Invited ReviewCentral nervous system: A modified immune surveillance circuit?
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)
- et al.
Disruption of central nervous system barriers in multiple sclerosis
Biochim. Biophys. Acta
(2011) - et al.
The cellular response in neuroinflammation: the role of leukocytes, microglia and astrocytes in neuronal death and survival
Clin. Neurosci. Res.
(2006) - et al.
Transmission routes of HIV-1 gp120 from brain to lymphoid tissues
Brain Res.
(1999) - et al.
Is damage in central nervous system due to inflammation?
Autoimmun. Rev.
(2004) - et al.
Differential expression of selectins by mouse brain capillary endothelial cells in vitro in response to distinct inflammatory stimuli
Neurosci. Lett.
(2006) - et al.
Afferent and efferent arms of the humoral immune response to CSF-administred albumins in a rat model with normal blood–brain barrier permeability
J. Neuroimmunol.
(1992) - et al.
Leukocyte-facilitated entry of intracellular pathogens into the central nervous system
Microbes Infect.
(2000) - et al.
In vivo detection of myelin proteins in cervical lymph nodes of MS patients using ultrasound-guided fine-needle aspiration cytology
J. Neuroimmunol.
(2005) - et al.
Serum antigen detection in the diagnosis, treatment and follow-up of neurocysticercosis patients
Trans. Roy. Soc. Trop. Med. Hyg.
(2000) - et al.
Mechanisms underlying inflammation in neurodegeneration
Cell
(2010)
Ovalbumin is more immunogenic when introduced into brain or cerebrospinal fluid than into extracerebral sites
J. Neuroimmunol.
Lymphocyte migration into the central nervous system: implication of ICAM-1 signalling at the blood–brain barrier
Vascul. Pharmacol.
Role of cervical lymph nodes in the systemic humoral immune response to human serum albumin microinfused into rat cerebrospinal fluid
J. Neuroimmunol.
How to drain without lymphatics? Dendritic cells migrate from the cerebrospinal fluid to the B-cell follicles of cervical lymph nodes
Blood
Leukocyte traffic in the central nervous system: the participants and their roles
Semin. Immunol.
“Classic” myelin basic proteins are expressed in lymphoid tissue
J. Neuroimmunol.
The potential role of dendritic cells in immune-mediated inflammatory diseases in the central nervous system
Neuroscience
Endothelin induction of adhesion molecule expression on human brain microvascular endothelial cells
Neurosci. Lett.
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
CD40 expressed by human brain endothelial cells regulates CD4+ T cell adhesion to endothelium
J. Neuroimmunol.
Essential role of VLA-4/VCAM-1 pathway in the establishment of CD8+ T-cell-mediated Trypanosomacruzi-elicited meningoencephalitis
J. Neuroimmunol.
Cerebral spinal fluid lymphocytes are part of the normal recirculating lymphocyte pool
J. Neuroimmunol.
Defining antigen-dependent stages of T cell migration from the blood to the central nervous system parenchyma
Eur. J. Immunol.
Suppression of experimental allergic neuritis by an antibody to the intracellular adhesion molecule ICAM-1
Brain
Immunologically privileged sites
Adv. Immunol.
Surface expression of alpha 4 integrin by CD4 T cells is required for their entry into brain parenchyma
J. Exp. Med.
Failed central nervous system regeneration: a downside of immune privilege?
Neuromol. Med.
The rapid isolation of clonable antigen – specific T lymphocytes capable of mediating autoimmune encephalomyelitis
Eur. J. Immunol.
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.
Subarachnoidal and intraventricular human neurocysticercosis: application of an antigen detection assay for the diagnosis and follow-up
Trop. Med. Int. Health
Presence of HTLV-I Tax protein in cerebrospinal fluid from HAM/TSP patients
Arch. Virol.
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
Isolation frequency of human immunodeficiency virus from cerebrospinal fluid and blood of patients with varying severity of HIV infection
AIDS Res. Hum. Retroviruses
Human immunodeficiency virus type 1 is present in the cerebrospinal fluid of a majority of infected individuals
J. Clin. Microbiol.
Cervical lymphatics, the blood–brain barrier, and the immune reactivity of the brain
Transfer of central nervous system auto antigens and presentation in secondary lymphoid organs
J. Immunol.
Leukocyte recruitment in the cerebrospinal fluid of mice with experimental meningitis is inhibited by an antibody to junctional adhesion molecule (JAM)
J. Exp. Med.
Intracerebroventricular injection of TNF-alpha promotes sleep and is recovered in cervical lymph
Am. J. Physiol.
E- and P-selectin are not required for the development of experimental autoimmune encephalomyelitis in C57BL/6 and SJL mice
J. Immunol.
Altered vascular permeability and early onset of experimental autoimmune encephalomyelitis in PECAM-1-deficient mice
J. Clin. Invest.
Cerebrospinal fluid dendritic cells infiltrate the brain parenchyma and target the cervical lymph nodes under neuroinflammatory conditions
PLoS One
Cited by (26)
Blood–brain barrier and nanovesicles for brain-targeting drug delivery
2022, Applications of Nanovesicular Drug DeliveryNeuron-intrinsic immunity to viruses in mice and humans
2021, Current Opinion in ImmunologyCellular players that shape evolving pathology and neurodegeneration following traumatic brain injury
2018, Brain, Behavior, and ImmunityLow, but not high, dose triptolide controls neuroinflammation and improves behavioral deficits in toxic model of multiple sclerosis by dampening of NF-κB activation and acceleration of intrinsic myelin repair
2018, Toxicology and Applied PharmacologyCitation Excerpt :Multiple sclerosis (MS) is a multifocal chronic autoimmune inflammatory disease of the central nervous system (CNS) which is also known as a perivascular demyelinating disease (Romo-González et al., 2012; Trapp and Nave, 2008; Goodin, 2014).
Tumor infiltrating immune cells in gliomas and meningiomas
2016, Brain, Behavior, and ImmunityCitation Excerpt :It has been suggested that upon stimulation, resident microglial cells can be rapidly activated via at least two functionally distinct morphological states, leading to activated microglia (which only express HLA-I) and reactive/amoeboid microglia (which express both HLA-I and HLA-II in association with an increased antigen presenting capacity) (Kettenmann et al., 2011; Yang et al., 2010). However, several reports have identified those cells residing in the perivascular space or the meninges as those displaying the greatest ability to present antigens to infiltrating T cells, for their subsequent stimulation and activation (Johnson et al., 2012; Romo-Gonzalez et al., 2012). As macrophages infiltrate the perivascular space, infiltrated T lymphocytes recognize the antigens presented by these APCs and they will subsequently act as effector adaptive immune cells (Romo-Gonzalez et al., 2012).