Mycobacterium tuberculosis and Immune Evasion

Many of you have likely heard of tuberculosis (TB), a potentially lethal, infectious disease caused by intracellular bacterium called Mycobacterium tuberculosis. Although this bacterium usually attacks the lungs, it can also affect other parts of the body including the brain, the spine, or the kidneys. Tuberculosis germs are spread through the air, particularly when an infected person coughs, sneezes, or vocalizes. Symptoms of tuberculosis include weakness, a chronic cough, night sweats, fever, and weight loss. Tuberculosis is one of the world’s deadliest diseases. In 2012, there were 1.3 million tuberculosis related deaths worldwide (World Health Organization 2013). In fact, one-third of the world’s population is infected (Centers for Disease Control and Prevention 2013).

It is important to distinguish between two tuberculosis conditions: latent TB and active TB (also known as TB disease). Latent TB is defined by the presence of a TB infection, but the bacteria remain in the body remain inactive and do not cause symptoms. This is because the immune system acts to “wall off” the bacteria using a cellular structure called a granuloma which forms around the invaders. Active TB occurs when the immune system cannot prevent the TB bacteria from multiplying in the body. A person with active TB will be contagious and exhibit symptoms. People most susceptible to developing active TB disease are those who have been recently infected by TB bacteria or those with medical conditions that weaken the immune system such as HIV infection, tobacco use, or diabetes mellitus. Specifically, 90% of infected patients will have latent TB, while only 10% will progress to disease (World Health Organization 2013). TB is generally curable with antimicrobial drugs, but in many underdeveloped nations, access to such health care is unattainable. If untreated, 50% of active TB disease cases are fatal (World Health Organization 2013). Additionally, resistance to the medicines is increasing. This is evidenced by the emergence of multi-drug resistant TB, which is the result of bacteria that do not respond to standard anti-TB drugs (Centers for Disease Control and Prevention 2013).

Clearly, TB is a relevant concern in today’s world. An October 2013 study by Heuer et al. (http://www.biomedcentral.com/1471-2172/14/48) examined the effects of two Mycobacterium tuberculosis antigens on human dendritic cell maturation and how this affects immune response. This study was investigating the viability of these antigens as vaccine candidates, while also examining how these antigens may be involved in immune reaction or immune evasion. Antigens are entities (in this case, an element of the Mycobacterium tuberculosis) that can bind to the antigen receptor of a T or B cell (leukocytes that mediate adaptive immunity). Dendritic cells are phagocytic leukocytes that process antigen material and function as antigen presenting cells. Specifically, infection of these dendritic cells by Mycobacterium tuberculosis leads to the downregulation of the expression of MHC class I and II and CD1 (cell surface proteins which present antigens to T cells). Therefore, if there are less of these antigen presentation molecules, antigens will not be effectively presented to T cells and NKT cells so effective immune responses won’t be promoted. This suboptimal immune response is considered to be a cause of susceptibility to Mycobacterium tuberculosis.

Eosinophils and asthma in mice

      Asthma is a disease that most Americans have knowledge of from childhood.  In grade school, there were always one or two children in class who either had to have their inhaler at the ready during recess and gym or were unable to take part in playground antics in fear of becoming short of breath.  As years passed, it became less obvious who was afflicted with asthma; as assignments would pile up, recess went away.  Yet, asthma remained.  It is not just an illness of childhood, it can affect people of any age, ethnicity and occupation.  It can be caused in part by genetic factors or by environmental triggers, especially proximity to smokers or excessively smoky areas.  This chronic disease emerges from the adaptive immune system’s response to “environmental assaults” and leads to constriction of the airway, coughing, tightness in the chest and shortness of breath.  The use of an inhaler with a corticosteroid will open the airway back up and allow the afflicted to breathe easy…at least until their next attack.  In order to better combat asthma, it is necessary to understand the mechanisms that make it so dangerous

      Asthma is a “type I hypersensitivity reaction,” meaning that it is caused by the secretion of a particular type of antibody, IgE, following a Th2 immune response. Th2 responses are one of the major types of immunity, and target extracellular pathogens. The Th2 class of helper T cells secrete cytokines that stimulate B cells to produce IgE, which can activate other types of cells to respond to antigens. When these IgE antibodies are targeted against environmental allergens, and not pathogens, type I hypersensitivity results, and when the response occurs in the bronchioles, it results in asthma. A recent study at the Mayo Clinic Arizona on asthma examined the role of eosinophils, a type of specialized white blood cell, in the regulation of dendritic cells and Th2 pulmonary immune responses with T cells in asthmatic mice.  There have been rumblings that the current description of eosinophils as “end-stage destructive effector cells” is not broad enough and that they in fact are involved with the secondary immune responses which lead to the activation and proliferation of memory T cells.  The DCs present the antigen to the lungs; in studies of asthma in mice, including this one, the mice were given additional DCs to better spread the allergen triggering antigen.  If a mouse has fewer eosinophils, then they generally will have reduced Th2 pulmonary abilities.   This study suggests that in allergen-specific T cell responses, eosinophils and DCs work together and are equally important and lead to a Th2 polarized immune response.  The eosinophils were found to have a profound impact on whether the inflammation of the respiratory tract goes by a Th2 pathway or a Th17 (a different “flavor” of immune response) pathway. 

      The relationship between the location of the eosinophils and their abundance, as compared with the accumulation of T cells during an asthma attack, was studied with three types of mice: eosinophil-null (PHIL mice), eosinophil-sufficient (wild type) and eosinophil-low (IL-5^-/- mice).  PHIL mice had absolutely no eosinophils in their system, while the IL-5^-/- mice had a partial loss of eosinophils compared to the wild type.  The mice were all treated with injections of an innocuous allergen under conditions that trigger asthma (OVA/Alum) and were subsequently exposed to airborne antigens.  The effects of the airborne antigens on the mice were then examined.  The comparisons between the three types of mice reveal information about whether or not the mice were able to accumulate DCs and eosinophils.  The draining lymph nodes of the PHIL mice did not acquire DCs in the 20 hours after they were exposed to the airborne antigens. In contrast, within 20 hours the nodes of the wild type mice acquired both eosinophils and MHC II activated DCs.  The researchers concluded that eosinophils are necessary for DCs to move to the lymph nodes and to cause T cell activation.  The mice that lacked the proper amount of eosinophils could not have the correct Th2 polarization in their lungs once they were exposed to an antigen, as the T cells were not properly activated in the LDLNs. 

      There is certainly more to be learned about eosinophils, DCs, T cells and their role in causing asthma.  The researchers suggest that eosinophils as monitors of localized immune responses can provide wonderful insights into the wider role of eosinophils in the immune system, as their impact on inflammation must certainly involve more than just allergies and asthma. 

Jacobsen, E. A., Zellner, K. R., Colbert, D., Lee, N. A., & Lee, J. J. (2011). Eosinophils regulate dendritic cells and Th2 pulmonary immune responses following allergen provocation. The Journal of Immunology, 187, 6059-6068.

Post by Jessie Solcz

Keep the hygiene, lose the inflammation: TGF-β and helminthic therapy

            Incidences of autoimmune and autoinflammatory diseases, such as type 1 diabetes, rheumatoid arthritis, and inflammatory bowel disease, are increasing in the developed world, and the annual costs of treatment amount to billions of dollars in the United States alone (1). There are numerous factors that can account for this rise in prevalence, including genetic differences and environmental factors. One factor that has been gaining support, both correlatively and experimentally, is the hygiene hypothesis: basically, since we have eliminated many of the prominent childhood diseases, children are “too clean,” and thus their immune systems, rather than focusing on pathogens, are stimulated to attack “self” targets instead, or target innocuous factors leading to allergy. In other words, infection with some types of pathogens, particularly parasitic worms such as roundworms, flatworms, and hookworms, can dampen the inflammatory responses that underlie many of these autoimmune/autoinflammatory conditions. We have largely eliminated these infections, which are transmitted through unclean drinking water and soil, in developed nations, thus accounting for some of the rise in autoinflammatory diseases.

            Some suffering patients have taken this idea to the extreme, and have deliberately infected themselves with parasites to try to alleviate their symptoms. Although this treatment is highly experimental and there is not a lot of clinical data demonstrating efficacy, anecdotal evidence suggests that some patients have observed marked reduction in symptoms following “helminthic therapy.” Obviously, there are many problems associated with introducing parasitic organisms into people, so if scientists can determine how helminthic infection tamps down inflammatory responses, it could potentially lead to novel anti-inflammatory treatments that don’t involve the parasites themselves.

            At the core of this issue are two major categories of immune responses, named “Th1” and “Th2” responses for the types of helper T cells that facilitate them. Th1 responses are inflammatory in nature, and involve the activation of macrophages and killer (CD8+) T cells. These responses are elicited by the secreted cytokine interferon-γ (IFN-γ), and typically target intracellular pathogens such as viruses. Th2 responses are mediated largely by B cells, which make antibodies, and are elicited by the cytokine interleukin-4 (IL-4). Th2 responses target extracellular pathogens, such as parasitic worms, and the rationale behind the hygiene hypothesis is that by eliminating many of these Th2 pathogens, the immune system “skews” towards Th1 responses. This, then, leads to increased inflammation and the associated autoinflammatory diseases. However, other responses caused by helminth infection, including the generation of regulatory T cells (T_Regs) and the secretion of immunomodulatory cytokines such as IL-10 and transforming growth factor-β (TGF-β), might also mitigate autoinflammatory disease. A recent paper by Hübner et al attempted to distinguish which of these mechanisms was responsible for the protection from autoimmunity accorded by helminth infection. They found that generation of a Th2 response was not required, but that the production of TGF-β was largely responsible for protection.

Regulatory T Cells in Patients with Whipple's Disease

Classical Whipple’s Disease (CWD) is a rare, multisystemic infection of the duodenal mucosa. Macrophages infected with Tropheryma whipplei, a gram positive bacterium, first attack the intestinal mucosa and then disperse throughout the body to the intestinal epithelium, capillary and lymphatic endothelium, synovium, heart, lungs, liver, brains, eyes and skin. Symptomatic manifestations are most commonly reported in the intestines, and include weight loss, diarrhea, and abdominal pain (Schijf et.al 394). Additionally, T.whipplei infection can spread to the brain and heart and cause inflammation of the heart muscle. [1]

Schinnerling and colleagues argue that host immune deficiency plays a major role in the persistence and systematic spread of CWD. The authors suggest that healthy adults generally display an efficient humoral, or antibody, and cellular immunological response that effectively combats T.whipplei. However, immunological defects are believed to weaken the immune response and enable the pathogen to successfully infect the host [2]. The defects present in the peripheral blood and the duodenal mucosa of CWD patient include, but are not limited to, impairment of T cell proliferation, and diminished Th1 reactivity.

T cells are a type of white blood cell that helps recognize and eradicate invading pathogens that cause disease. Th1 cells are a brand of T cells that specialize in intracellular pathogen disposal. Specifically, Th1 cells secrete IL-2, IFN­-y, and LT, which are cytokines, or signaling chemicals, that initiate a robust inflammatory response. A Th1 response is generally avoided in mucosal tissues because inflammation is an aggressive immune response that can damage the delicate tissue of the mucosa. Consequently, a Th2 response is initiated in the mucosa to avoid cell damage and effectively combat extracellular pathogens. Th2 cells secrete cytokines, such as IL-4, IL-5, and IL-10, to suppress a Th1 response and initiate antibody production. Antibodies neutralize pathogens without damaging surrounding host cells [3].

iNKT Cells Protect Post-Stroke Patients from Infection

Stroke is the second leading cause of death in the Western world after heart disease (Donnan et al. 2008). The medical condition is characterized by the rapid death of brain cells in a localized area due to inadequate supply of oxygen. There are two types of strokes: ischemic (lack of blood flow) and hemorrhagic (leakage of blood). Increased susceptibility to infection is the major cause of death that results from stroke (Kimura et al. 2005; Langhorne et al. 2000). The main mechanism behind the increased susceptibility seen in post-stroke patients is immunosuppression. If you think about this situation from the brain’s perspective, it makes a lot of sense for the body to promote immunosuppression after an ischemic attack because this protects the post-ischemic brain from tremendous inflammation. However, there is always a catch. Although the brain is protected from inflammation, post-stroke immunosuppression leaves the body prone to infection. The mechanism behind the observed immunosuppression is not well established. However, a recent study by Wong et al. (2011) reveal the role of invariant NKT (iNKT) cells in the immunosuppression process. NKT cells are a type of T cell that shares characteristics with both T cells and natural killer cells. NKT cells express both an αβ T cell receptor and molecules associated with NK cells. iNKT cells are so called invariant because they possess the invariant T cell receptor α chain. Many iNKT cells recognize the CD1d molecule, which binds self and foreign lipid antigens. iNKT cells are also primarily located in the liver and the spleen

In the study, Wong et al. used a rodent model of stroke called midcerebral artery occlusion (MCAO) in order to mimic the condition of stroke. Normally, iNKT cells move through the hepatic blood vessels. However, when they are activated by CD1d ligands, their movement is restricted. Using intravital spinning disk confocal microscopy, a technique that allows researchers to study living blood vessels in the context of inflammation and coagulation, the authors examined the movement of the iNKT cells both before and after inducing stroke in the animals. They found that after stroke, there was a significant reduction in the movements of iNKT cells and an increase in the number of stationary iNKT cells. These results suggest that brain injury is capable of changing the movement behavior of iNKT cells.

Protect Your Unborn or Newborn Baby: Secondhand Smoking’s Association to Asthma

Do you know someone with asthma? Chances are that you do. In 2009, over 8% of the US population reported that they currently had asthma. Interestingly, asthma rates are the highest among children and teenagers (Akinbami et al., 2011). Allergic asthma in particular is the type of asthma that is most commonly found in children. Allergic asthma, also known as atopic asthma, affects the lower respiratory tracts. Inhalation of an allergen leads to the release of granules from sensitized cells called mast cells that are located in the mucus of a person’s nose or bronchi (which serve as passageways into his or her lungs). The release of these granules and other molecules favour inflammation. This causes abundant amounts of mucus to be secreted and the tightening of a person’s airways. Asthmatics routinely report feelings of constriction in their chest as well as wheezing. Given this information, you might ask the following question: what factors contribute to the development of allergic asthma? Exposure to cigarette smoke during fetal development and during a child’s infancy has been shown to be a risk factor for allergic asthma (DiFranza et al., 2004). Mice exposed to secondhand smoke (SS) early-on after birth also seem to develop respiratory infections (Phaybouth et al., 1006), and can be used as a model for this disease. The specific contributions of exposure to smoke that is either prenatal (before birth) or early postnatal (after birth) in the development of allergic asthma, however, is not well understood. Also, the specific way in which exposure to cigarette smoke leads to asthma is not understood in great detail. To shed some light on these topics, researchers decided to use a mouse model to study the development of allergic asthma (Singh et al. 2011).

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.