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

Asthma and Food Allergy

Asthma is a chronic inflammatory disorder afflicting the lower respiratory tract, characterized by a narrowing of the air passages. Roughly one in ten American children has asthma, and an estimated 6.5 million children under the age of 18 have been diagnosed with the condition. The prevalence of asthma is increasing, particularly amongst children, and the World Health Organization (WHO) estimates that each year 15 million disability-adjusted life-years are lost, and approximately 250,000 asthma deaths are reported [2]. Similarly, food allergy affects around 5.9 million children in the US, or 8% of children under 18 years of age. Moreover, nearly 2 out of every 5 children with food allergy have a history of severe reactions. In these cases, accidental exposure to an allergenic substance may result in breathing difficulties, an abrupt drop in blood pressure, and even death [3]. Both asthma and food allergies have serious implications, particularly amongst pediatric victims, and in a significant number of children, the two conditions are associated. Diagnosis with both asthma and food allergy presents a risk factor for fatal anaphylactic reactions.

Asthma and food allergy present examples of Type I Hypersensitivity (type I HS), in which an individual’s immune system incorrectly recognizes substances that are normally harmless as threatening invaders. As a result, an immune response is inappropriately mounted against them. The triggers for type I HS are referred to as allergens because they are antigens that cause allergy. Type I hypersensitivity reactions occur rapidly following the introduction of allergen in the body, and a particular subset of antibodies, called IgE, become implicated in the pathology of the immune response. These IgE antibodies, in cases of allergy, are directed against the allergen particles (including components of pollen, pet dander, or nuts, for example). During an asthma attack, inhalation of allergy-inducing substances or environmental triggers causes inflammation of the air passages, such that airways become constricted and breathing becomes quite difficult. In an allergic reaction to a food allergen (i.e. peanuts, soy, milk, eggs, wheat, or fish), a variety of possible symptoms may manifest, depending on whether the inflammatory response is induced in the mouth, the gastrointestinal tract, or enters the blood stream becoming systemic or provoking symptoms in a separate location of the body. In both asthma and food allergy, the exposure to allergen stimulates mast cells, a type of cell involved in inflammatory processes, to release the contents of their granules (cellular vesicles that contain substances like histamine, serotonin, and proteases). These fast-acting mediators are responsible for the rapid onset of initial symptoms associated with type I hypersensitivities because they are preformed within the cell, ready to be released upon activation. Histamine promotes blood vessel dilation and permeability, or leakiness, mucus production, itching, sneezing, and contraction of bronchial smooth muscle. Similarly, serotonin is associated with vasodilation and bronchial smooth muscle contraction. Proteases released by the mast cells are also involved in mucus production, as well as in increased blood pressure.

Approximately 4-6 hours following onset of these reactions, various white blood cells (leukocytes) migrate to the allergen-laden tissue. Especially significant in this stage of allergic reaction are eosinophils, which possess receptors on their surfaces that bind to IgE antibodies coating the allergen. Upon interaction of these receptors with the IgE-allergen complexes, the eosinophils undergo degranulation, similarly to the mast cells described above. The contents released from the eosinophil granules include leukotrienes, platelet-activating factor (PAF), major basic protein, eosinophil cationic protein, and eosinophil-derived neurotoxin; when these substances diffuse into the surrounding tissue, they cause substantial damage to cells. Because the cells that line the airways exhibit elevated sensitivity to these mediators, symptoms of asthma are attributed predominantly to eosinophil activation during allergic reaction. This pathology is known as eosinophilic airway inflammation and is considered a distinguishing feature of asthma. Furthermore, worsening airway inflammation in pediatric cases of asthma is correlated with exacerbating symptoms. While asthma severity is known to be associated with eosinophilic airway inflammation, as well as with a co-diagnosis of food allergy, it had not been determined whether this type of inflammation is exacerbated in asthmatic children with food allergies, until quite recently. A study published in Pediatric Allergy and Immunology examined the hypothesis that eosinophilic airway inflammation is higher in children with both food allergies and asthma [1].

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).