Immune Hypersensitivity Lecture Notes PDF

Chapter 18: Immune Hypersensitivity  Lecture outline Immune Hypersensitivity (HS) Hypersensitivity Type 1 Hypersensitivity-Allergy Atopy Asthma Hives Anaphylaxis Food allergies Type 1 HS therapy  Immune Hypersensitivity Mostly immune response...

Chapter 18: Immune Hypersensitivity  Lecture outline Immune Hypersensitivity (HS) Hypersensitivity Type 1 Hypersensitivity-Allergy Atopy Asthma Hives Anaphylaxis Food allergies Type 1 HS therapy  Immune Hypersensitivity Mostly immune response is helpful as it protects against pathogen attack. In most cases, secondary response to a pathogen is so effective that individual does not get sick. However, in certain cases/conditions, a primary response is followed by a secondary response that hurts rather than helps the individual. Such disorders are called immune hypersensitivities.  Immune Hypersensitivity Allergic/Hypersensitivity response is not necessarily an increased response to antigen, but rather an inappropriate immune response which causes tissue damage including serious disease or even death. Allergic responses are increasing in the Western world, and rapidly becoming epidemic.  Hypersensitivity (HS) Reactions Immunologist classify hypersensitivities in four types based on the their underlying mechanisms: – Type 1–IgE-mediated hypersensitivity/Allergy – Type 2–Direct antibody-mediated Cytotoxic hypersensitivity – Type 3 -Immune Complex-mediated Hypersensitivity – Type 4- Delayed type hypersensitivity (DTH) /Cell- mediated Allergy  Hypersensitivity (HS) Reactions All hypersensitivities develop in 2 stages: – Sensitization stage: is the primary immune response to an Ag. – Effector stage: is a secondary immune response. – In this context, hypersensitivity is defined as any excessive or abnormal secondary immune response to an antigen.  Humoral & delayed hypersensitivity Hypersensitivity reaction may occur during development of a humoral or cell-mediated immune response. Hypersensitivity responses generated by antibody (Ab) or antigen-antibody complexes are referred to as immediate hypersensitivity (HS). In immediate hypersensitivity, symptoms are observed within very short periods (minutes or hours) after the antigen encounter by a sensitized person. Humoral hypersensitivity include Type 1 /Immediate hypersensitivity, Type 2, and Type 3 hypersensitivities. Delayed-type hypersensitivity (DTH) is a cell-mediated response, so-named because of delay of symptoms until days after sensitization. Overview of four types of hypersensitivities The complex mix of humoral & cell-mediated immune reactions often present in clinical hypersensitivity disorders blur the boundaries between the 4 categories. Hemolytic disease of the newborn  Allergy: IgE-mediated (type 1) hypersensitivity(HS) The term ‘allergy’ is interchangeably used with type I hypersensitivity (HS). The most commonly recognized forms of allergy & ≥half of the US population suffers with this type of allergy. Allergies occur in individuals who express IgE Abs directed against certain innocuous Ags in the environment. These types of Ags are called allergens. Include allergy to pollen/hayfever, asthma, atopic dermatitis and food allergies etc. The term allergen refers to specifically to nonparasitic antigens capable of stimulating type 1 HS responses in allergic persons on repeated exposure. Has the hallmarks of a normal humoral response. Examples of common allergens  Type 1 contd…. Most allergens are small, soluble, glycosylated proteins or protein bound substances having a molecular weight between 15-40 kilo daltons. Most people encountering such Ags produce IgM, IgG, and IgA abs that successfully clear the Ags without causing any symptoms. However, in individuals who make IgE Abs to these Ags, reactions are triggered that led to side effects which can range from itching & swelling to breathing difficulties & even shock or death.  Type 1 contd…. The response to allergen is generally very rapid & occurs within 30 minutes of the encounter, so that type I HS is also known as ‘immediate’ HS. Why only some people produce IgE Abs to allergens is a mystery. Mechanisms are not fully understood? Another term for allergy is ‘atopy’. People referred to as ‘atopic’ have a hereditary predisposition to development of immediate HS against common environmental Ags.  Type 1 contd…. Two types of atopic/allergic reactions: Systemic or local. A systemic atopic response is called ‘anaphylaxis’ and affects the entire body. In local atopic reaction, the allergic symptoms depend on the anatomical location of the affected tissue and are generally confined to that site. Examples: – Hay fever (atopic rhinitis): IgE-mediated response to allergen in the nose. – Atopic asthma: a reaction in the airway and lungs that results in inflammation. – Atopic dermatitis (eczema) or atopic urticaria (hives): local atopic responses in the skin.  Mechanisms underlying Type 1 HS Type I HS has a sensitization stage and an effector stage. Sensitization stage: Allergen-specific Th2 effector cells produce large amount of IL-4, IL-5 & IL-13 that cause isotype switching towards IgE of allergen-activated B cells (rather than IgG or IgA). Thus, plasma cell secrete allergen-specific IgE in response to allergen during a primary response. Some IgE Abs bind to allergen in its site of penetration, whereas other IgE cause HS by binding to Fc receptors (FcεRs) specific for IgE constant region on the mast cells/basophils and this causes sensitization of these cells. FcεRs are expressed by a variety of innate immune cells including tissue mast cells, basophils and eosinophils.  Sensitization stage of type 1 HS Mast cells & basophils coated with allergen- specific IgE become like bombs waiting to be triggered by a subsequent encounter with the allergen. These sensitized mast cells & basophils can remain armed in this way for an extended period. Fig 18.1.  Effector phase of Type 1 HS Effector phase: Second time exposure to same allergen/Ag crosslinks the membrane-bound IgE on sensitized mast cells & basophils triggers the effector phase. The effector phase takes place in two phases: the ‘early phase reaction’ and the ‘late phase reaction’.  Effector phase of Type 1 HS Early phase reaction: Primarily mediated by the degranulation (release of contents of intracellular granules) of sensitized mast cells in the target tissue. The symptoms induced by the release of granule contents depend on the localization of mast cells and the particular affects the mediators have on the local tissues. Mast cells are abundant in the skin; in loose connective tissue surrounding blood vessels, nerves and glandular ducts; and in the mucosae. Mast cell degranulation most likely evolved to combat parasites, and so induces coughing, sneezing, tearing of eyes, scratching of the skin, and/or cramping of the gut and diarrhea.  Early phase reaction of Type 1 HS The fact that fast-acting mediators are pre-formed and stored in mast cells granules accounts for the immediate nature of type 1 HS responses & rapid onset of symptoms. Symptoms are then sustained for several hours by action of newly generated mast cell mediators that require some type of synthesis for their formation including cytokines (pro-inflammatory-TNF, IL-1 & IL-6) & chemokines. Membrane breakdown products of spent mast cells can also serve as inflammatory mediators. The best mediator of the early phase reaction of type I HS is ‘histamine’.  Early phase reaction of Type 1 HS Histamine & platelet activating factor (PAF) bind to their specific receptors on smooth muscle cells supporting blood vessels & induce them to relax. This results in vasodilatation and increases in blood flow to local area. Simultaneously, histamine & leukotrienes induce contraction of endothelial cells lining the blood vessels & increase vascular permeability. Action of histamine on sensory nerves causes itching of eczema & sneezing of hay fever. Fig 18.2. Histamine also induces the increased mucus secretion in the bronchioles in asthma.  Late phase reaction of Type 1 HS About 4-6 hours after the initiation of a type 1 HS reaction, the late phase reactions occurs. As shown in Fig 18.3, leukocytes such as Th2 cells, eosinophils, sensitized basophils, macrophages and neutrophils exit the circulation in response to tactic factors released during early phase reaction. These cells migrate into allergen-contaminated tissue & are activated to carry out their destructive effector functions. Eosinophils are particularly prominent during the late phase reaction, and airway epithelium are especially sensitive to the damaging proteins they produce. Indeed, the clinical symptoms of asthma can be attributed mainly to eosinophils activation. Late phase reaction of Type 1 HS  Examples of Type 1 HS reactions Type 1 hypersensitivity clinical manifestations range from 1. Systemic atopy: Anaphylaxis  Include life threatening conditions such as systemic anaphylaxis. 2. Localized hypersensitivity reactions (atopy) such as hay fever and eczema. They are merely annoyances. The nature of clinical symptoms depend upon  the route by which the allergen enters the body.  on allergen concentration and  on the prior allergen exposure of the host. It is unclear why some atopic people have a tendency to develop one type of clinical manifestation (e.g. urticaria), while others develop another affliction (such as asthma). Localized hypersensitivity reactions (Atopy) Include a wide range of IgE-mediated disorders such as allergic rhinitis (hay fever), atopic urticaria (hives on skin) atopic dermatitis (eczema). Allergic rhinitis (Hay fever) Prototypical example of a type 1 HS. Hay fever symptoms result from the inhalation of common airborne allergens (pollens/mold spores), which react with IgE molecules bound to sensitized mast cells in conjunctivae and nasal mucosa. Histamine & other pro-inflammatory mediators released by mast cells cause the symptoms of hay fever which include tearing, runny nose, sneezing, coughing and blockage of nasal mucosa. About 20% of individuals in the developed world suffer from allergic rhinitis or hey fever.  Atopic asthma Organ-specific (local) type 1 hypersensitivity reaction. About 10-20% of children and adults living in developed countries suffer from atopic asthma. Allergic/atopic asthma: caused by airborne or blood borne allergens such as pollens, dust, fumes, & insect products. Similar to hay fever, asthma is trigged by degranulation of mast cells but instead of nasal mucosa it occurs in lower respiratory tract. The resulting contraction of the bronchial smooth muscle leads to bronchoconstriction which can be severe. Airway edema, mucus secretion & inflammation contribute to bronchial constriction and obstruction. Most clinician consider asthma an inflammatory disease.  Atopic asthma The neutrophils & eosinophils infiltration and activation causes significant tissue injury by releasing toxic enzymes, oxygen radicals and cytokines. The patient complains of tightness in the chest and begin to wheeze or gasp for air. This increased propensity to experience symptoms that result in narrowing of the airway is termed ‘airway hyper- responsiveness’ and is a hallmark of atopic asthma. Asthma can be fatal if an acute attack totally blocks the airway.  Atopic asthma Histologically, the airway of an asthmatic patient appears chronically inflamed with mast cells, eosinophils, lymphocytes & neutrophils. Basement membrane of the airway is increased in thickness, bronchiolar smooth muscle layer is enlarged & increased mucus is present. Over 50 distinct inflammatory mediators are associated with asthma symptoms. High levels of pro-inflammatory cytokines are found in the lung secretion of asthmatic patients. Plate 18.1. Normal versus Asthmatic bronchial mucosae.  Atopic urticaria (Hives) Type 1 HS in which sensitized skin mast cells degranulate & release mediators that cause swollen, reddened patches on the skin known as ‘hives’ or ‘wheal and flare reaction’. Whitish wheal in the center of hive is composed of leukocytes that have escaped the blood vessels due to increased permeability. The flare is the ring of redness seen surrounding the wheal due to increased blood flow into this area. Intense itching & pain of hives are caused by stimulation of skin nerve endings by histamine. Allergies to latex, hair chemicals, food additives, insect bites & some drugs are Plate 18.2. Atopic urticarial associated with acute urticaria. (Wheal & flare reaction).  Atopic dermatitis (Eczema) Atopic dermatitis (allergic eczema): is an inflammatory disease of skin and another example of atopic condition. Most frequently observed in young children (infants). Serum IgE is usually elevated. It results in excessive dryness and an itchy rash that is more scaly than in urticaria. Eczematous lesions may affect different parts of the body at different ages. Atopic dermatitis is more chronic in nature than urticaria & is often associated with respiratory allergies later in life. Individual with eczema tend to be more susceptible to skin infections because the barrier function of skin is compromised.  Systemic Atopy (SA): anaphylaxis Shocklike & often fatal state which occurs usually within minutes of a type 1 HS reaction. It is usually initiated by an allergen introduced directly into the blood or absorbed from the gut or skin. Symptoms include labored respiration, a significant drop in blood pressure leading to anaphylactic shock, followed by contraction of smooth muscles leading to defecation, urination and bronchiolar constriction. This leads to asphyxiation, which can lead to death within 2-4 minutes of exposure to the allergen. If SA is not treated quickly, it can be fatal.  Systemic Atopy (SA): anaphylaxis A wide range of Ags trigger SA in susceptible humans i.e. bee venom, wasp, hornet & ant stings; drugs such as penicillin, insulin & antitoxins; & seafood & nuts. Epinephrine(adrenalin) is the drug of choice for treating SA. It counteracts the effects of histamine & leukotrienes by relaxing smooth muscles & reducing vascular permeability. It also increases cardiac output.  Food allergies Common food allergens for children are found in cow’s milk, eggs, peanuts, tree nuts, soy, wheat, fish & shellfish. Among adults: nuts, fish & shellfish are prominent culprits. Most food allergens are water-soluble glycoproteins that are relatively stable to heat, acid & proteases & therefore, digest slowly. Allergen crosslinking of IgE on mast cells among upper or lower gastrointestinal tract can induce localized smooth muscle contraction & vasodilation and thus such symptoms as vomiting or diarrhea. Mast cell degranulation along the gut can increase permeability of mucous membranes & the allergen can enter the bloodstream. Basophils also play significant role in acute food allergy.  Genetic basis for type I hypersensitivity The susceptibility of individuals to atopic responses has a strong genetic component that has been mapped to several possible loci. Atopy tends to run in families. Many of the atopy associated gene loci (multigenic) encode proteins involved in the generation & regulation of immune responsiveness e.g. innate immune receptors, cytokines and chemokines and their receptors, and MHC proteins. Th1 cells (produce IFN-γ) reduce type 1 hypersensitivity responses but Th2 cells (IL-4, IL-5, & IL-13) enhance them. Downregulation of IL-4 production is considered as a possible treatment for allergic individuals. Other proteins that have been implicated in the hereditary predisposition to allergy and asthma include  Transcription factors and  Proteins that regulate epigenetic modifications.  Diagnosis of Type 1 hypersensitivity Commonly, the type 1 hypersensitivity is identified and assessed by skin testing. Skin testing is inexpensive and relatively safe diagnostic approach. This involves injecting small amount of potential allergens intradermally or by superficial scratching the skin, and observing for an immediate indication of mast cell degranulation. “Wheal and flare” (redness and swelling) response within 30 minutes of injection in positive reaction. Less commonly, other methods of assessing type I hypersensitivity are to measure the serum level of total IgE or allergen specific IgE using ELISA or Western Blot technologies.  Type 1 hypersensitivities can be controlled medically Treatment always begins with measures to avoid contact with known allergens (practically difficult to follow). Many immunological & pharmaceutical interventions are available. Reduction of Hyposensitization: Immunotherapy allergen specific with repeated injections of Th2 cells. increasing doses of allergens which causes a shift towards IgG (blocking Ab). It does not work in every individual for every antigen. This mode of treatment attacks the disease mechanism of the allergic individual at the source & when it works, is far the most effective way to manage allergies. It can reduce or even eliminate symptoms for months or years.  Antihistamines, Leukotrienes antagonists & inhalation corticosteroids Antihistamines are the most useful drugs for symptoms of allergenic rhinitis but are not very effective in asthma. Antihistamines drugs inhibit histamine activity by binding and blocking histamine receptors on target cells. H1 receptors are blocked by Ist-generation antihistamines such as diphenhydramine & chlorpheniramine. They are quite effective in controlling the symptoms of allergic rhinitis but they have many side effects.  Antihistamines, Leukotrienes antagonists & inhalation corticosteroids IInd-generation antihistamines such as fexofenadine exhibit less cross-reactivity with muscarinic acetylcholine receptors and cause less side effects (less sedation). Leukotriene antagonists (specially montelukast) are comparable in effectiveness to antihistamines. Inhalation therapy with low-dose corticosteroids are used to reduce the inflammation & severity of asthma attacks.  Immunotherapeutics & other medications Use of humanized monoclonal anti-IgE Abs. Omalizumab was the first anti-IgE Ab approved in the US by FDA and is available as a pharmacological agent. Omalizumab binds the Fc region of IgE and interferes with IgE-FcεR interactions. Omalizumab has been used for treatment of allergic rhinitis and allergic asthma but problem is its higher cost. Several drugs block release of allergic mediators by interfering with various biochemical steps in mast cell activation and degranulation e.g.  Disodium cromoglycate (Cromolyn sodium),  Theophylline–common drug for the treatment of asthma.  Epinephrine, or epinephrine agonist (like albuterol) and  Cortisone.  The Hygiene hypothesis Asthma incidence has increased dramatically in the developed world over the last two decades but air quality was not the only factor contributing to this increase. Various studies suggested that children exposed to a farm environment either prenatally or neonatally were less likely to suffer from hay fever, atopic dermatitis, asthma & wheezing compared to control population. Exposure of children to day care situations & older siblings also correlated with a reduction in asthma incidence. Hygeine hypothesis: proposes that exposure to some pathogens during infancy and youth benefits individuals by stimulating immune responses and establishing healthy balance of T-cell subset activities so that no one response (Th1 or TH2)dominates. Hygiene hypothesis has been advanced to explain increases in the incidences of all allergic responses.  Next lecture Chapter 18: Immune hypersensitivity.