Nervous Tissue As An Immune Compartment: The Dialect Of The Immune Response In The CNS
Fabry Z, Raine CS, Hart MN
Immunol Today 1994 May;15(5):218-24
Univ of Iowa College of Medicine, Dept of Pathology, Iowa City 52242
PMID# 8024682; UI# 94296540
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.
Cytokine-NeuroTransmitter Interactions In The Brain
De Simoni MG, Imeri L
Biol Signals 1998 Jan-Feb;7(1):33-44
Universita degli Studi, Istituto di Ricerche, Farmacologiche Mario Negri, Milano, Italia
PMID# 9588324; UI# 98249955
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: Intrinsic ImmunEffector Cell Of The Brain
Gehrmann J, Matsumoto Y, Kreutzberg GW
Brain Res Brain Res Rev 1995 Mar;20(3):269-87
Univ Hospital, Dept of Pathology, Zurich, Switzerland
PMID# 7550361; UI# 96031752
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:
- PeriVascular Cells are enclosed within the Basal Lamina
- 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.
Immune Cell Entry To The CNS - A Focus For ImmunoRegulation Of EAE
Owens T, Tran E, Hassan-Zahraee M, Krakowski M
Res Immunol 1998 Nov-Dec;149(9):781-9; discussion 844-6, 855-60
Montreal Neurological Institute, NeuroImmunology Unit, Montreal, Canada
PMID# 9923633; UI# 99120508
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.
Astrocytes In Multiple Sclerosis Lack ß-2 Adrenergic Receptors
De Keyser J, Wilczak N, Leta R, Streetland C
Neurology 1999 Nov 10;53(8):1628-33
Academisch Ziekenhuis Groningen, Dept of Neurology, The Netherlands
PMID# 10563603; UI# 20025127
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.
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.
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 Cell Activation And Proliferation Precedes The Onset of CNS Autoimmunity
Ponomarev ED, Shriver LP, Maresz K, Dittel BN
J NeuroSci Res 2005 Aug 1;81(3):374-89
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, Wisconsin 53201-2178, USA
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.
CD40 Expression By Microglial Cells Is Required For Their Completion Of A Two-Step Activation Process During Central Nervous System Autoimmune Inflammation
Ponomarev ED, Shriver LP, Dittel BN
J Immunol 2006 Feb 1;176(3):1402-10
Blood Research Institute, BloodCenter of Wisconsin, Milwaukee, WI 53201, USA
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.
Thus, our findings demonstrate that CD40 expression on Microglial Cells is necessary to complete their activation process during EAE, which is important for disease progression.