Immune System & Cells

For far too long, the Immune System has been viewed in isolation from the rest of the Body's Organ System. But now it is clear that the Immune System is an integral part of the Organ and Physiological Systems of the whole organism.

Especially, the Immune and Endocrine Systems share many Ligands and Receptors that result in constant and important bidirectional communication.

A new and important function for the Immune System is to serve as a Sensory Organ for NonCognitive Stimuli such as infectious agents and Tumors. On the other hand the NeuroEndocrine system can perform important ImmunoRegulatory activities.

It also suggest that Brain is not more an Immunologically privileged site. Recent studies provide a new view of ImmunoReactivity to Antigens from the Nervous System and to Immune and Inflammatory Responses in Brain.

These may be influenced both by the circulating Cytokines derived from the Immune System and/or those endogenously produced within the NeuroEndocrine System.

There is a growing body of evidence that Cytokines are an integral part of the Central Nervous System with an important NeuroModulatory role in Neural mechanisms regulating Stress Responses, Hormonal changes and various kinds of behavior.

The mutual informatory circuit inside of the Immune, Nervous and Endocrine Systems suggest that they all form the superinformation system with pivotal regulatory role in living organisms.

Overall, the recognition of the Immune System as our Sixth Sense may ultimately provide the new understanding of Physiology required for successful diagnostic and therapeutic programs against disease and stress involving Immune-NeuroEndocrine Communication. (Tab. 5, Ref. 35.)

There are numerous observations reporting that Phagocytes expressing Major Histocompatibility Complex (MHC) Class II molecules are associated with the Central Nervous System (CNS) in normal and pathological conditions.

Although MHC Class II expression is necessary for Antigen presentation to CD4⁺ T-Cells, it is not sufficient and Co-Stimulatory molecules are also required.

We review here recent in vivo studies demonstrating that the Microglia and PeriVascular Macrophages are unable to initiate a Primary Immune Response in the CNS MicroEnvironment, but may support Secondary Immune Responses.

Although in vitro studies show that Microglia do not support a Primary Immune Response leading to T-Cell proliferation, they do show that Microglia may protect the CNS from the unwanted attentions of AutoReactive T-Cells by inducing their Apoptosis.

The lack of cells in the CNS Parenchyma with the ability to initiate a Primary Immune Response has a cost, namely that Pathogens may persist in the CNS undetected by the Immune System.

The Central Nervous System (CNS) can be invaded and damaged by a variety of microbes. The host response to such injury involves CNS Cells, and in many cases Hematogenous Cells also.

Recent experiments indicate that Astrocytes, Macroglial resident cells of the CNS, play key roles in this process. The Astroglial production of Trophic Factors and elimination of NeuroToxins are likely to fulfill important protective and reparative functions during CNS infection.

In addition, Astrocytes could, in concert with Microglia Cells, regulate the recruitment and activity of infiltrating Hematogenous Cells through their expression of Cytokines, Proteases, Protease Inhibitors, Adhesion Molecules, and ExtraCellular Matrix Components.

Although previous experiments suggested that Astrocytes might initiate Inflammatory DeMyelinating Disease by presenting CNS Antigens to AutoReactive Immune Cells, current evidence points against such a detrimental activity.

In view of the generally beneficial role of Astrocytes, impairments of Astroglial function by microbes or host-derived factors have the potential to contribute to Neurologic Disease.

Diseases in which this PathoGenetic process may be relevant include HIV-1associated Cognitive/Motor Complex and Spongiform Encephalopathies.

The Brain MicroVessel Endothelial Cells (BMVEC) that form the Blood-Brain Barrier are uniquely positioned to influence Immune Responses within the Central Nervous System.

As the biological interface separating the blood from the Brain ExtraCellular Fluid, BMVEC regulate the entry of Leukocytes into the Brain. In addition, through the release of various soluble factors that affect Immune Responses, BMVEC may modulate Immune Responses in the Brain.

This review addresses the interplay between the Immune System and the Blood-Brain Barrier as it relates to the regulation of CNS defense and Immunity.

The Central Nervous System has the capacity to initiate and regulate Immune Responses by allowing restricted entry of Peripheral Immune Cells and providing a MicroEnvironment that is conducive to the activation of Immune Effector Cells.

In this commentary, we discuss the ability of two Glial Cells types, Astrocytes and Microglia, to function as APCs.

In particular, we focus on the phenotypic and functional distinctions between Astrocytes and Microglia that may contribute to their differing abilities to effectively present Ag to CD4⁺ Cells.

Here, Zsuzsa Fabry and colleagues address the question of whether the unique cellular environment of the Central Nervous System (CNS) contributes to the observed differences in Immunological functions between the CNS and other organs.

In particular, they discuss the significance within the CNS of the Blood-Brain Barrier, the nonconstitutive expression of Major Histocompatibility Complex (MHC) molecules, the unusual set of potential Antigen-Presenting and Effector Cells, and the production of Immune or NeuroMediators from various cellular sources.

The data reviewed in this study show that Immune-active molecules, such as infectious agents and their components, and Cytokines, may induce profound alterations in several NeuroTransmitters in the CNS.

The activation of the Immune System elicits fever, behavioral and NeuroEndocrine changes and may be involved in NeuroPathological changes occurring in CNS conditions.

These effects may be achieved through and accounted for by the changes induced in central NeuroTransmitters and in the NeuroEndocrine System by Immune challenges.

The present review will summarize the available evidence of the reciprocal interactions between Cytokines and NeuroTransmitters in the CNS.

Microglia form a regularly spaced network of resident Glial Cells throughout the CNS. They are Functionally, Morphologically, and ImmunoPhenotypically related to cells of the Monocyte/Macrophage lineage.

In the ultimate vicinity of the Blood-Brain Barrier, two specialized subsets of Macrophages/Microglia can be distinguished:

1. PeriVascular Cells are enclosed within the Basal Lamina
2. JuxtaVascular Microglia make direct contact with the Parenchymal side of the CNS Vascular Basal Lamina, but
   • represent true IntraParenchymal resident Microglia

Bone Marrow chimera experiments indicates that a high percentage of the PeriVascular Cells undergoes replacement with Bone Marrow-derived Cells.

In contrast, JuxtaVascular Microglia like other resident Microglia form a highly stable pool of CNS Cells with extremely little turnover with the Bone Marrow compartment.

Both the PeriVascular cells and the JuxtaVascular Microglia play an important role in initiating and maintaining CNS AutoImmune injury.

Due to their strategic localization at a site close to the Blood-Brain Barrier, their rapid inducibility for MHC Class II Antigens and their potential scavenger role as Phagocytic Cells.

The constantly replaced pool of PeriVascular Cells probably represents an entry route by which HIV gets access to the Brain. Microglia are the first cell type to respond to several types of CNS injury.

Microglial activation involves a stereotypic pattern of Cellular Responses, such as proliferation, increased or de-novo expression of ImmunoMolecules, recruitment to the site of injury and functional changes, e.g., the release of CytoToxic and/or Inflammatory Mediators.

In addition, Microglia have a strong Antigen Presenting function and a pronounced CytoToxic function. Microglial activation is a graded response, i.e., Microglia only transform into intrinsic Brain Phagocytes under conditions of Neuronal and or Synaptic/Terminal Degeneration.

In T-Cell-mediated AutoImmune injury of the Nervous System, Microglial activation follows these lines and occurs at an early stage of disease development.

In Experimental AutoImmune EncephaloMyelitis (EAE), Microglia proliferate vigorously, show a strong expression of MHC Class I and II Antigens, Cell Adhesion Molecules, release of reactive Oxygen intermediates and inflammatory Cytokines and transform into Phagocytic Cells.

Due to their pronounced Antigen Presenting function in vitro, activated Microglia rather than Astrocytes or Endothelial Cells are the candidates as intrinsic Antigen Presenting Cells of the Brain.

In contrast to Microglia, Astrocytes react with a delay, appear to encase morphologically the inflammatory lesion and may be instrumental in downregulating the T-Cell-mediated Immune injury by inducing T-Cell Apoptosis.

T-Cell-derived Cytokines are therefore individually unnecessary and collectively insufficient for Microglial response.

This somewhat provocative interpretation does not exclude a role for T-Cell Cytokines in induction of a Microglial response in EAE, but it may be easier to show a non-requirement then to prove such a role.

The point that emerges is that Cytokine production in the CNS Parenchyma is itself dependent on the prior infiltration of Immune Cells, and that without Immune Cell entry, EAE does not occur.

This identifies events at the BBB, and in particular in the PeriVascular space, as critical ImmunoRegulatory events in development and progression of EAE.

Background
In MS, T-Cells reactive to Myelin proteins can cross the Blood-Brain Barrier and release proinflammatory Cytokines, such as Interferon-gamma.

These can induce Glial Cells to express Class II Major Histocompatibility Complex (MHC) molecules, which are required to present Myelin Antigens to the T-Cells in order to mount a proper AutoImmune Response.

Both Microglia and Astrocytes can function as Antigen-Presenting Cells. In contrast to Microglia, endogenous suppressors, including NorEpinephrine, regulate Astrocytic Class II MHC expression.

The effects of NorEpinephrine are mediated through activation of P2 Adrenergic Receptors.

Objective & Methods
To investigate P, Adrenergic Receptors in Astrocytes in MS.

ImmunoCytochemical techniques were applied in postmortem Brain tissue from 10 patients with MS, three patients with a Cerebral Infarction, six controls, and in Spinal Cords from three patients with ALS.

Results
ß2 Adrenergic Receptors were visualized on Astrocytes in White Matter of controls, and they were prominently expressed in reactive Astrocytes at the boundary of Cerebral Infarctions and in the Lateral CorticoSpinal Tract in ALS.

In MS, ß2 Adrenergic Receptors could neither be visualized on Astrocytes in Normal-Appearing White Matter nor in reactive Astrocytes in chronic active and inactive Plaques.

Whereas, they were normally present on Neurons. MHC Class II-positive Astrocytes were only visualized in chronic active plaques.

Conclusions
Because Astrocytic ß2 Adrenergic Receptors are involved in suppressing inducibility of MHC Class II molecules.

We suggest that their lack of expression may play an important role in the induction or perpetuation of AutoImmune reactions in MS.

Microglial Cells are Central Nervous System (CNS) resident cells that are thought to become activated and contribute to the inflammation that occurs in the human Autoimmune Disease Multiple Sclerosis (MS).

This has never been proven, however, because Microglial Cells cannot be phenotypically distinguished from Peripheral Macrophages that accumulate in MS inflammatory lesions.

To study the kinetics and nature of Microglial Cell activation in the CNS, we used the animal model of MS, Experimental Autoimmune Encephalomyelitis (EAE).

And induced EAE in Bone Marrow (BM) chimera mice generated using Major Histocompatibility Complex (MHC)-mismatched donor BM, allowing the separation of Microglial Cells and Peripheral Monocytes/Macrophages.

We found that Microglial Cell activation was evident before onset of disease symptoms and infiltration of Peripheral Myeloid Cells into the CNS.

Activated Microglial Cells underwent proliferation and upregulated the expression of CD45, MHC Class II, CD40, CD86, and the Dendritic Cell marker CD11c.

At the peak of EAE disease, activated Microglial Cells comprised 37% of the total Macrophage and Dendritic Cell populations and colocalized with infiltrating Leukocytes in inflammatory lesions.

Our findings thus definitively demonstrate that during EAE, Microglial Cells become activated early in EAE disease and then differentiate into both Macrophages and Dendritic-Like Cells, suggesting they play an active role in the pathogenesis of EAE and MS.

(c) 2005 Wiley-Liss, Inc.

Microglial Cells are Monocytic lineage cells that reside in the CNS and have the capacity to become activated during various pathological conditions.

Although it was demonstrated that activation of Microglial Cells could be achieved in vitro by the engagement of CD40-CD40L interactions in combination with ProInflammatory Cytokines.

The exact factors that mediate activation of Microglial Cells in vivo during CNS Autoimmunity are ill-defined.

To investigate the role of CD40 in Microglial Cell activation during Experimental Autoimmune Encephalomyelitis (EAE).

We used bone marrow chimera mice that allowed us to distinguish Microglial Cells from Peripheral Macrophages and render Microglial Cells deficient in CD40.

We found that the first step of Microglial Cell activation was CD40-independent and occurred during EAE onset. The first step of activation consisted of Microglial Cell proliferation and up-regulation of the activation markers MHC Class II, CD40, and CD86.

At the peak of disease, Microglial Cells underwent a second step of activation, which was characterized by a further enhancement in activation marker expression along with a reduction in proliferation.

The second step of Microglial Cell activation was CD40-dependent and the failure of CD40-deficient Microglial Cells to achieve a full level of activation during EAE was correlated with reduced expansion of Encephalitogenic T-Cells and Leukocyte infiltration in the CNS, and amelioration of clinical symptoms.