Immunology

As we all know the normal function of the immune system is to differentiate selfantigen from non self. The disorder in immune system could be ether: deficiency or hypersensitivity. When a harmless antigen enters the body, in normal situations we would have a simple immune response or even non. But the abnormal is to do one of these scenarios: 1)respond normally but doesn't turn of (chronic inflammation) which will lead to tissue damage. 2) excessive response (hypersensitivity) which will lead to collateral damage. In this lecture we will discuss hypersensitivity; Hypersensitivity reaction (HSR): a disorder caused by an excessive or inappropriate immune response. Causes of HSRs: 1) Immune response directed against host tissue. Autoimmune diseases: inappropriate response when the immune system recognize the self-antigen as non self. 2) Inadequate control of immune response against pathogenic microbes. Mycobacterium tuberculosis the inflammation continue. 3) Immune response against commensal microbes or environmental antigen. Allergy happen because of harmless protein "allergens", Allergy is the most common disorder of the immune system (prevalence of about 20% in developed countries). The classification of HSR is based on type of immune response and the effector mechanism resulting in tissue injury. But in the past it was classified based on the duration the body need until manifestation: 1|P ag e Notes about the table;  Type one need seconds to minutes.  Type 2 and 3: need hours but the difference is that: 2 autoantigen fixed on cell or tissue then an autoantibody comes and bind to it causing cell or tissue injury. 3 soluble antigen and when the antibody binds to it they form a complex that circulate the circulation then this complex will be trapped within kidney or joints producing inflammatory manifestation.  Type 4 needs 48-72 hours.  Type 5: used to a part of type 2. The complex formation doesn’t cause damage to cells or tissues but instead it causes hyperfunction. An example is thyroid gland graves disease: in normal situations thyroid hormones (T3/T4) are secreted because of (HSL) pituitary gland hormone but in the case of graves the antibody binds against (HSL) receptor stimulating the release of (T3/T4) "hyperthyroidism". Allergens: harmless antigen that cause allergy, have common characteristics LIKE: multivalent (large) protein or glycoprotein with protease activity. Now we will discuss type 1 exact mechanism: The encounter of an antigen (Ag) that induces allergy (allergen) will result in a humoral response with plasma cells secreting IgM that that will class switch to IgE because of : 1- Route of administration of allergens. 2- Douse of allergens 3- TH2 cells which cause cellular response by activation of CTL's " cell mediated response" It's cytokines promote IgE production and it includes IL-4, IL-5, IL-10 and IL-13. whereas a TH1which cause humoral response will inhibit its production. 2|P ag e What to know about IgE : a. IgE has four constant region domains b. IgE represents the Abs with the lowest concentration in serum of a normal individual likely due to: O The t1/2 of IgE is short compared to other Abs. O IgE is produced only in response to a select group of Allergen or helminthiasis. O IgE is usually sequestered into FcεRI mainly present on mast cells and basophils. FcεRII(CD23) are present on B cells. c. IgE binds with high affinity to its receptors on mast cell and basophil surfaces. sensitization (priming):The process of IgE coating of mast cells and basophils , which follows the first exposure to an allergen but it doesn’t produce any reaction. Mast cells and basophils contain preformed- we can see it under microscopy- mediators (e.g. histamine and hepamin) and because the already formed they give immediate response, and are able to synthesize new meditators upon cross linking of IgE on its surface. Subsequent exposure to the same allergen cross links the membrane-bound IgE on sensitized mast cells and basophils, causing degranulation of these cells with release of preformed and newly synthesized inflammatory mediators. What really happen is: Cross linking of two Fc.RI results in mast cell and basophil causing intracellular signaling that will end up with degranulation, however this is not the sole mechanism of degranulation Type I hypersensitivity responses are divided into an immediate early response and one or more late phase responses. 3|P ag e 1- The early response occurs within minutes of allergen exposure and results from the release of histamine ,leukotrienes ,and prostaglandins from local mast cells. 2-The mediators released during the course of the immediate reaction induce localized inflammation. Cytokines released from mast cells(TNF-αand IL-1) , increase the expression of CAMs on endothelial cells, facilitating the influx of neutrophils, eosinophils ,and TH2 cells that characterizes the late phase of the response. what determine that switching will be to IgE? Cytokine environment, the presence of IL-4, IL-13.BUT if we have beta factor switching will be to IgA. VIP notes: 1) We need IL-5 for the recruitment of eosinophils. 2) We can have degranulation of mast cells without IgE but we don’t consider it allergy . Manifestations of allergy: 1) Vasodilation. (may cause a shock) 2) Mucous secretion. 3) Bronchoconstriction 4) Skin rash, redness. The clinical manifestations of allergic reactions are related to the tissue mostly affected and to the biological effects of the mediators that are released during degranulation of mast cells and basophils including:  Histamine: increased permeability of venules, contraction of intestinal, bronchial and arterial smooth muscles.  Leukotrienes and prostaglandins: bronchoconstriction, increased vascular permeability, and mucus production.  Cytokines (IL-4, IL-5 and IL-13): recruitment and activation of inflammatory cells. Some allergic reactions continue for a long time as a result of TH2 mediated eosinophil migration and subsequent release of its mediators including peroxidase and major basic protein (late phase response). 4|P ag e The cause of allergy: The cause of allergy is likely related to complex gene-environment interactions. (atopy + the exposure to certain environment conditions). The evidence on that the monozygotic twins don’t always have the exact same allergy. Atopy: The genetic tendency to develop allergy. It includes possible associations with HLA type, IgE production, FcεRI and II, several cytokines and chemokines with its receptors among others not associated with a certain gene. The hygiene hypothesis-not proved yet- was formulated based on the observation that disorders involving the immune system are becoming more common in the developed countries especially in adults, while diarrhea and respiratory infections are more common in children in developing countries. Allergens first exposure normally comes to kids but the second exposure in adulthood. Allergic rhino-conjunctives: “hay fever”. One of the most common allergic conditions. And very similar to common cold. Caused by airborne allergens. Characterized by seasonality. Mostly in spring. The symptoms include watery exudation of the conjunctivae, nasal mucosa, and upper respiratory tract, as well as sneezing and coughing. Asthma ( the exam has a Q on this ) “Characterized by recurrent reversible airflow obstruction and bronchial smooth muscle cell hyper-responsiveness”. The majority of asthmatic attacks are triggered by IgE-mediated responses to allergens such as pollens, dust, fumes or insect products; thus termed atopic asthma. The rest of asthmatic attacks are triggered independently of allergen stimulation and termed intrinsic asthma. The triggers include exercise, drugs or cold. Both atopic and intrinsic asthmatashare the same pathophysiology, hence are considered together. The underlying airway edema, mucus secretion, and inflammation contribute to the bronchial constriction and to airway obstruction leading to the clinical manifestations such as shortness of breath and wheezing. Atopic dermatitis (eczema) Often associated with mutations in filaggrin leading to defective skin barrier and increased exposure to environmental Ags. 5|P ag e Food allergy Causes GI symptoms, however, respiratory symptoms suggests systemic Ag exposure. Common food items causing food allergy include eggs, shellfish and peanut. Anaphylaxis systemic type 1 (IgE-mediated, immediate) HSR. The word anaphylaxis is recognized and feared by most health care providers because of its association with potential death from cardiovascular collapse or asphyxiation caused by laryngeal edema. As with other type I HSR examples, the first exposure to an allergen in genetically predisposed individuals will lead to priming (sensitization). Re-exposure to the same allergen systemically will cause the cross-linking of IgE that are bound to its high-affinity receptors on mast cells and subsequent release of inflammatory mediators including histamine. Management of allergy: •General measures include the identification of the culprit allergen and its avoidance. •Drug treatment aims at blocking the effect of allergy inflammatory mediators (e.g. antihistamines, β2-adrenergic agonists, epinephrine). •Topical steroid (anti-inflammatory). •Sodium cromoglycate(reduces mast cell degranulation). •Desensitization (immunotherapy). It aims to improve allergy symptoms caused by a specific allergen. Allergen is injected subcutaneously in escalating doses (possible mechanisms include induction of TH1 response or induction of T reg response that inhibits the polarized TH2 response Skin testing: we bring a blat with the most common allergens, then we divide the skin into squares and in each one we test an allergen then wait see if any reaction happen. j j ‫ع‬ 6|P ag e