Immunological aspects of allergy and anaphylaxis part 45

Treatment is multifactorial. Environmental measures to eliminate allergen exposure should always be attempted. Inhaled corticosteroids remain the mainstay of medical treatment as they down-regulate multiple inflammatory reactions in the lungs. Other adjuncts such as leukotriene receptor antagonists modify significant mediators of allergic inflammation present in asthmatic airways. Newer treatments include monoclonal antibodies directed against IgE (anti-IgE therapy), which have shown some success in decreasing asthma symptoms and the need for oral or inhaled corticosteroids.

Immunological aspects of allergy and anaphylaxis part 44

Immunology of asthma

From a histopathological standpoint, the inflammation in allergic asthma involves the entire thickness of the airway. Findings include generalized edema, denudation of the epithelium, subbasement membrane thickening, and smooth muscle and mucous gland hyperthropy. This pocess begin when dendritic cells, a subset of antigen-presenting cells found in the lung tissue, process inhaled antigens and present them to T lymphocytes through the interaction of the receptor molecule CD28 on T cells and its ligand CD80 on dendritic cells. This interactions result in T lymphocyte development down the TH2 pathway. TH2 lymphocytes are characterized by release of a family of proinflammatory cytokines, including IL-3, IL-4, IL-5, IL-13, tumor necrosis factor-α (TNF-α), and granulocyte-macrophage colony-stimulating factor. These cytokines promote development, activation, and survival of eosinophils. In addition, IL-4, IL-5, IL-13 and TNF-α activate endothelial cell adhesion proteins, ICAM-1 and VCAM-1, which assist inflammatory cell movement from blood vessels into the airway. IL-4 and IL-13 are key stimuli of B cells for antigen-specific IgE production, which initiates the allergic cascade. as a whole, these complex immunological processes lead to the pathologic processes that characterize asthma.

Immunological aspects of allergy and anaphylaxis part 43

As in allergic rhinitis, recent advances in understanding the immunology of asthma have important therapeutic value, and immune manipulation will likely become an important modality in the treatment of asthma.

Immunological aspects of allergy and anaphylaxis part 42

ALLERGIC ASTHMA

The lung provides the fundamental function of gas exchange. As the terminal level of the respiratory tract after the nasal cavity and pharinx, it is constantly exposed to airborne  particulate matter. Allergic asthma is the manifestation of a pulmonary immune response to various inhaled substances.
Clinically, the cardinal symptoms include:

• generalized but reversible airway obstruction
• wheeze
• dyspnea
• cough

Symptoms can range from mild to life threathening. Typical allergens include house dust mite, pollen, cockroach epithelium, animal dander and fungi.

Immunological aspects of allergy and anaphylaxis part 41

EXPERIMENTAL MODEL

Recent research into the underlying immunological mechanisms of rhinitis has borne new insight into the pathophysiology of allergic rhinitis. Prior understanding favored initial IgE production in regional lymph nodes or bone marrow. Failure of prior experiments to co-localize IgE protein within B cells to the local tissue environment weighed heavily against localized tissue IgE production. In the past ten years, however, a growing body of research has challenged the former dogma that IgE production occured remotely from the allergen-tissue interface. Studies of local messenger RNA (mRNA) support the hypothesis of local protein synthesis. Durham and colleagues, using a combination of insitu hybridization and immunohistochemistry, showed that cells expressing epsilon-heavy chain mRNA (Cε) were present in the nasal mucosa of allergic individuals, and marked increases of these cells occured on exposure to allergen. Furthermore, the increases seen in IgE and Cε mRNA after allergen challenge were inhibited by topical corticosteroids, favoring a localized process. In addition, Kleinjan and colleagues used similar techniques to demonstrate finally IgE-producing B cells in the nasal mucosa. Biopsies were obtained from normal subjects and from seasonal and perennial subjects during pollen season and during house dust exposure. The study found no differences in B-cell numbers, either CD19 (B cells) or CD138 (immunoglobulin-secreting plasma cells) in allergic and normal patients. Allergic patients, however, exhibited  significantly greater numbers of IgE-positive B cells than normal patients, and allergen-positive cells were only found  in allergics with almost all such cells staining positive for IgE or CD138. The combination of these factors suggests local IgE production may take place in the mucosa during natural allergen exposure

Immunological aspects of allergy and anaphylaxis part 40

Treatment of allergic rhinitis involves environmental control  for indoor allergens, reduction of swelling and congestion by nasal corticosteroids or oral leukotriene receptor antagonists, and relief of rhinorrhea and nasal pruritis by oral or nasal antihistamines. Recalcitrant cases may require desensitization by immunotherapy (allergy shots).

Immunological aspects of allergy and anaphylaxis part 39

Over the next four to eight hours, the mediators released during the initial response set off  a sequence of events, with enhanced inflammatory responses known as the late-phase response. In this phase, cytokines and  various mediators released earlier promote the influx of other    immune cells by enhancing      expression of vascular cell adhesion molecules (VCAMs) that help traffic circulating  eosinophils, neutrophils, and lymphocytes to the nasal endothelium. Although each of these  cell types plays  a role in the late response, eosinophils appear to be the main effector cell in allergic rhinitis. Nasal obstruction and secretions can lead to secondary effects, including ear and sinus infections, sleep apnea, and asthma exacerbations. Furthermore, the inflammmatory cytokines may circulate to the central nervous system, eliciting malaise, irritability, and impaired  concentrations.

Immunological aspects of allergy and anaphylaxis part 38

Within minutes of allergen inhalation in sensitized individuals, IgE antibodies fixed to mast cells and basophils trigger release of acute preformed mediators such as histamine and tryptase in the early-phase response. Shortly afterward, de novo generation of mediators, including cysteinyl-leukotrienes (LTC4, LTD5 and LTE4) as well as prostaglandine D2 (PGD2) occurs. These substances cause a pronounced  inflammatory  response leading  to the typical symptoms of paroxysmal sneezing, nasal pruritis and congestion, clear rhinorrhea, and palatal itching.

Immunological aspects of allergy and anaphylaxis part 37

CLINICAL DISEASE STATES

Allergic rhinitis is the most common allergic disease, affecting 25% of the population. It consist of two forms, seasonal and perennial. Seasonal allergic rhinitis is commonly referred to as "hay fever" or "rose fever" and is triggered by pollens with a typically well-defined season of germination. Perennial allergic rhinitis has similar symptoms, yet involved substances are present year round, including animal dander, dust mites, and mold. In both forms, allergens interact with mast cells or basal cells in the nasal mucosa. They are then presented by antigen-presenting cells such as dendritic cells and macrophages. CD4 lymphocytes are stimulated by this presentation to release  interleukins including IL-3, IL-4, IL-5, IL-13, and other cytokines that promote local and systemic IgE production by plasma cells. In addition, these cytokines lead to enhanced  chemotaxis, inflammatory cell recruitment, proliferation , activation, and prolonged immune cell survival in the airway mucosa.

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Typical primary symptoms include nasal congestion, runny nose or rhinorrhea, as well as itchy palate and ears. Secondary symptoms include involvement  of the middle ears, eustachian tubes, and sinuses, inducing symptoms such as headache, ear pain, and decreased hearing. Multiple central nervous system complaints may occur, including fatigue, irritability, anxiety, and even depression. As in other atopic disease, the pathophysiology of allergic rhinitis involves specific IgE production after exposure to airborne allergens.

Immunological aspects of allergy and anaphylaxis part 35

The nose has five major functions, including:

• olfaction
• aiding speech
• airflow to the lungs
• humidifying and warming air
• filtering potentially irritating particles from the air

Allergic reactions occuring in the nose can have severe effects on all levels of function, usually divided into primary and consequential, or secondary symptoms.

Immunological aspects of allergy and anaphylaxis part 34

ALLERGIC DISEASE OF THE RESPIRATORY TRACT

The nature of the respiratory process involves inhalation of airborne allergens. As a result, the components  of the respiratory tract, including the nose, sinuses, and lungs, are disproportionately affected by allergic disease. In clinical practice, the common manifestations include seasonal or perennial allergic rhinitis, allergic sinusitis, and allergic asthma. The former two are often described together as allergic rhinosinusitis. Although clinically distinct, each condition involves similar underlying immunologic processes.

Immunological aspects of allergy and anaphylaxis part 33

Magone and colleagues applied such a model to evaluate the role of various cytokines, including IL-4, IFN-γ, and IL-12, in the early and late phases of ocular allergy using knockout (KO) mice and neutralizing antibodies. In this model,  multiple mice experimental groups, including:

• ragweed-sensitized wild type
• IL-4KO type
• IL-12KO type
• IFN-γKO type
• anti-IL-12/mAb-treated
• anti-IFN-γ m-Ab-treated mice were challenged with ragweed allergen ten days after immunization.

An additional group received recombinant murine IL-12. They found the anti IL-12 antibody-treated and IL-12KO type mice failed to show allergic cellular infiltration into the conjunctiva. IFN-γKO type mice, however, had a significantly stronger immediate-type hypersensitivity reactions and prolonged allergic cellular infiltration after ragweed exposure. Overall, their data provided evidence of IL-12 as an inducer of the late phase of ocular allergy. Additionally, the data suggest IFN-γ as a limiting factor of the late phase and a potential therapeutic cytokine in the prevention of chronic allergic disease. Further research is aimed at preventing initial sensitization to allergens.

Immunological aspects of allergy and anaphylaxis part 32

Experimental Models

Animal models of ocular allergies have been developed in the past years to establish new therapeutic approaches and assess immunological mechanisms. The current animal models are based on sensitization to and subsequent challenge with small numbers of allergens such as ovalbumin (Ova), ragweed pollen, or cat epithelium. The murine model of allergic conjunctivitis represents the presently preferred species for investigating the immunological basis of the disease.

Immunological aspects of allergy and anaphylaxis part 31

Treatment is aimed at reducing the local inflammation. Ocular mast cells stabilizer drops such asolopatadine are the mainstay of treatment. In addition, treatment of nasal symptoms with nasal anti-inflammatory sprays promotes patency of the nasolacrimal duct. This combination treatment allows the eye to drain excess allergens, therefore diminishing allergic responses in the eye.

Immunological aspects of allergy and anaphylaxis part 30

Atopic keratokonjungtivitis is observed in approximately 15 to 40% of patients with atopic dermatitis. Whereas allergic conjunctivitis is usually a self-limiting process,  atopic keratoconjunctivitis is chronic and can potentially cause loss of vision. Immunological and immunohistochemical studies reveal mast cells, IgE antibody, eosinophils, and other inflammatory cells in similar quantities to those found in allergic conjunctivitis. The finding of lymphocyte involvement explains the chronic nature of the disease as well as the threat to sight.  Additional findings include antibodies to ICAM-1 and HLA-DR throughout the ocular epithjelium, suggesting increased antigen presentation. Also, increased level of RANTES, an eosinophil homeostasis chemokine, are observed in immunochemical studies of the epithelium. Fibroblast numbers are increased in the connective tissue with an increased level of collagen compared with normal tissue. This infiltration is likely critical to the sight-threathening nature of the disease.

Immunological aspects of allergy and anaphylaxis part 29

The  major signs and symptoms include itching and a clear or white stringy discharge. A "cobblestone" appearance is typical. It is commonly associated with contact lens use. Foreign bodies and ocular sutures or prosthetics may be causal as well. Treatment typically involves  avoidance of the inciting process or use of ocular anti-inflammatory agents such as cromolyn sodium or topical corticosteroid.

Immunological aspects of allergy and anaphylaxis part 28

Giant papillary conjunctivitis is a chronic inflammatory process that leads to the production of giant mucosal ducts, or papillae, on the conjunctival lining of the upper eyelids. The immunopathologic mechanism is complex and is theorized to be a mechanical trauma culminating in a mast cell-mediated delayed-type hypersensitivity.