Wekerle, 1993). Immune surveillance occurs in most of the tissues, with few immune privileged exceptions that include the testicles, the anterior chamber of the eye and the central nervous system (CNS; Medawar, 1948, Barker and Billingham, 1977, Wekerle, 1993).

The CNS has structural properties that influence the immune reactivity. Among these features are the presence of the blood–brain barrier (BBB), the absence of lymphatic drainage and the reduced expression of Major Histocompatibility Complex Class II molecules (MHCII). The presence of the BBB interferes with the afferent arm of immune surveillance by preventing immune effector cells and molecules from entering the CNS, which in turn prevents an interaction between T cells and CNS antigens (Wekerle, 1993, Cserr and Knopf, 1990). The absence of lymphatic drainage restricts the efferent arm of the immune surveillance by preventing CNS antigens from reaching nearby lymphatic nodes (LNs), thus restricting the activation of lymphocytes. Finally, the low expression of the MHCII hinders antigen presentation and T cells re-activation. From this perspective, the immune privilege was regarded as a passive non-reactive state associated with the isolation of the CNS from the immune system. Nevertheless, these anatomical and structural elements are much more than passive barriers. For example, the physiological drainage of the cerebrospinal fluid (CSF) into the lymph and the blood circulation provides alternative routes for interstitial liquid antigens draining (Cserr and Knopf, 1990). Previous studies show that the BBB permits the selective access of some T cells (Ben-Nun et al., 1981, Naparstek et al., 1983). Finally, although under normal conditions CNS resident cells have a low or null expression of the MHCII, an inflammatory stimulus is capable of inducing rapidly its expression (Neumann, 2001, Carson et al., 2006).

For all these reasons, the concept of CNS immune privilege should be reassessed and rethought, especially because in the past the entry of immune elements into the CNS has been always associated with damage or disease development (Ransohoff et al., 2003, Bechmann, 2005).

Section snippets

CNS antigens draining routes

Adequate immune surveillance requires that both antigens and antigen-presenting cells (APCs) can reach the secondary lymphoid organs; this makes lymphatic drainage essential. In peripheral organs, resident APCs capture local antigens and migrate via afferent lymphatic vessels to the nearby LNs for antigen presentation (Oo et al., 2010; see Fig. 1). The CNS, however, lacks a traditional lymphatic system; consequently CNS antigens draining must occur through alternative routes.

One possible route

Peripheral stimulation in the lymphatic nodes

Lymphoid organs present a functional specialization for distinct anatomical sites for carrying out immune responses with particular characteristics against local antigens (Wolvers et al., 1999, Kraal et al., 2006). For instance, ileal Peyer’s patches provide oral tolerance to many dietary antigens and commensal bacteria. In order to induce tolerance, local DCs capture antigens, migrate to the mucosa-draining LNs and generate antigen-specific suppressive T cells (Fig. 1). The failure to induce

Lymphocytes migration to CNS

Although it was believed that leukocytes were excluded from the CNS by the BBB making immune surveillance impossible, it is now known that BBB does not prevent CNS leukocyte trafficking. Indeed, T, B and NK lymphocytes as well as cells of the macrophage/monocyte lineage have been detected in the CNS under normal conditions (Hickey, 1999), CNS perivascular macrophages are continually replaced (Hickey and Kimura, 1988) and lymphocytes can gain access to CSF either by traversing BBB to the

Antigen presentation in the CNS

In physiological conditions, CNS presents low expression of MHCII molecules. Therefore, resident brain cells would be unable to present specific antigens to T lymphocytes. The absence of professional APCs in brain parenchyma could prevent the initiation and propagation of immune responses (Neumann, 2001). Nevertheless, pre-activated T lymphocytes in the immune organs may migrate to the brain parenchyma and release pro-inflammatory cytokines (IFN-γ, TNF-α) inducing MHCII molecules into almost

CNS modified immune surveillance: multiple sclerosis as an example

Traditionally immune surveillance involves well-coordinated events between the focus of inflammation and the local lymphoid organs(Fig. 1; Oo et al., 2010).

Despite its structural properties CNS can be monitored by a modified immune surveillance circuit (Fig. 2). Multiple sclerosis clearly shows that immune surveillance is possible in the CNS, though with particular characteristics of its own.

Multiple sclerosis is an autoimmune disease characterized by inflammation, demyelinization and axonal

Conclusions

Active immune surveillance in the CNS is integrated by a modified immune circuit resulting in protection from possible brain damage (Baron et al., 1993). This implies a dynamic communication between the CNS and the secondary lymphoid organs. Based on the CNS physiology, three characteristics emerge that are immunologically relevant to the circulation of CNS antigens and their drainage. First, the movement of interstitial fluid and CSF through the subarachnoid space allows antigen access to

Conflict of interest statement

All authors declare that there are no conflicts of interest.

Acknowledgments

The authors thank Dr. Ruy Pérez Tamayo for his helpful comments on this manuscript and Bernardo Pohlenz for his assistance with figures.

References (83)

  • L.B. Gordon et al.

    Ovalbumin is more immunogenic when introduced into brain or cerebrospinal fluid than into extracerebral sites

    J. Neuroimmunol.

    (1992)
  • J. Greenwood et al.

    Lymphocyte migration into the central nervous system: implication of ICAM-1 signalling at the blood–brain barrier

    Vascul. Pharmacol.

    (2002)
  • C. Harling-Berg et al.

    Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid

    J. Neuroimmunol.

    (1989)
  • E. Hatterer et al.

    How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes

    Blood

    (2006)
  • W.F. Hickey

    Leukocyte traffic in the central nervous system: the participants and their roles

    Semin. Immunol.

    (1999)
  • H. Liu et al.

    “Classic” myelin basic proteins are expressed in lymphoid tissue

    J. Neuroimmunol.

    (2001)
  • M.K. Matyszak et al.

    The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system

    Neuroscience

    (1996)
  • R.M. McCarron et al.

    Endothelin induction of adhesion molecule expression on human brain microvascular endothelial cells

    Neurosci. Lett.

    (1993)
  • Z. Mojtahedi

    Th2-biased immune response in cervical lymph nodes: animal models of Graves’ disease might administer autoantigen to body regions where lymphatics drain to cervical lymph nodes

    Med. Hypotheses

    (2005)
  • K.M. Omari et al.

    CD40 expressed by human brain endothelial cells regulates CD4+ T cell adhesion to endothelium

    J. Neuroimmunol.

    (2003)
  • E. Roffê et al.

    Essential role of VLA-4/VCAM-1 pathway in the establishment of CD8+ T-cell-mediated Trypanosomacruzi-elicited meningoencephalitis

    J. Neuroimmunol.

    (2003)
  • T.J. Seabrook et al.

    Cerebral spinal fluid lymphocytes are part of the normal recirculating lymphocyte pool

    J. Neuroimmunol.

    (1998)
  • A.S. Archambault et al.

    Defining antigen-dependent stages of T cell migration from the blood to the central nervous system parenchyma

    Eur. J. Immunol.

    (2005)
  • J.J. Archelos et al.

    Suppression of experimental allergic neuritis by an antibody to the intracellular adhesion molecule ICAM-1

    Brain

    (1993)
  • C.F. Barker et al.

    Immunologically privileged sites

    Adv. Immunol.

    (1977)
  • J.L. Baron et al.

    Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma

    J. Exp. Med.

    (1993)
  • I. Bechmann

    Failed central nervous system regeneration: a downside of immune privilege?

    Neuromol. Med.

    (2005)
  • A. Ben-Nun et al.

    The rapid isolation of clonable antigen – specific T lymphocytes capable of mediating autoimmune encephalomyelitis

    Eur. J. Immunol.

    (1981)
  • S. Bhagavati et al.

    Detection of human T-cell lymphoma/leukemia virus type I DNA and antigen in spinal fluid and blood of patients with chronic progressive myelopathy

    N. Engl. J. Med.

    (1988)
  • R.J. Bobes et al.

    Subarachnoidal and intraventricular human neurocysticercosis: application of an antigen detection assay for the diagnosis and follow-up

    Trop. Med. Int. Health

    (2006)
  • L. Cartier et al.

    Presence of HTLV-I Tax protein in cerebrospinal fluid from HAM/TSP patients

    Arch. Virol.

    (2005)
  • F. Chaves-Borges et al.

    Detection of Toxoplasma gondii soluble antigen, SAG-1(p30), antibody and immune complex in the cerebrospinal fluid of HIV positive or negative individuals

    Rev. Inst. Med. Trop. S. Paulo

    (1999)
  • F. Chiodi et al.

    Isolation frequency of human immunodeficiency virus from cerebrospinal fluid and blood of patients with varying severity of HIV infection

    AIDS Res. Hum. Retroviruses

    (1988)
  • F. Chiodi et al.

    Human immunodeficiency virus type 1 is present in the cerebrospinal fluid of a majority of infected individuals

    J. Clin. Microbiol.

    (1992)
  • H.F. Cserr et al.

    Cervical lymphatics, the blood–brain barrier, and the immune reactivity of the brain

  • A.F. de Vos et al.

    Transfer of central nervous system auto antigens and presentation in secondary lymphoid organs

    J. Immunol.

    (2002)
  • A. Del Maschio et al.

    Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM)

    J. Exp. Med.

    (1999)
  • J.B. Dickstein et al.

    Intracerebroventricular injection of TNF-alpha promotes sleep and is recovered in cervical lymph

    Am. J. Physiol.

    (1999)
  • A. Döring et al.

    E- and P-selectin are not required for the development of experimental autoimmune encephalomyelitis in C57BL/6 and SJL mice

    J. Immunol.

    (2007)
  • D. Graesser et al.

    Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice

    J. Clin. Invest.

    (2002)
  • E. Hatterer et al.

    Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions

    PLoS One

    (2008)
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