Can a virus stabilize Multiple Sclerosis?

Multiple Sclerosis (MS) is a neurodegenerative disease in which the neurons in the central nervous system (CNS; brain and spinal cord) cannot communicate effectively. The root of the disease is the degradation of the sheath of fat that surrounds some CNS neurons (myelin) - thus disrupting the effectiveness with which the neurons can survive and signal to each other. This destruction of the neurons is largely thought to be a result of the body attacking itself (an autoimmune disease), and not originating from an outside bacteria or virus; this hypothesis is largely the result of mice models that show that injecting components of this myelin sheath into a mouse will make the mouse exhibit MS-like symptoms.

Ref: http://health.howstuffworks.com/diseases-conditions/musculoskeletal/multiple-sclerosis1.htm

Although it seems as if this disease's cause is well-known and can be modeled well in animals, effective therapies to MS have proven hard to develop - one reason for this is that MS is different in almost every patient as to when it is symptomatic or not. This variation is so great that MS is characterized into many types of the disease such as relapse-remitting MS (RRMS) which the patient experiences many symptoms for months and then relapses into a largely symptom free condition, only to repeat in the future. Further, secondary progressing MS (SPMS) is a type of the disease - when symptomatic - declines at a devastating rate. There are more types, such as some that do not relapse and a continual decline is observed. It has been hypothesized that the Epstein-Barr virus (EBV; commonly known to cause mononucleosis) has some influence on this stability of disease - although results have not been very conclusive. This variability in the disease, as you can assume, confounds scientists researching therapies and potential cures to this devastating disease.

In hopes of elucidating why this variability is so great in this disease and if EPV has a role in disease stability, Annunziata et al in Italy investigated the role of EPV-positive B cells in disease severity. By extracting B cells from patients with MS, they examined the spectrum of antibodies that were produced by the MS patients of varying disease type. Initially, they identified 7 monoclonal antibodies (mAbs) that were found to bind a specific epitope (105-120) in one of the components of myelin that surround the neurons, MBP (myelin-basic protein). They chose this epitope of MBP because these mAbs were detected in the more 'stable' MS patients - and hoped to find something unique in these patients' body responses to the disease. Further testing included myelin-reactive T cells from MS to be evaluated in environments of the mAbs. Interestingly enough, only 3 mAbs showed dose-dependent inhibitory effects to the T cells - which are thought to contribute to the damaging environment in MS.

Innate Immune System may be more involved in Multiple Sclerosis than Previously Thought

        Among the many types of autoimmune disorders perhaps the most interesting and least understood disorders are those in which the immune system attacks the central nervous system.  Multiple Sclerosis (MS) is an autoimmune disorder in which invading lymphocytes attack the protective insulation of neurons called myelin.  The disease is neurodegenerative and leaves patients wheelchair bound within a few short decades of its clinical presentation.  While scientists have unraveled many of the pathological hallmarks of the disease, its cause and effective treatment remain elusive. 

Lesions in an MS brain

            A new study in the Journal of Immunology published this month investigates the types of white blood cells that are involved in the attack of white matter (myelin) in the brain.  Previous studies have identified a subset of Helper T cells as a major cause of the pro-inflammatory environment which leads to the ultimate degeneration which is characteristic of the disease.  These cells are part of the adaptive immune systems which targets very specific pathogens and in some cases (like in MS) accidentally targets cells or proteins that are part of the body’s normal function.  However, the new article presents data that demonstrates that innate immune cells called neutrophils may be playing a role in the initial stages of the disease.  These innate immune cells are non-specific to any particular protein but instead identify and attack cells with general molecular patterns associated with invading pathogens.  This is the first time it has been shown that neutrophils have been involved in MS.  

New EAE Models More Accurately Reflect MS

Multiple Sclerosis (MS) affects about 400,000 people in the United States. In MS, the myelin sheath that coats our neuronal axons is degraded, as are the cells that produce myelin (also known as oligodendrocytes). MS is considered an autoimmune disease because the attack is facilitated by our body’s own immune system. This degradation of the myelin sheath affects the ability of our neurons to transmit electrical signals to each other. This manifests itself in the symptoms often associated with MS: numbness in limbs, paralysis and vision impairment.

In order to study MS, researchers often employ the use of animal models. Specifically, Experimental Autoimmune Encephalomyelitis (EAE) is a well recognized mice model that mimics the progression of MS. EAE is considered a Th1 focused disease with T cells secreting primarily IFNϒ. T cells are immune cells in the body that participate in cell-mediated killing of foreign pathogens (1). In MS, they recognize our myelin as a foreign substance and proceed to destroy it. One way they do this is by secreting cytotoxic cytokines, such as the aforementioned IFNϒ. When inducing EAE in mice, this Th1 response is ensured by injecting a myelin peptide(to mount an immune response against) along with complete Freunds adjuvant (CFA), which contains a bacterium called M. Tuberculosis (CFA).

Aside from IFNϒ, IL-23 has emerged as a notable cytokine because mice deficient for it remained protected against EAE pathology. Furthermore, IL-23 promotes the differentiation of inflammatory Th17 cells (2). Numerous EAE models currently exist; some more representative of MS in certain clinical regards (e.g., onset, clinical progression, and remission). Therefore, it’s vital to always explore new EAE models in an effort to find one that best represents human MS. In a recent study by Smith et al. 2011, researchers replaced M. tuberculosis with C. rodentium (CRA)in the injected adjuvant. CRA is a bacteria known to induce an IL-23 dependent Th17 response (as opposed to the aforementioned M.tuberculosis-mediated Th1 response) to find out whether different EAE phenotypes would emerge.

Multiple Sclerosis: the Good, the Bad, and the Ugly of TNF

Multiple sclerosis (MS) is a disease that affects over 2.5 million people worldwide. It is typically first diagnosed in patients in their 20s and 30s and is most common among women (Trapp and Nave, 2008). MS is characterized by areas in which myelin, a collection of lipids and proteins that forms a protective and insulating layer around portions of neurons, is destroyed (also known as demyelination). This damage occurs most often in the brain and spinal cord, impairing the transmission of signals among nerve fibers. MS is considered to be an autoimmune disease because a person’s immune system attacks self tissues, in this case myelin and myelin-producing cells. A large amount of this damage it is thought to stem from the activation of autoreactive CD4+ T cells that recognize peptides from the myelin sheath. (In healthy patients, these CD4+ T cells - also known as “helper” T cells - are not autoreactive and help B cells produce antibody.) As the disease course of MS progresses, symptoms increase in severity and include dizziness, impaired thinking, tremors, and difficulty walking.

Tumor Necrosis Factor (TNF) is a cytokine (a subset of small cell-signalling proteins) that has been linked to MS and is expressed by many cell types (Grivennikov et al., 2005). This protein can trigger either cell death or cell survival and can it also mediate inflammation. Inflammation is a local response at a site of infection caused by the influx of leukocytes, which are cells that attempt to combat infection; infiltration of inflammatory cells is common in the brains and spinal cords of MS patients. High levels of TNF have also been observed in MS and other autoimmune disorders (Hohnoki et al., 1998); blockade of TNF is actually an approved treatment for some of these diseases, including rheumatoid arthritis (Feldmann and Maini, 2001). Nevertheless, the role that TNF plays in MS is still controversial.

A model called Experimental Autoimmune Encephalomyelitis (EAE) can be used among mice to study multiple sclerosis. EAE is induced by injecting mice with proteins that comprise myelin. In a recent study, published in the Journal of Immunology, Kruglov and colleagues (et al., 2011) used an EAE model to assess the roles of different cellular sources of TNF during EAE. The mice were scored daily on the basis of their clinical symptoms on a scale ranging from 0 to 6, where 0 = no disease and 6 = moribund.

B Cell Derived IL-15 Enhances CD8 T Cell Cytotoxicity and is Increased in Multiple Sclerosis Patients

Multiple sclerosis (MS) is an autoimmune disease that causes damage to the tissue of central nervous system (CNS). Specifically, multiple sclerosis results from unregulated inflammation that damages a nerve’s myelin sheath – protective coating that protects and insulates the axon of a nerve cells. When the myelin is damaged, transmission of CNS signals is slow and inefficient [1]. Damaging inflammation can occur in the brain, optic nerve, and spine and result in a variety of debilitating symptoms including: muscle spasms, numbness, tremors, weakness, difficulty walking, and problems with coordination [2].

Previous research has confirmed that CD8 T cells significantly contribute to the pathogenesis, or development of multiple sclerosis. Activated CD8 T cells are believed to secrete pro-inflammatory cytokines, or intracellular chemical signals, which release lytic enzymes upon recognition of a target cell surface receptor. Lytic enzymes are proteins that facilitate the breakdown of cell components. CD8 T cells bind to target cells that are damaged or infected with a pathogen, and release a granule containing lytic enzymes. The binding of an activated CD8 target cell initiates granule mediated cell destruction. In the case of MS, autoreactive CD8 T cells bind to healthy nerve cells and release lytic enzymes, resulting in damage to the myelin sheath [3].

Schneider and colleagues argue that IL-15 significantly contributes to the development of multiple sclerosis. IL-15 is a cytokine that regulates the development, activation, and proliferation of CD8 T cells. Previous research has concluded that elevated levels of IL-15 have been detected in a number of inflammatory diseases including rheumatoid arthritis, celiac disease, psoriasis, and inflammatory bowl disease. Additionally, elevated levels of IL-15 have also been identified in the peripheral blood of MS patients. In the present study, researchers hope to explore the role that B cells play in producing IL-15 in the peripheral blood of MS patients. In addition, the authors hope to explore the effect of IL-15 on enhancing CD8 T cell activity.

Commensal Microorganisms in the Gut: Friend or Foe?

Before we leave a public bathroom, how many times do we see or hear the phrase, “Did you wash your hands?” Chances are, we have seen or heard this plenty of times. As children, we were often reminded by our parents to wash our hands before and after eating, after handling dirty items, or after going to the bathroom. The obvious reason is to eliminate the germs that we have come into contact with throughout the day. However, as we all know, bacteria are not entirely harmful to our well-being. In fact, some bacteria in our gut function to keep us healthy. They help digest food, aid us in acquiring vitamins and nutrients, train our immune system, and compete with pathogenic bacteria that may otherwise be harmful to us. As such, they are called commensal microorganisms. Certain diseases caused by pathogenic bacteria are treated by a process called fecal matter transplant. This medical procedure involves the introduction of the normal gut flora obtained from the stool of a healthy donor in order to restore the gut microbiota of the infected individual. The concept behind this procedure is that the commensal microorganisms obtained from the stool will eventually outcompete the pathogenic bacteria responsible for the disease. For example, Pseudomembranous colitis, which is caused by Clostridium difficile, uses fecal matter transplant as one feasible treatment option. In the process, non-pathogenic bacteria are introduced into the colon of the patient in order to outcompete C. difficile for resources. However, is the commensal microbiota as beneficial as it is portrayed? Studies aimed towards understanding the pathology of multiple sclerosis (MS) would beg to differ.

MS is an autoimmune disorder of the central nervous system (CNS) where the myelin sheath, which wraps around the axon and facilitates the conduction of nerve signaling, is attacked by the immune system. The resulting demyelination causes signals between neurons to be delayed and this consequence is manifested through clinical symptoms that include numbness, motor dysfunction, and vision problems. In terms of the immune response, MS is mostly associated with increased CD4+ T cell infiltration into the CNS. This T cell infiltration is also accompanied by increased production of autoantibodies by B cells, which can attack the specific myelin proteins that make up the myelin sheaths. Several studies are aimed towards understanding what goes awry in MS, however, numerous questions remain unanswered regarding this disorder. Microbial infection has been attributed to this autoimmune disorder (Ascherio et al. 2007). As mentioned earlier, the commensal microbiota has been linked to the treatment of certain diseases by outcompeting pathogenic microorganisms. Therefore, could the microbiota also play a role in treating MS? A recent study shows that in the case of MS, commensal microbiota triggered autoimmune demyelination instead of alleviating MS symptoms.

Bye-Bye B Cells, Hello MS Treatment

Multiple sclerosis is a chronic inflammatory disease that affects the brain and spinal cord, or central nervous system (CNS), leading to sensory and motor impairments. MS is more common in women than in men and is typically diagnosed between the ages of 20 and 40. Approximately 400,000 individuals in the United States currently have MS and more than 2.1 million people worldwide live with the disease. MS is diagnosed as one of two forms, either relapsing-remitting (RRMS) or primary progressive (PPMS). The vast majority of patients are initially diagnosed with RRMS, which is characterized by periods of exacerbation, or flare-ups, followed by periods of remission. Patients with PPMS do not experience remissive phases. Most of the medications approved for MS treatment are aimed toward ameliorating the relapsing-remitting disease course. Currently, MS is commonly treated with an interferon beta (IFN beta) drug, which reduces disease activity, in combination with other medications that target the various symptoms experienced by patients (2).

The clinical presentation of MS varies from person to person; however, pathologically, the disease results from an autoimmune attack on myelin sheath (a protective covering around nerve fibers). Immune cells (lymphocytes) become self-reactive against certain proteins that make up myelin and subsequently destroy it. This process is called demyelination. When the myelin sheath is damaged, signaling between nerve cells becomes slowed or prevented altogether. As a result, simple tasks like walking become quite difficult, and patients may experience vision impairments, episodes of numbness and tingling, loss of balance and coordination, as well as other symptoms. Unfortunately, the mechanism through which an individual develops MS is not entirely understood, and therefore, the repertoire of treatment targets is limited. In order to gain a better understanding of the cause and progression of MS, researchers use various animal models of the disease. The most commonly used MS model is experimental autoimmune encephalomyelitis (EAE), which can be induced in a variety of animal species including certain rodents and non-human primates. In the upcoming November issue of the Journal of Neuropathology and Experimental Neurology, a study by Kap and colleagues investigates whether or not B cell depletion (an experimental treatment for MS) is a valid therapeutic target (1). The authors employed an EAE study in the common marmoset (monkey species). Marmosets were first utilized to examine the clinical and pathological features of MS in 1996, and have been found to exhibit a disease course more closely related to human MS than that observed in rodent models. The marmoset EAE model demonstrates widespread demyelination in both white matter and grey matter of the CNS, strongly resembling the conditions of MS in humans. Furthermore, marmosets have similar immune and nervous system genes to humans, establishing another advantage of using this model (3).

Breaching the Great Wall: Attack of the Immune Cells on the Central Nervous System

The brain is considered the most complex living structure known in the universe. This organ is responsible for controlling all bodily functions ranging from heart rate to motor functions. Given the complexity and importance of the brain, it is vital that proper defenses are maintained, one of which is the blood brain barrier. The blood brain barrier (BBB), as the name implies, serves as an anatomical barrier against invading pathogens by blocking their entry into the brain. Think of it as the Great Wall of China that was built in order to protect the Chinese empire against invasion by nomadic tribes. In this analogy, the brain would be considered the Chinese empire. Similar to the bricks and stones making up the Great Wall, tight junctions present between the endothelial cells of the blood vessels make up the BBB and they function to allow passage of only certain molecules such as oxygen. Even molecules such as glucose must undergo an active transport mechanism in order to pass through the BBB. The central nervous system (CNS) is considered an immunoprivileged organ in that CNS antigens are not accessible to immune cells in the periphery. Likewise, peripheral immune cells and pathogens cannot easily penetrate the BBB.

During the course of various neurological diseases such as multiple sclerosis (MS), vascular dementia, and stroke, this great wall becomes compromised thereby triggering the infiltration of immune cells into the CNS. This process in turn causes inflammation. Studies on animal models of these diseases aim to unravel the mechanisms by which certain immune cells breach the BBB (Simka, 2009). Unraveling such mechanisms provides therapeutic targets for future investigations in the hope of finding an effective treatment.