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).

A Mechanism for Low Zone Tolerance and Implications for Allergies

Allergic reactions occur when the immune system reacts to an allergen found in the environment, promoting hypersensitivity towards the substance. These reactions are normally quite docile but can become very severe. These allergens can be quite common (such as peanuts, shellfish, gluten, etc.), raising the question: why do some people initiate an immune response to them and others don't? One answer is low zone tolerance (LZT), which involves the repeated exposure to small doses of an antigen. At the other end of the spectrum is high zone tolerance, occurring when individuals are exposed to a high dose of an antigen. LZT is believed to be one of the main routes by which tolerance to an antigen is developed. Failure to install LZT may be due to a high dose exposure during the first initial contact, leading to contact allergies (Luckey et al. 2011). Contact allergies are fairly prevalent in the population, affecting approximately 10% (Cavani et al. 2007). Therefore, allergies are just another example that bolsters the importance of immune tolerance. Autoimmunity is an additional example of when tolerance goes wrong, specifically when the immune system initiates an attack against itself.

Lucky et al. (2011) decided to examine the mechanism by which LZT is initiated, a process which is largely unknown. Previous research by Lucky's group determined that LZT is maintained by CD8+ suppressive T cells, a certain subset of T cells. These cells are induced to develop after stimulation by IL-10, a chemical messenger, which is secreted by helper T cells. The authors connected this information with another chemical messenger hypothesized to regulate the LZT response, Tumor Necrosis Factor (TNF). TNF is a cytokine messenger which is secreted as part of the immune response and has a myriad of functions from promoting inflammation and apoptosis to exerting immunosuppressive effects. TNF binds to two receptors TNFR1(p55) and TNFR2 (p75) (Locksley et al. 2001). These two different receptors are what give TNF such dual-sided functions.

Wandering between Two Worlds: A Closer Look at the Neuroimmune Communication

Do you pass out when you see blood? Have you ever been so emotionally shocked that the next thing you know, you are lying on the floor surrounded by people asking if you are all right? Fainting is a consequence of direct stimulation of the vagus nerve. This nerve is often termed, the “wandering” nerve, because as it leaves the brainstem, it “wanders” through organs in the neck, thorax, and abdomen. This means that the vagus nerve regulates various tasks such as heart rate, swallowing, speech, and breathing – tasks that are vital for our existence. Most of us likely know someone suffering from hypertension and the cardiac diseases associated with high blood pressure. However, low blood pressure can be as equally dangerous because it can lead to stimulation of the vagus nerve, which causes the blood flow to be redirected from the brain to the heart and the rest of the body. Such a temporary lack of blood flow and oxygen to the brain triggers vasovagal syncope, a fancy term for what we call fainting. During emotional shock, there is an increased stimulation of the vagus nerve, which in turn leads to slowing of the heart thereby causing a blood pressure drop and hence, fainting. Stimulation of the vagus nerve does not only result in fainting, but it also triggers vomiting. If you are an EMT, this is the reason why an oropharyngeal airway (OPA) must only be used on unconscious patients without a gag reflex. Insertion of the OPA in the back of the pharynx may stimulate the vagus nerve and result in vomiting, thereby presenting an airway obstruction.

This wandering nerve is not only involved in the physiological tasks that are vital for us, but it has also been implicated as an immunomediator thereby presenting a linkage between the nervous and the immune system. Research aimed towards understanding the mechanisms behind neuroimmune communication has been gaining popularity in recent years. For instance, receptors for the neurohormone, melatonin, a regulator of the circadian rhythm, has been found on human T cells, hence giving melatonin regulatory functions in the immune system as well (Lardone et al. 2011). Likewise, cytokines secreted by immune cells also control neural and glial activity in the brain such as neuroplasticity, a phenomenon that takes place during learning and memory where new neural synapses are formed or reorganized (Huh et al. 2000). Furthermore, major histocompatibility complex (MHC) proteins, which allow antigen presentation in the immune system, are also found in neurons (Trakhtenberg and Goldberg, 2011). If cytokines released by immune cells can regulate neuronal function, can other neurotransmitters released by neurons also regulate immune function?

Trick or Treat: Trick your Immune System and Turn off your Peanut Allergy

“We think we’ve found a way to safely and rapidly turn off the allergic response to food allergies,” 

says Paul Bryce, an assistant professor at Northwester University

Anaphylaxis is the body’s severe, allergic reaction to an allergen. It occurs after the initial exposure to a foreign substance such as a peanut or bee sting venom causes a body to become sensitized to that substance.  On a second exposure to this foreign substance, the body recognizes it as an allergen triggering an adverse reaction, which can result in anaphylaxis. Typically within 15 to 30 minutes of exposure, the body undergoes a severe reaction.  Some of the symptoms include throat swelling, an itchy rash, low blood pressure and/or shock which can eventually lead to loss of consciousness and death.  During anaphylaxis, tissues from different parts of the body release histamine and other cytokines that can cause the airways to tighten the throat to close.  According to the National Institutes of Health (NIH), approximately 15,000 to 30,000 episodes of anaphylaxis and 100 to 200 related deaths occur each year within the United States.

            From an immunological perspective, anaphylaxis is classified as a type 1 hypersensitivity. In type 1 hypersensitivity, an antigen producing cell (APC) presents an antigen to a CD4+ Th2 cell which stimulates B cell proliferation, differentiation and production of IgE antibodies specific to the antigen.  The IgE antibodies bind to Fc receptors on the surface of mast cells and basophils.  These coated cells are termed “sensitized” by the IgE. When the body is exposed to the same allergen another time, the bound IgE on these sensitized cells cross-link. This interaction signals the release of active mediators of inflammations such as histamine, leukotriene, and prostaglandin to the surrounding tissues which leads to anaphylaxis.

 All of this research raises the question of why do some people develop hypersensitivity while others do not? The exact mechanism as to why some individuals are more prone to type-I hypersensitivity is not fully understood. However, previous research has shown that individuals with this form of sensitivity produce more TH2 cells that secrete IL-4, IL-5 and IL-13 which promote isotype switching to the IgE production observed in this allergic response.

            For highly allergic individuals, even the smallest amount of allergen can provoke anaphylaxis. Currently avoidance and symptom control are the most widely used means to cope with most allergies. Therefore in his study titled Antigen-Fixed Leukocytes Tolerize Th2 Responses in Mouse Models of Allergy, Smarr and his team of researchers attempted to find a more pragmatic cure for allergies.  In previous research projects, Smarr’s team has demonstrated that intravenous administration of peptides attached to the surface of syngeneic splenic leukocytes termed Ag-coupled splenocytes (Ag-SPs) with the chemical crosslinking agent 1-ethyl-3-(39-dimethylaminopropyl)-carbodimide (ECDI) safely and efficiently induced Ag-specific immune tolerance.  This enabled the team to attach an antigen the hypersensitive person would normally recognize as foreign and attack, such as antigens from peanuts, to white blood cells called leukocytes.  When these modified white blood cells were reintroduced into the individual the individual would not experience the life-threatening allergic reaction because their immune system now recognizes the antigen as safe. Their previous success with this model in autoimmune studies with TH1/Th17 mediated models encouraged them to extend their work with this model to study Th2 models associated with food allergies.

The Defense Against Infection Deserves a Complement

For most of us, developing a bacterial infection is at a minimum no fun, and usually quite irritating. We don’t really consider what actually goes on inside of our bodies, and as a result, fail to appreciate the vast population of cells and molecules dutifully combating the bacterial invaders. Maybe we ought to reconsider our sentiments towards being sick.

The immune response following each attack of a foreign entity (‘pathogen’) on our bodies is highly complex and actually pretty amazing. Two types of responses may occur – the innate and the adaptive immune responses. The innate response is the first line of defense, and is mitigated by physical barriers like the skin and mucosa lining our digestive and respiratory tracts, as well as by actions like sneezing and coughing. White blood cells (‘leukocytes’) carry out various functions like phagocytosis (engulfing and digesting a large pathogen into small parts) and target cell lysis (killing), which are examples of induced innate responses. If the innate response does not effectively clear our bodies of the pathogen, then certain immune cells (‘lymphocytes’) are subsequently activated to launch a highly specific and intense counterattack involving antibody secretion and precise killing of pathogen.

An important connection between the two types of immune responses is established by something called the complement system. Complement is composed of a collection of various serum (present in bodily fluid) proteins that become sequentially triggered in a closely controlled cascade. The chronological activation of each component protein in the complement system can be thought of as a medley relay race in swimming, where each swimmer swims a different stroke, and the first swimmer must finish his or her part of the race before the next swimmer can begin. However unlike a relay race, where the winners receive an award, complement activation results, for example, in the killing of a pathogen, or in the coating of a pathogen with a particular complement protein (called ‘opsonization’). Opsonization is important in helping leukocytes engulf and digest pathogens more easily, so that the foreign entity may be cleared from circulation and tissue with greater efficiency. Many of the complement proteins are named with the letter C followed by numbers 1-9. Other proteins are named as Factors that have been assigned a single letter (i.e. Factor B, Factor D, etc.). The complement system can be activated by three biochemical pathways: classical, lectin, and alternative. The classical pathway is dependent on the presence of antibody, which means that the adaptive response must be initiated before complement can be activated. However, the lectin and alternative pathways are purely part of innate immunity, and do not involve the interaction with antibody. This review will focus on lectin and alternative complement activation, as an article recently published elucidated a novel role of a protein interestingly involved in both of these pathways (1).

It Takes Two To Tango: CD4 T Cells and APCs Interact in Stages

The cell-cell contacts formed between a lymphocyte and antigen-presenting cell (APC) are a prerequisite for activation. This contact, the immunological synapse, facilitates communication between the cells which leads to the lymphocyte's effector abilities, be it targeted killing or secretion of chemical messengers. However, activation isn't simply a 'one touch' mechanism, but rather requires three distinct signals and plenty of time. For CD 4 T cells (helper T cells), the first signal is binding of its T cell receptor (TCR) to a peptide-MHCII complex on an APC, followed by co-stimulatory contacts between other surface molecules, and finally the secretion of cytokine chemical messengers. This dance between the T cell and APC can last as long as six hours (Huppa et al. 2003)! Once activated helper T cells can differentiate into effector cells and memory cells. Effector helper T cells secrete signaling molecules to help orchestrate the actions of other immune cells (think of them as a conductor of a band). Memory helper T cells can also complete similar functions but these cells persist over time so that if the pathogen attacks again the immune response may be quicker. In a recent study (Ueda et al. 2011), this interaction between helper T cells and APCs was analyzed over time. The authors recognized that six hours is a long time for two cells to be engaged, thus there must important intra- and intercellular events occuring during this period. They analyzed and characterized four distinct stages which occur during this six hour dance-a-thon between the helper T cell and APC.

In this study, the authors used two types of APCs, a class of B cells (CH27) and bone marrow derived dendritic cells (BM-DCs). The helper T cells were isolated from a trangenic TCR mouse line. The APCs were designed to present a specific antigen on their surface, moth cytochrome c (MCC). Simply, the two cell types were incubated together and then froze under high pressure. High pressure freezing helps to faithfully preserve the cell contacts which will be analyzed (Osumi et al. 2006). Three specific microscopy methods were utilized, electron microscopy with 3D tomography (EM), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). EM simply involves shooting a beam of electrons through a sample at different angles to visualize the 3D structure of larger molecules within a cell. SEM and TEM are similar variants, SEM usually results in a better resolution for molecules on the surface of a cell while TEM is better for internal examination of a cell.

A Chronic Viral Infection May Affect Ability to Fight Off Bacteria

The prevalence of viruses like HIV and Hepatitis C, which cause chronic infections, raises questions about the long-term effects of infection on the immune system. These questions include: How does the immune system’s composition change in response to a chronic infection? How do the immune system’s effector functions change? How is a defense mounted against other simultaneous infections? In a recent PLoS Pathogens article, Zajac and coworkers address some of these questions. They describe a population of cells, called exhausted T cells, which develop from chronic viral infection and have a reduced ability to fight bacteria.

The presence of an intracellular pathogen, like a virus, rallies a population of T cells to combat the virus. Among the cells produced are effector and memory CD8+ T cells. Effector CD8+ T cells are capable of lysing (killing) cells infected with the same virus that induced their production. Memory CD8+ T cells, on the other hand, wait for further stimulation (a second infection with the same virus) to proliferate and produce the next generation of effector cells. These functions constitute an adaptive response, where T cells respond to one antigen (the virus) specifically.

In addition, effector and memory CD8+ T cells can mount a broader innate-like response that does not require the presence of the specific antigen that induced their production. For example, if effector or memory CD8+ T cells receive cytokines (molecular signals) IL-12, IL-18, and IL-21, produced in response to an infection, they can secrete a cytokine called IFN-gamma that helps other cells take action against the infection. Here the memory and effector cells are responding not to one antigen, but any antigen that induces production of IL-12, IL-18, and IL-21.

While it was already known that exhausted T cells, produced from persistent viral infection (think: less effective versions of effector/memory cells), mount weaker adaptive responses than normal effector or memory T cells (2), Zajac and coworkers found that exhausted T cells mount weaker innate-like responses, as well.

Anti-myelin antibodies in Pediatric Multiple Sclerosis

Multiple Sclerosis (MS) is an autoimmune disease that affects the brain and spinal cord, otherwise known as the central nervous system (CNS). Though common symptoms include numbness in limbs, paralysis, and vision impairment, the progression of the disease varies person to person. Additional symptoms such as seizures may accompany pediatric MS which affects 8,000-10,000 children in the United States. Pediatric MS is a difficult area to study because of its low prevalence and differences from adult MS.

The autoimmune component of MS refers to the degradation of the myelin sheath, a lipid-rich tissue that encapsulates our neuron’s axons and mediates the conduction of signals throughout our body. The attack on myelin is carried out by T cells, a type of white blood cell, which recognize our myelin as a foreign entity and subsequently destroy it. This autoimmune response is further characterized by the production of myelin specific antibodies, that is, proteins secreted by B cells to target specific pathogens (1). Without myelin, the body develops the aforementioned symptoms. In a study published by O’Connor and colleagues in the journal of neuroimmunology, researchers examined the levels and binding characteristics of antibodies for immature (pediatric) and mature (adult) human MBP (a protein that makes up myelin) in the serum of children with MS and controls in an effort to better understand the contribution of antibodies in early MS onset and how it further illuminates the differences between pediatric and adult MS.

Finally Reaching Out: Ralph Steinman Wins Nobel Prize for Fingery Find

This past Monday the Nobel Prize in Physiology or Medicine was awarded to a very deserving candidate: Ralph Steinman. Steinman, however, never received the final good news, as he passed away from pancreatic cancer just three days prior to the announcement. He is the first laureate to be awarded a posthumous Nobel Prize, which is against the regulations of the foundation.¹ Steinman was awarded the prize for his discovery of dendritic cells, “a kind of sentinel”² looking for pathogens in the body.

Dendritic cells (DCs) were given their descriptive name due to their physiological appearance, with many finger-like extensions that protrude from the main cell body increasing the surface area of the cell for the intake and output of information from and to other cells in the body. Dendritic cells come in several different types. Some DCs, called “migratory” DCs, roam the periphery of the body searching for foreign substances or dead cells that they can engulf. The internalized substances are then processed in the DC and presented on the cell’s surface, so that a passing B or T cell might recognize the presented pathogen and go find it in the body to fight. “Resident” DCs reside in the lymph nodes of the body, sampling the lymph for pathogens and undergoing the same pathways of processing and presenting pathogens as the migratory DCs.

Steinman first discovered dendritic cells in 1973, and died three days before his work was recognized with the highest of honors: the Nobel Prize. Upon his initial discovery, the scientific community was hesitant to accept Steinman’s finding, as his results did not seem reproducible. Reproducibility is the hallmark of a significant scientific finding, and so it was not until many years later, when dendritic cells were isolated in large quantities, that Steinman’s finding was widely accepted and celebrated. Modernly, dendritic cells are arguably considered to be one of the most significant elements of the immune system. Dendritic cells are antigen-presenting cells (APCs), which gives them the capability to express both endogenous and exogenous antigens, and they also possess the ability to activate B and T cells, which have cytotoxic capabilities.