Immune System & Cells

Even though the Immune privileged status of the Central Nervous System (CNS) limits access of Systemic Immune Cells through the Blood-Brain Barrier (BBB), an Immune Response can occur in this compartment with or without major breach of the BBB.

In this review, we consider properties of resident cells of the CNS, that participate in regulating the Neural Antigen (Ag).

Ag-directed Immune Responses implicated in AutoImmune Diseases such as Multiple Sclerosis (MS).

Under such conditions, the CNS is usually viewed as the target or victim of the Immune assault, because such Immune Responses are thought to be initiated and regulated within the Systemic Immune Compartment (Lymph Nodes).

The CNS-endogenous cells may themselves, however, initiate, regulate and sustain an Immune Response.

We consider the Immune Regulatory Functions within the CNS in terms of events occurring within the CNS Parenchyma (Microglia, Astroglia) and at the Vascular Interface.

These regulatory functions involve Antigen presentation to T-Cells and polarization of the Cytokine response of these cells.

Such responses may contribute not only to the overall tissue injury in primary Immune Disorders but also in a wide range of Traumatic, Ischemic and Degenerative Processes.

Copyright 2000 Wiley-Liss, Inc.

Immunological privilege of the Central Nervous System (CNS) has often been viewed as the summation of mechanisms that are protective of, but extrinsic to, the CNS.

Their primary role has then been seen as isolating the CNS from the organism as a whole.

Experiments in recent years indicate that the CNS itself may have an Innate Immune System comprised of Astrocytes and Microglia capable of regulating the initiation and progression of Immune Responses.

Thus, Immunological privilege should be considered as an intrinsic property of the CNS that could involve direct CNS: Immune Cell interactions.

Malfunctions of these intrinsic mechanisms could play significant roles augmenting or even initiating CNS-directed AutoImmunity and Inflammation.

The Brain constitutes an environment that is specifically designed to accommodate, regulate and shape Immune Responses.

On one hand, the Central Nervous System (CNS) has traditionally been regarded as an Immunologically privileged organ, owing to local tissue barrier and ImmunoSuppressive MicroEnvironment.

On the other hand, activated Microglia and Astrocytes express MHC and Adhesion/Costimulatory molecules, release reactive Oxygen intermediates and Cytokines, and participate in local Immune Regulation.

Bidirectional interactions between Immune and Neuroglial components occur in response to infectious and traumatic lesions.

Glial Cells may facilitate and amplify Immune Effector mechanisms within the CNS.

Cytokines and Chemokines within the CNS constitute a specialized CNS-Cytokine network, and regulate the development and recovery from AutoImmune Diseases within the CNS.

The interactions between Glial Cells and Lymphoid Cells are constituents of a complex Immune Regulatory system within the CNS.

New data on the cross-talk between the CNS and the Immune Systems are envisaged, and followed by an attempt to create a synthesis of current knowledge.

The Central Nervous System (CNS) is considered to be an Immunological privileged site.

However, inflammatory reactions in response to Virus infections, in Multiple Sclerosis (MS) and in Experimental AutoImmune EncephaloMyelitis (EAE) suggest that there are definite connections between the CNS and the Immune System.

In this review, we examine evidence for Afferent and Efferent pathways of communication between the CNS and the Immune System.

The pivotal role of regional Lymph Nodes in T-Cell mediated AutoImmune Disease of the CNS, and the factors involved in Lymphocyte targeting of the CNS.

Afferent pathways of Lymphatic drainage of the Brain are well established in a variety of species, especially rodents.

Fluid and Antigens appear to drain along PeriVascular Spaces populated by ImmunoCompetent PeriVascular Cells.

Drainage pathways connect directly via the Cribriform Plate to Nasal Lymphatics and Cervical Lymph Nodes.

Soluble Antigens draining from the Brain induce AntiBody production in the Cervical Lymph Nodes.

Using a model of cryolesion-enhanced EAE, we review the role of Lymphatic drainage and Cervical Lymph Nodes in the enhancement of Cerebral EAE.

If a Brain wound in the form of a cryolesion is produced 8 days post inoculation (dpi) of Antigen in the induction of acute EAE, there is a 6-fold increase in severity of Cerebral EAE by 15 dpi.

Removal of the Cervical Lymph Nodes significantly reduces such enhancement of EAE.

These findings suggest that drainage of Antigens from the Brain to the Cervical Lymph Nodes, in the presence of activated Lymphocytes in the Meninges or CNS, results in an enhanced second wave of Lymphocytes targeting the Brain.

In examining the Efferent Immune pathway by which Lymphocytes home to the CNS, several studies have characterized the phenotype of infiltrating T-Lymphocytes by the use of ImmunoCytoChemistry or FACS analysis.

T-Cells infiltrating the CNS are recently activated/Memory Lymphocytes typified by their high expression of CD44, LFA-1 and ICAM-1 and low expression of CD45RB in the mouse.

Following the induction of EAE in susceptible mice, ICAM-1 and VCAM-1 are dramatically upregulated on CNS vessels.

Lymphocytes bind to such vessels via the interaction of their known Ligands, LFA-1/Mac-1 and alpha 4-Integrins, at least in vitro.

It appears that alpha 4-Integrin plays a key role in Lymphocyte recruitment across the Blood-Brain Barrier and may be a major factor in Lymphocyte targeting of the CNS.

Definition of factors involved in the afferent and efferent connections between the CNS and the Immune System may clarify mechanisms involved in Immune privilege of the CNS and may open significant therapeutic opportunities for Multiple Sclerosis.

Because the skull bones, the CerebroSpinal Fluid, the Blood-Brain Barrier (BBB), and the Meninges effectively shield the Central Nervous System from other tissues, it was proposed that the Brain is an 'Immunologically privileged' organ.

However, with recent evidence that in response to invasion by MicroOrganisms, resident cells, such as Astrocytes and Microglia can fully mount an Immune Response, this long-standing view has been rethought and revised.

Over the last two decades, both Astrocytes and Microglia have been shown to secrete numerous Cytokines.

And, therefore, it is presently widely accepted that these cells actively participate in an integrative communicative pathway between resident Immune Cells of the CNS and those of the Periphery.

While clearly implicated in the initiation, maintenance, and suppression of Immune Responses, Cytokines produced by these cells (e.g. Astrocytes and Microglia).

As well as the responses of these cells to Cytokines produced elsewhere, has also been shown to propagate CNS damage.

Therefore the potential involvement of these cells in NeuroDegenerative Disorders has been raised and subjected to intense experimentation.

The objective of this synopsis is to review the role played by Astrocytes in the initiation and modulation of Immune Responses.

There is overwhelming evidence that Cytokines, Peptide Hormones and NeuroTransmitters, as well as their Receptors, are present in the Brain, Endocrine and Immune Systems.

The structure and pattern of synthesis of these Peptides by Leukocytes appear similar to those synthesized in the NeuroEndocrine System, although some differences exist.

Once secreted, these Peptide Hormones may function as endogenous regulators inside of each system and also in bidirectional communication between the Immune and NeuroEndocrine Systems.

Such communication suggest an ImmunoRegulatory role for the Brain and a Sensory Function for the Immune System.

Which, may sense stimuli that are not recognized by the Central and Peripheral Nervous Systems (NonCognitive Stimuli).

The Plasma Hormone concentrations contributed by Lymphocytes usually do not reach the levels required, when the Pituitary Gland is the source.

But because Immune Cells are mobile, they have the potential to deposit the Hormone locally at the target site (Paracrine).

Several ImmunoRegulatory Cytokines, including IL-1, IL-2, IL-6, IFN- and TNF are produced not only in the Immune System but in the NeuroEndocrine System as well.

They have profound effects on NeuroEndocrine functions especially on HypoThalamic Pituitary Axis. NeuroEndocrine influences that modulate the Immune function mainly include mental and physical stress.

It can reduce the resistance of Organism to Infectious Diseases and Malignancies by compromising the Immune System directly or indirectly.

The Brain is not an Immunologically privileged site and therefore may become the target of Immunologic attacks resulting in NeuroImmunological Diseases with an AutoImmune Component.

The impact of Psychological and PsychoSocial factors on the Immune System is studied by PsychoNeuroImmunology.

Whereas, NeuroEndocrine Immunology is generally interested in the interactions between the Immune and NeuroEndocrine Systems under physiological and pathological conditions.

The recognition of the identity of Ligands and Receptors in the Immune, Nervous, and Endocrine Systems suggest a radically altered view of the Immune Systems impact on other tissues and Organ Systems, and vice versa.

This will undoubtedly change our understanding of Physiology, and consequently should profoundly impact the practice of medicine.

The long-standing view that the Brain is isolated from the effects of the Immune System has recently been challenged.

With experimental evidence suggesting that in response to invasion by MicroOrganisms, the CNS can mount its own defense by resident cells, such as the Microglia and Astrocytes.

Both cell types produce and secrete a number of Cytokines and therefore can potentially modulate and integrate the communication between Hematogenous Cells and resident cells of the CNS.

This manuscript will commence with a brief overview of Astrocytic functions in the CNS, and proceed to discuss Astrocytic responses that may regulate CNS inflammation.

Specifically, it will address (1) the function of Astrocytes as the Antigen Presenting Cells (APCs) of the CNS, and (2) the role afforded by Astrocyte-derived Cytokines, and Astrocytic responses to Cytokines secreted elsewhere, in mediating and sustaining Immune Responses.

Finally, some recent experimental evidence on the possibility that Astroglial impairment by Pathogens may contribute to the Etiology of Neurologic Diseases will be highlighted.

The Blood-Brain Barrier (BBB) plays a crucial role in Central Nervous System (CNS) homeostasis.

Serving as the Brain's protective shield it regulates soluble factor and cellular exchanges from blood to Brain.

Critical to its function, the BBB is composed of Brain MicroVascular Endothelial Cells (BMVEC), a Collagen matrix, and Astrocytes.

Astrocytic endfeet surround the BMVEC Abluminal surface and influence the 'tightness' and trafficking role of the Barrier.

In NeuroDegenerative Disorders (for example Stroke, Multiple Sclerosis and HIV Encephalitis) the BBB becomes compromized.

This is, in part, Immune mediated. An accumulating body of evidence demonstrates that the cellular components of the BBB are themselves ImmunoCompetent.

PeriVascular cells (Astrocytes, Macrophages and Microglia Cells) and BMVEC produce inflammatory factors that affect BBB permeability and expression of Adhesion Molecules.

These affect cell trafficking into the CNS. Leukocyte BBB migration can be influenced by Cytokines and Chemokines produced by Glia.

Astrocytes and Macrophages secrete a multitude of factors that affect Brain Immune Responses.

Interactions between BMVEC, Leukocytes and/or Glia, Immunological activation and noxious (infectious, toxic and Immune-mediated) Brain insults all appear to play important roles in this BBB cell trafficking.

New information gained into the mechanisms of Leukocyte-Brain penetration may provide novel insights in the PathoGenesis and treatment strategies of NeuroDegenerative Disorders.

Both Genetic and environmental factors contribute to the development of AutoImmunity.

Animals and humans exposed to natural infections have a reduced rate of AutoImmune Diseases. There is increasing evidence that Immune stimulation prevents AutoImmune Diseases.

Our hypothesis is that the process of the development of Pathogenic cells involved in AutoImmunity can be modulated by early stimulation of the Immune System in AutoImmunity prone individuals.

This allows for the upregulation of Cytokines and Growth Factors that influence the generation of Regulatory Cells involved in AutoImmunity.

As we live in a 'cleaner environment' the decreasing chances of natural infection in the general population may contribute to the induction of AutoImmunity.

Because, the developing Immune System is not exposed to stimulation that may be necessary to generate regulatory cells involved in the modulation and prevention of AutoImmunity.

Immunization with certain vaccines may provide an alternative approach to stimulate the Immune System to modulate or prevent the generation of Pathogenic Cells involved in AutoImmunity by induction of Regulatory Cells.

Copyright 2000 Academic Press.