Immune System & Cells

A large number of clinical and experimental observations indicate that Immune Responses may be modulated by the Central Nervous System (CNS).

The Immune System (IS) and CNS are known to communicate via the Endocrine and the Autonomic Nervous System.

In this overview, we will focus on the ImmunoModulating role of NeuroTransmitters and NeuroPeptides.

Immune Cells appear to express membrane Antigens similar to those of Neural Cells. Similarities re-enforce analogies between CNS and IS Cells.

The concept that the CNS modulates Immune functions implies that the Immune System feeds back information to the CNS.

In fact, InterLeukins have NeuroEndocrine functions whether they are produced at the Periphery by Immune Cells or at the CNS level by Glial Cells.

Finally, the possible Endocrine functions of Lymphocytes are described and it is suggested that a complete regulatory loop between Immune and Neuro-Endocrine Systems exists.

Studies in Neuro-ImmunoModulation are of great importance from a theoretical point of view, the CNS-IS inter-relationships may not be considered only between the CNS and the Periphery.

But, also at the level of the Immune Micro-Environment which may be considered as an Immune-Neuro-Endocrine Complex.

In a healthy state, the Central Nervous System (CNS) is believed to be an Immunologically privileged site.

Which does not participate in the Immune Reactions of the rest of the body, and in which identifiable components of the Immune System are rare or non-existent.

In this study, an ImmunoHistoChemical examination of the CNS of F1 hybrid rats following induction of Graft-Versus-Host Disease (GVHD) was carried out.

To determine whether specific Immune Reactions in the normal CNS could occur during a Systemic Immune Reaction.

The results revealed extensive Parenchymal and Vascular expression of Class I and II Major Histocompatibility Complex (MHC) encoded cell surface molecules.

The strongest expressors of Class I and II molecules were Endothelial Cells and Parenchymal Cells, respectively.

The latter being apparently activated Microglia, in the Cerebrum and Cerebellum of rats with GVHD.

In addition, occasional scattered Lymphocytes were detected in the CNS of GVHD rats without Blood-Brain Barrier disruption.

Thus, evidence was obtained for the presence of Immune Response such as MHC Antigen expression and Lymphocyte infiltration in the CNS during a strong Systemic Immune Response such as GVHD, Microglia and Endothelial Cells apparently playing an important role.

Immune Responses in the Central Nervous System (CNS) have traditionally been regarded as representing the intrusion of an unruly, ill-behaved mob of Leukocytes into the well-ordered and organized domain of thought and reason.

However, results accumulated over the past few years suggest that, far from being an Immunologically privileged organ, T-Lymphocytes may be regular and frequent visitors to the CNS, for purposes of Immune surveillance.

Here, Trevor Owens and colleagues propose that the Brain itself can regulate or shape Immune Responses therein.

Furthermore, given that the Immune Cells may be subverted to AutoImmunity, they suggest that the study of inflammatory AutoImmune Disease in the Brain may shed light on the ability of the local environment to regulate Immune Responses.

Multiple Sclerosis (MS) is an Inflammatory Disease which exclusively affects the White Matter of the Central Nervous System (CNS).

Although there is a localized Immune Response within the CNS, Immune abnormalities that correlate with disease activity are also found in the Peripheral Immune Compartment of MS patients.

These abnormalities primarily involve ImmunoRegulatory defects in T-Cell function that are associated with T- and B-Cell hyperactivity.

In this review, David Hafler and Howard Weiner discuss the evidence that there are T-Cell abnormalities in MS similar to those observed in other AutoImmune Diseases such as Systemic Lupus Erythematosus and Rheumatoid Arthritis.

And that the ImmunoRegulatory defects in the blood of MS patients appear to be accompanied by the rapid migration of Activated T-Cells from the peripheral blood to the CNS.

That ImmunoTherapy directed at the Peripheral Immune Compartment affects the disease process supports their argument.

Specifically, total Lymphoid Irradiation of the Peripheral Immune Compartment ameliorates Progressive MS whereas systemic treatment with IFN- makes the disease worse.

They conclude that the CNS inflammatory response is closely linked to, and in some ways dependent upon, the Peripheral Immune Compartment.

Experimental Allergic EncephaloMyelitis (EAE) is an inflammatory DeMyelinating Disease of the Central Nervous System (CNS) which has many clinical and pathological features in common with Multiple Sclerosis (MS).

Comparison of the HistoPathology of EAE and MS reveals a close similarity suggesting that these two diseases share common PathoGenetic mechanisms.

Immunologic processes are widely accepted to contribute to the initiation and continuation of the diseases and recent studies have indicated that Microglia, Astrocytes and the infiltrating Immune Cells have separate roles in the PathoGenesis of the MS lesion.

The role of Cytokines as important regulatory elements in these Immune Processes has been well established in EAE and the presence of Cytokines in cells at the edge of MS lesions has also been observed.

However, the role of Chemokines in the initial inflammatory process as well as in the unique DeMyelinating event associated with MS and EAE has only recently been examined.

A few studies have detected the transient presence of selected Chemokines at the earliest sign of Leukocyte infiltration of CNS tissue and have suggested Astrocytes as their cellular source.

Based on these studies, Chemokines have been postulated as a promising target for future therapy of CNS inflammation.

This review summarized the events that occur during the inflammatory process in EAE and discusses the roles of Cytokine and Chemokine expression by the resident and infiltrating cells participating in the process.

The Central Nervous System (CNS) is considered to be a severely disadvantaged site for the elicitation of Immune Responses.

1. First, there is no specialised Lymphatic drainage.

2. Both Glia and Neuronal Cells normally do not express appreciable levels of Major Histocompatibility Complex molecules.

3. The Vasculature of the CNS is, at least in most places, lined by Endothelial Cells that have tight junctions and form a barrier (the Blood-Brain Barrier) against most molecules and cells present in the circulation.

4. The cells most important in the initiation of Immune Response, the Leucocyte Dendritic Cell, are not present.

Nevertheless, the existence of Inflammatory Diseases of this tissue, occurring naturally as in Multiple Sclerosis or in animals after Peripheral Immunization with CNS AutoAntigens, indicates that the Immune System can access and recognize Antigens in this site.

How this is achieved has become clearer in recent years and primarily seems to involve extravasation of activated but not resting T-Cells across the Blood-Brain Barrier.

And, recognition of Antigen on Macrophage-like PeriVascular Cells, rather than cells within the CNS Parenchyme such as Astrocytes or Microglia.

The processes involved in Immunological patrolling of the CNS and development of AutoImmune Inflammatory Disease are reviewed.

Presentation of Antigens for the CNS follows the same general rules as for other tissues.

However, the presence of special CNS cells with Immune Functions plus the Blood-Brain Barrier (BBB) suggests that differences in the way that the Immune System functions in the CNS might help to explain why some AutoImmune Diseases are unique to the CNS.

Irrespective of whether CNS Antigen presentation takes place inside or outside the CNS (or both), the BBB clearly plays a major role in CNS Immune Function.

The BBB governs the quantity and type of Lymphocytes that enter the CNS by way of specific Adhesion-Molecule binding between Lymphocytes and Endothelium and possibly by selecting for Antigen-specific Lymphocytes in Antigen-recognition events.

Recent experimental evidence confirms the interrelationships between the Central Nervous, NeuroEndocrine and Immune Systems. Indeed, extensive duality exists in the use of NeuroTransmitters, Hormones and Receptors each system displays.

In the present annotation, the effect of Cytokines, soluble mediators of Immune function, on the CNS and NeuroEndocrine Systems is addressed.

And conversely, we discuss the modification of the Immune compartment by the Sympathetic Nervous and NeuroEndocrine Systems, with particular reference to the role of NorAdrenaline and CorticoSterone.

Dysfunction between the systems is considered in the context of AutoImmune conditions, with emphasis on Experimental Allergic EncephaloMyelitis and the contribution of CorticoSterone-driven T-Cell Apoptosis to recovery from the disease.

Finally, we speculate on the relevance of NeuroImmune interactions in the PathoGenesis of Multiple Sclerosis.

Multiple Sclerosis (MS), a putative AutoImmune Disease of unknown Etiology, is characterized by CNS PeriVascular inflammation, Foci of DeMyelination, and elevated Intrathecal production of OligoClonal IgG's.

T and B-Cells, Macrophages, and Microglia are all implicated in contributing to the initiation and perpetuation of the disease.

In this brief review we discuss the possible role of T-Cells, B-Cells, Macrophages, and Microglia in contributing to the initiation and perpetuation of Inflammation and DeMyelination in MS.

Data from the rodent model of MS, Experimental AutoImmune EncephaloMyelitis (EAE) supporting a Immunological basis for the pathology of MS is noted.

This paper discusses recent data suggesting an interaction of the above-mentioned cells, as well as Serum and CSF proteins including Complement and Anti-Myelin/Oligodendrocyte AntiBodies, in the PathoGenesis of MS and EAE.

Additionally, this review describes each cell type including the clinical and experimental evidence for their contribution to the Immunologically mediated pathology of MS.

Following the description of the role of individual cells, there is consideration of: the possible interaction of cells with the Blood-Brain Barrier (BBB) under normal and pathologic inflammatory conditions; the traffic of cells into the CNS in inflammation; and the role of Antigen presentation within the CNS in the initiation, and perpetuation, of the CNS Immune Response.