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Review
. 2012 Apr;122(4):1172-9.
doi: 10.1172/JCI58648. Epub 2012 Apr 2.

The adaptive immune system in diseases of the central nervous system

David C Wraith  1 , Lindsay B Nicholson
Affiliations
Review

The adaptive immune system in diseases of the central nervous system

David C Wraith et al. J Clin Invest. 2012 Apr.

Abstract

Tissues of the CNS, such as the brain, optic nerves, and spinal cord, may be affected by a range of insults including genetic, autoimmune, infectious, or neurodegenerative diseases and cancer. The immune system is involved in the pathogenesis of many of these, either by causing tissue damage or alternatively by responding to disease and contributing to repair. It is clearly vital that cells of the immune system patrol the CNS and protect against infection. However, in contrast to other tissues, damage caused by immune pathology in the CNS can be irreparable. The nervous and immune systems have, therefore, coevolved to permit effective immune surveillance while limiting immune pathology. Here we will consider aspects of adaptive immunity in the CNS and the retina, both in the context of protection from infection as well as cancer and autoimmunity, while focusing on immune responses that compromise health and lead to significant morbidity.

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Figures

Figure 1
Figure 1. Physical barriers protecting the brain.
The brain is the most highly protected organ in the body. It is protected from physical insult by the skull and associated tissues. The BBB provides protection from pathogens in the blood and from the cells and antibodies of the immune system. The BBB is more effective than other vascular-tissue barriers because the endothelial cells form tight junctions of high electrical resistance that limit transcellular movement of molecules. The glia limitans, formed from parenchymal basement membrane and astrocytic foot processes, forms a further barrier between blood and neuronal tissue.
Figure 2
Figure 2. Immunological barriers protecting the brain.
Cells of the CNS, including (A) astrocytes, (B) neurons, and (C) microglial cells express FASL. Activated T cells upregulate FAS and are, therefore, susceptible to apoptosis in the CNS. (B) Neurons respond to contact with T cells by secreting TGF-β, which in turn promotes the generation of regulatory T cells. (C) Resident microglial cells express B7-H1, a costimulatory molecule that promotes secretion of the anti-inflammatory cytokine IL-10, and indoleamine 2,3-dioxygenase (IDO), which converts tryptophan (TRP) to kynurenic acid (KYN). Metabolites of tryptophan induce FAS-independent apoptosis in neighboring cells.
Figure 3
Figure 3. Comparison of the BBB and BCSFB.
Brain barriers are made up of the endothelial BBB and the epithelial BCSFB. (A) The BBB has two protective layers, the endothelium with tight junctions and the glia limitans, made up of parenchymal basement membrane and astrocyte foot processes. (B) In contrast to the CNS parenchyma, microvessels in the choroid plexus are fenestrated, allowing free diffusion between the blood and CSF. The BCSFB is made up of the choroid epithelial cells with their unique tight junctions.
Figure 4
Figure 4. Current and future therapies for MS.
The holy grail for treatment of autoimmune disease is to design a drug that will selectively target the cells causing the disease, avoid nonspecific immune suppression, and have minimal adverse effects. Increasingly specific approaches target the adaptive immune response to antigens in the CNS. Examples of these include antilymphocyte drugs (alemtuzumab), anti–T cell drugs (daclizumab), drugs targeting lymphocyte migration (natalizumab and fingolimod), APL (GA), and the target antigen (myelin peptides or DNA vaccine).
Figure 5
Figure 5. Adaptive immune responses in the CNS.
Immune responses in the CNS may be helpful or harmful. Constant immune surveillance is required to control infections in the CNS, to control transient infections, or to maintain latent infections. Depletion of immune cells may lead to virus reactivation, while cross-reacting antibodies, which arise as a result of infection, autoimmune disease, or cancer, may cause movement disorders. Chronic inflammation arises when the adaptive immune response fails to eradicate an infection or alternatively responds to a CNS antigen, leading to autoimmune disease.
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