Interactions between the central nervous system and the immune system

The central nervous system (CNS) is isolated from the blood circulation. This is made possible by a specialized group of vessels that do not let cells or even macromolecules pass through this barrier called the blood-brain barrier¹. This barrier is composed of specialized endothelial cells that have strong tight junctions formed by occludins and claudins 1, 3, 5, and 12².

Other proteins such as junctional adhesion molecules and cell-selective adhesion molecules have be found in tight junctions. These characteristic endothelial cells are found at the capillary and postcapillary levels of the blood-brain barrier (BBB). Other important characteristics are the lack of fenestrations of capillaries and high numbers of pericytes. Between these two basal membranes, few antigen presenting cells expressing MCH-class II exist. These cells are important for the recognition of the immune cells and the breach of the BBB.

Differences in the blood barrier are found throughout the CNS. One example of such a difference is the microvessels of the meninges which are more reactive to cytokines, allowing for increased leaking of the blood vessels due to a lack of astrocytes. Another difference is found in the choroid plexus, which extends from the ventricular surface into the lumen and is protected from the blood-cerebrospinal barrier. This barrier is organized as one layer of cuboidal epithelium containing microvilli. It also has microvessels with fenestrations and intercellular gaps. The chorionic epithelial cells that have tight junctions which inhibit the paracellular diffusion provide protection to the CNS in the ventricles. Although the brain exhibits such a sophisticated barrier, it is not exempt from the immune system surveillance. The immune system and the CNS interact in different ways. One type of interaction is called the neuroendocrine-immune network. In this network, the immune system communicates with the hypotalamic-pytuitary-adrenal gland axis and hypothalamic-pituitary glands axis, which are involved in stress responses and the prevention of immune responses that are harmful. The lack of communication between the immune and neuroendocrine systems may increase the susceptibility of acquiring infectious diseases, neoplasia, and autoimmune diseases³.

The quantity of T cells in the blood circulation cannot cross the BBB, instead, they use another route. They travel against the blood flow into the subarachnoid vessels and remain in close contact with blood vessels of the pia mater. Using the receptors LFA-1, which help in their crawling, and a key adhesion molecule VLA-4, effector T cells can penetrate the BBB. These processes are evident in the autoimmune disease encephalomyelitis (EAE). EAE is mediated by CD4 T cells, which enter the CNS and activate resident microglia. The activation of microglia results in an inflammatory response that leads to the recruitment of macrophages, which destroy the CNS. Therapeutic targets are being studied in order to treat patients with autoimmune diseases that target the CNS. These therapies consist of targeting integrins and membrane receptors, and then blocking them by using antibodies. In EAE, blocking the VLA-4 adhesion molecule has proven to be an effective therapy that has stopped the crawling and transmigration of T cells⁴.

Autoimmune Diseases and Related Clinical Cases to illustrate interactions between the CNS and the immune system

Myasthenia Gravis

Myasthenia gravis (MG) is an organ specific autoimmune disease in which antibodies against the nicotinic acetylcholine receptor (AChR) on the neuromuscular junction are generated. The binding of the antibody to the AChR impedes the binding of acetylcholine (Ach) and stimulates internalization of the receptor, thereby blocking the transmission of nerve impulses by Ach⁵. Although ACh continues to be released from the presynaptic bulb, it is rapidly destroyed by acetylcholinesterase in the synaptic cleft. Since this neurotransmitter is needed for relaying messages to muscles, MG impedes proper transmission of the message resulting in the characteristic symptoms of the disease: ptosis, diplopia, and fatigability.

 

Causes and Immunopathology:

The thymus plays a central role in MG since a breakdown in self-tolerance mechanisms causes T cells to become reactive to the AChR. Self-reactive T cells then signal B cells to secrete IgG against the AChR. Infections with a virus containing an amino acid sequence similar to that in the nicotinic AChR may activate the T cells. Serum from affected patients can transfer similar disease symptoms to animal recipients, thus proving the pathogenic role of the ACh autoantibodies⁵. Furthermore, as IgG is the only maternal serum protein that crosses the placenta from mother to fetus, pregnant woman with MG transfer the disease to their newborn infants. This occurrence is clear evidence that MG is caused by an IgG antibody⁶. MG is classified as a Type II hypersensitivity response because IgG antibodies bind to normal cellular receptors and interfere with their functioning.

Preferential involvement of extraocular and levator palpebrae muscles in MG is thought to be a result of the precision needed to maintain alignment of the visual axes. Even minute damage to the extraocular muscles causes such severe muscle weakness that the first symptom to develop in patients is blurred or double vision. This muscle weakness might not be sensed in the early stages of the disease in the limb muscles as they can compensate by recruiting additional motor units. Although the levator palpebrae muscle is more similar to other skeletal muscles, it is under constant neuronal stimulation, which makes this muscle prone to neuromuscular fatigue⁷.

The spectrum of homeostatic disorders caused by MG goes beyond that of the CNS. For example, nicotinic AChR are also found in the hypothalamus meaning that an antibody against the AChR not only affects the neuromuscular junction (NMJ), but also affects the endocrine system (see figure 2). This effect is not as obvious or as damaging as that seen in the NMJ because the hypothalamus has other activating receptors that mask the effects of the antibody against AChR. Such other receptors include norepinephrine and serotonin receptors (5- HT). As seen in the image above, inhibition of the hypothalamic-adenohypophyseal axis causes a reduction in cortisol levels. Reduced levels of cortisol in turn enhance the immune system and promote the production of IL-1, IL-2, IL-6, and TNF- alpha.  In fact, studies have shown that stressed animals produce high levels of cortisol which causes thymic involution. Thymic involution is one of the treatments for MG and is usually achieved by the administration of glucocorticoids, such as prednisone⁸.

Symptoms:
The symptoms of myasthenia gravis include: ptosis or “drooping eyelid” because of weakness of the eyelids, diplopia or “double vision” because of weakness of the eye muscles, difficulty swallowing because of weakness in the oropharyngeal muscles, and general weakness in the limb muscles. The muscle weakness is increased during exercise and reduced by rest. If left untreated, this disease may progress to cause respiratory dysfunction, which can further bring about a decrease in vital capacity (the amount of air exhaled in one breath)^{6, 9}. Many patients experience an intermittent worsening of symptoms triggered by infections, emotional stress, surgeries, or medications, particularly during the first year of the disease¹⁰

Therapy or Treatments:

Therapies for these patients include the administration of anti-acetylcholinesterase drugs (e.g. Neostigmine) and glucocorticoids (e.g prednisone), either alone or as a combined therapy. Anti-acetylcholinesterase drugs increase the amount of acetylcholine present in the synaptic cleft and glucocorticoids serve as immunosuppresants. When the aforementioned therapy does not work a thymectomy is often performed^8,9.

Clinical Case

A 65- year-old comes to the physician with ptosis and double vision. Upon questioning, the patient said that these problems are minor in the morning when he wakes up, but become worse as the day progresses and with repetitive muscle use. He has noted difficulty lifting objects and exercise intolerance. When the doctor asked the patient to look to the right and then to the left he noticed limitations in the ocular movements of both eyes. The doctor suspects MG and orders a radiological examination of the chest and AChR antibody testing of his serum. The radiological examination showed evidence of thymic enlargement and high amounts of AChR antibody. The diagnosis of MG was confirmed.

Multiple Sclerosis (MS):

MS is an autoimmune disease characterized by the demyelination of the axons of the brain and spinal cord [see figures 5 and 6]. These myelin sheaths that cover nerve cells are essential for transmitting proper nerve impulses throughout the entire body. When they are damaged, the nerve impulses are disrupted and eventually stop. MS is a progressive disease, meaning that the neurodegeneration gets worse over time. MS gets its name from the buildup of scar tissue, known as plaque [see figures 5 and 6], in the gray matter of the brain specifically in the area where the demyelination occurred. There are different types of MS [see figure 7]. This devastating disease affects more than 2.5 million people worldwide. According to recent studies, MS affects women more than it does men. The usual age of onset is between 20 and 40 years of age¹¹.

Causes and Immunopathology:

The definitive cause of MS is still unknown. It is speculated that genetic and environmental factors may influence the occurrence of MS. Doctors do believe it is caused mainly by an autoimmunity response of T cells on myelin proteins and oligodendrocytes. Expression of the HLA class 2 and HLA class 3 genes, a defective BBB, and vitamin deficiencies, especially vitamin D, have all been theories of the cause. Recently, studies have shown that IL-17, T helper 17 cells, B cells, CD8 T cells, and regulatory CD4 and CD8 T cells contribute to the pathogenesis of MS¹¹.

Symptoms: [see figure 8]

MS has many symptoms and all of them are associated with nerve information. These may include sensory, motor, visual, and cognitive symptoms. Patients suffering from MS usually have relapses of symptoms followed by periods of remission. The most common are muscle weakness, muscle spasms, muscle atrophy, fatigue, blurry vision, numbness, decreased balance, decreased coordination (ataxia), eye pain, mood swings, depression, dementia, erectile dysfunction, bladder and bowel incontinence, and neuralgia. Symptoms may change and sometimes worsen due to the continuity of the demyelination.

Therapy or Treatments:

There is no actual cure for MS although there are many beneficial treatments available for patients. Numerous drugs are administered to minimize the effect of attacks, each drug aiming at specific symptoms. Corticosteroids are given to neutralize the inflammation that occurs in a relapse. Beta interferons are used to slow the progressiveness of the disease. Physical therapy has had positive results in the mediation of the major symptoms. Patients that lead an active life and exercise have had better results than patients that lead an inactive lifestyle. These patients usually have less relapses and their symptoms become more manageable. Muscle relaxants are also important due to the painful muscle problems presented with MS¹².

A new hope:

In 2009 an Italian doctor, Dr. Paolo Zamboni developed a new type of treatment for MS. Encouraged by his wife, who suffered the devastating illness, he opted for a lifeline. Being a vascular surgeon, he came to realize that many veins in the brain were closed in MS patients, due mainly to stenosis. He called it chronic cerebrospinal venous insufficiency. The abnormal venous drainage of the azygous and internal jugular veins allegedly created a surplus amount deposited iron in the brain which, in turn, triggered an immune response. These veins were usually near the sites of the plaques caused by the demyelination. He then performed an endovascular procedure, balloon angioplasty, in which he reopened the veins and redirected blood flow. Two years after the procedure was performed on his wife and 65 other patients, 73% did not present a single symptom of MS, including his wife. Dr. Zamboni’s ideas have been perceived with mixed reviews. His liberating scientific approach has not been approved by all, creating a sort of controversy. Although it is a risky procedure, many have had a positive reaction to it, and some making it public with self made videos explaining their personal situations. Living with MS must be a devastating and especially a difficult thing. If there is a lifeline, everybody should be exposed to it, regardless of national medical approval¹³.

Clinical Case

A 36-year-old woman has had recurrent numbness on her right wrist, right thumb, and right index finger for a period of two months. She goes to the doctor to check for carpal tunnel syndrome. Upon evaluation, she also explains that she has been having problems with her vision. She states that her eyes get blurry from time to time. This has only happened twice so she felt it was due to stress. She also confesses of having difficulty swallowing, which she believes was caused by an allergic reaction. The doctor suspects a neurologic problem and orders her to have an MRI. The MRI with intravenous gadolinium showed small active plaques in the brain. An early diagnosis of MS was made. A lumbar puncture was then issued for confirmation. Electrophoresis of the cerebrospinal fluid showed abnormal levels of IgG antibodies, confirming MS.

Guillain-Barré Syndrome

Guillain-Barré Syndrome is an uncommon autoimmune disorder in which the body attacks part of the peripheral nervous system.

Causes and Immunopathology:

Although extensive research is underway, the exact cause or nature of the syndrome is not yet defined. The onset of symptoms begins to occur after a viral or bacterial infection affects the gastrointestinal or respiratory systems. In recent years, it has been discovered that autoantibodies attacking the peripheral nervous system leads to demyelination, which is thought to be brought about via the action of activated macrophages, T-1 helper cells, and cytokines. Antibodies target macrophages to invade the axon at the nodes of Ranvier, leading to axonal loss¹⁴. Due to the loss of myelin sheaths, peripheral nerves fail to transmit signals to the CNS, leading to loss of the ability of muscles to respond to cerebral commands. The cerebral cortex also fails to receive sensory signals from peripheral nerves. Motor and sensory signal pathways from extremities to the CNS are the longest, and therefore, the most vulnerable to lesions¹⁵.

Symptoms:

Symptoms usually first appear a few days or weeks after the infection. The onset of symptoms usually begins with loss of strength and tingling sensations in the lower extremities, specifically the legs, and rapidly extends in an upward fashion. The muscle weakness can become so serious that it can cause paralysis. In severe cases, ventilatory failure is caused by paralysis of the airway and respiratory muscles, specifically the diaphragm. The patient then must be put on a respirator to facilitate breathing. Cardiovascular instability is based on the association of the autonomic nervous system, leading to changes in blood pressure, arterial hypotension in particular, and cardiac arrhythmias. Other symptoms include arterial hypotension, uncoordinated movement, facial paralysis, palpitations, and blurred vision¹⁶.

Therapy or Treatments:

Although there is no known cure for Guillain-Barré Syndrome, therapies exist that aid in the recovery of these patients. The main purpose of these therapies is to maintain the patient's body function during the recovery period. Such therapies focus on the ventilatory dysfunction and cardiovascular instability presented by the patients. Plasmapheresis, or plasma exchange therapy, is commonly used in severe cases of Guillain-Barré syndrome. This type of therapy consists of the removal of the patient’s blood via a catheter system, separation of plasma from blood typically by means of centrifugation or filtration, and the return of the treated blood, which now does not contain the disease-causing autoantibodies¹⁷.

Clinical Case

A 35 y/o female patient presents to the emergency room because of bilateral tingling sensation and loss of strength in her lower extremities. She tells the attending physician that she had gotten sick with diarrhea after eating at her favorite restaurant, just a week prior to this visit. After a couple of days she seemed better, but then the diarrhea came back. Now she is experiencing clumsiness, bilateral uncoordinated movement and tingling sensations of upper and lower limbs, facial paralysis, and dysphagia. Upon examination, her temperature was 102 F and she did not have the normal knee-jerk reflexes in her legs. Results of a spinal tap indicate an abnormal amount of protein in cerebrospinal fluid, confirming the physician’s diagnosis of Guillain-Barré Syndrome.

Multiple Choice Questions

1) The blood-brain-barrier (BBB) is a physical and molecular barrier that prevents the passage of noxious substances from the blood to the brain. However, differences in the BBB throughout the central nervous system vary. Leaking of the blood vessels of the meninges is an example of such a difference. Lack of which of the following contributes to this leaking difference?

A. Cerebrospinal fluid (CSF)

B. GLUT-1 transporter

C. Astrocytes

D. Ependymal cells

E. Satellite cells

2) A 48-years-old man arrives at the emergency room at San Juan Bautista Medical Center (SJBMC) presenting with confusion, dizziness, numbness, and nausea. You suspect brain edema and order an MRI, which confirms your diagnosis. The characteristic inflammation of this condition results from disturbing the integrity of the strong tight junctions between endothelial cells. Loss of which of the following components is responsible for disturbing the integrity of the tight junctions?

1. Connexins
2. Claudins
3. Desmoplakin
4. Keratin
5. Cadherins
6. Catenins

3) Multiple Sclerosis (MS) is an autoimmune disease that attacks its own tissues, especially the central nervous system. Encephalomyelitis (EAE) serves as an animal model of MS. To better understand this disease, a group of mice were injected with proteins that produce myelin (induced EAE). These proteins create an autoimmune response against the mice’s own myelin. It is believed that effector T cells cross the blood-brain-barrier (BBB) and mediate myelin sheath damage. Using your knowledge, through what mechanism do effector T cells cross the BBB?

A. Simple diffusion

B. Active transport

C. Releasing chemicals that destruct the barrier

D. Using LFA-1 and VLA-4

E. Phagocytosis

Critical Thinking Questions

1) What type of hypersensitivity explains the pathogenesis of Guillain-Barre Syndrome?

2) How does an acetylcholinesterase inhibitor help in the treatment of myasthenia gravis? Mention the main secondary effects of the drug associated with the (a) digestive tract, (b) heart rate, (c) airway passages, and (d) sweat glands.

3) In Multiple Sclerosis (MS), a release of central nervous system antigens occurs, initiating the onset of an autoimmune disease. Describe the immunological mechanism that is thought to be responsible for the destruction of the myelin sheaths of nerve cells in patients with MS.

Videos

Guillian Barre:

http://www.youtube.com/watch?v=kDspLPFhkS4&playnext=1&list=PLCC1C17B3B2B8F8B9

Myasthenia Gravis:

Video 1: http://www.youtube.com/watch?v=ZscXOvDgCmQ

Video 2: http://www.youtube.com/watch?v=2NEjf347Xpk&playnext=1&list=PL056F54D88A6FABF8

References

1. Engelhardt B. The blood-central nervous system barriers actively control immune cell entry into the central nervous system. Current Pharmaceutical Design [serial online]. 2008; 14(16): 1555-1565. Available from: MEDLINE, Ipswich, MA. Accessed March 26, 2011.

2. Prendergast C, Anderton S. Immune cell entry to central nervous system--current understanding and prospective therapeutic targets. Endocrine, Metabolic & Immune Disorders Drug Targets [serial online]. December 2009; 9(4): 315-327. Available from: MEDLINE, Ipswich, MA. Accessed March 26, 2011.

3. Bottasso O, Morales-Montor J. Neuroimmunomodulation during infectious diseases: mechanisms, causes and consequences for the host. Neuroimmunomodulation [serial online]. 2009; 16(2):65-67.

4. Bartholomäus I, Kawakami N, Flügel A, et al. Effector T cell interactions with meningeal vascular structures in nascent autoimmune CNS lesions. Nature [serial online]. November 5, 2009; 462(7269): 94-98. Available from: MEDLINE, Ipswich, MA. Accessed March 26, 2011.

5. Murphy, K., Travers, P., & Walport, M. (2008). Janeway's Immunobiology. New York, NY: Garland Science.

6. Geha, R., Rosen, F., (2008). Case Studies in Immunology: A Clinical Companion. 5 ed. P.243 -246. New York, NY: Garland Science.

7. Huges, B., Moro, M., Kaminiski, H. Pathophysiology of Myasthenia Gravis. Semin Neurol 2004; 24(1): 21-30. DOI: 10.1055/s-2004-829585.

8. Dunn, A.J (2000). Interactions Between the Nervous System and the Immune System. Psychopharmacology - The Fourth Generation of Progress. http://www.acnp.org/g4/gn401000069/ch069.html

9. Siegel, A., Sapru, H. (2006). Essential Neuroscience. P. 130-131. Philadelphia, PA: Lippincott Williams & Wilkins.

10. Meriggioli, M.N; Sander, D.B. (2009). Autoimmune myasthenia gravis: emerging clinical and biological heterogeneity. The Lancet Neurology, Volume 8, Issue 5, Pages 475 – 490.doi:10.1016/S1474-4422(09)70063-8.

11. Kasper, H., Shoemaker, J. Multiples sclerosis immunology, The healthy immune system vs the MS immune system. Neurology. 2010;74(1):s2-s8. DOI: 10.1212/WNL.0b013e3181c97c8f.

12. Dalgas, U., Ingemann-Hansen, I., Stenager, E. Review: Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training. Multiple Sclerosis Journal. 2008;14(1): 35-53. DOI: 10.1177/1352458507079445.

13. Bartolomei, I., Dall’Ara, S., Galeotti, R., Malagoni, A., Menegatti, E., Tacconi, G., Zamboni, P. Chronic cerebrospinal venous insufficiency in patients with multiple sclerosis. Journal of Neurology Neurosurgery & Psychiatry. 2009;80:392-399 DOI:10.1136/jnnp.2008.157164.

14. Hughes, Richard AC; Cornblath, David R. Guillain-Barré Syndrome. The Lancet. 2005 Nov; 366(9497): 1653-1666.

15. Radziwill, AJ; Kuntzer, T; Steck, AJ. Immunopathology and treatments of Guillain-Barré syndrome and of chronic inflammatory demyelinating polyneuropathy. Rev Neurol (Paris). 2002 Mar; 158(3): 301-10.

16. NINDS. National Institute of Neurological Disorders and Stroke. Guillain-Barré Fact Sheet. http://www.ninds.nih.gov/disorders/gbs/detail_gbs.htm. Updated May 2, 2011. Accessed May 2, 2011.

17. Hund, Ernst F. MD; Borel, Cecil O. MD; Cornblath, David R. MD; Hanley, Daniel F. MD; Mckhann, Guy M. MD. Intensive management and treatment of severe Guillain-Barre syndrome. Critical Care Medicine. 1993. 21(3):433-446.