Week 3, Lecture 3 - Allery and Type I hypersensitivity: Clnical consequences

What are the characteristics of Type I hypersensitivity?

- Strong genetic predisposition - Positive family history of allergic diseases - Clinical symptoms indicate specific organs involved (lungs = asthma) and severity (anaphylaxis) - Basophils and eosinophils are involved in continuing inflammatory process (cytokines) and contributing to tissue damage.

What are the steps of developing a Type I hypersensitivity reaction?

1. First exposure to allergen 2. Antigen activation of TH2 cells and stimulation of IgE class switching in B cells - The TH2 cells that are activated preferentially produce cytokines associated with Type I hypersensitivity (IL-4, IL-5, IL-13) 3. Production of IgE 4. Binding of IgE to FcεRI on mast cells 5. Repeat exposure to allergen 6. Activation of mast cell -> release of mediators 7. Immediate hypersensitivity reaction and a late phase reaction (6-24 hours after repeat exposure to allergen)

What are the mediators involved in Type I reactions?

1. Histamine 2. Proteases (Tryptase, chymase) 3. Leukotriene 4. Cytokines The late reaction consists of cytokines (TNF)

What cells are involved in Type I reactions?

1. T-lymphocytes 2. B-lymphocytes 3. Mast cells 4. Basophils 5. Eosinophils

How much of the general population have allergies? What antibody is involved?

20% of population have an allergic reaction to environmental antigens. They are called "allergic" or "atopic." The antibody involved is IgE

What are the phases of a Type 1 hypersensitivity reaction?

A bimodal response 1. Immediate phase reaction (~1 hour) 2. Late phase reaction (6-24 hours)

What is Type I hypersensitivity?

Aka Immediate Hypersensitivity, reactions are clinically characterized by rapid reaction (within minutes) after antigen exposure. Hypersensitivity reactions are immune-mediated disorders where the host tissue is damaged Type I reactions are IgE mediated • Associated with onset of symptoms in minutes • Eosinophils, mast cells, basophils and Th2 lymphocytes are important in inflammatory process • Examples: Asthma, allergic rhinitis, food allergy • Once the underlying inflammatory mediators are understood, the clinical presentation and treatment become clear

What is allergic rhinitis?

Allergic rhinitis is an immediate type I hypersensitivity reaction to allergens in the environment. Histamine released leads to itching and vasodilation. The vasodilation leads to nasal congestion, increased mucus production, and edema. Examples include cat and ragweed allergy.

What is asthma in relation to type I hypersensitivity?

Asthma is a reversible airway obstruction. One of the possible triggers include type I hypersensitivity to allergens in the environment. Exposure leads to bronchospasm of the airway smooth muscles, leading to clinical signs of wheezing, coughing, and shortness of breath. Bronchiole constriction.

What is the role of B-lymphocytes in Type I reactions?

B cells can also recognize the allergen and once they recognize their specific allergen, they become antigen presenting cells. After presenting to the Th-lymphocyte and activating them, the B cell is reciprocally activated to class switch to IgE antibody producing plasma cells.

What is the role of basophils in Type I reactions?

Basophils are found in the peripheral blood, but can be recruited in sties of inflammation. Similar to mast cells, basophils bind IgE via the FcεRI. They also similarly degranulate to produce similar mediators as mast cells (histamine, tryptase, leukotrienes, and prostaglandins)

What happens with repeated exposure to antigen?

Chronic allergic disease, which includes remodeling and tissue damage: - asthma - allergic rhinitis (hay fever) - food allergy - eczema (atopic dermatitis) - drug allergy

What do cytokines do in Type I hypersensitivity?

Cytokines are proteins that bind to other cells and mediate a change in host response.

How do you treat allergic rhinitis?

Decrease inflammation by reducing inflammatory chemical messengers (such as IL-1β) and reducing expression of inflammatory enzymes (COX-2) Treatment includes avoidance of allergens, antihistamines, intranasal corticosteroids, and leukotriene receptor antagonists.

What is the role of eosinophils in Type I reactions?

Eosinophils are recruited to tissue by late-phase cytokines (IL-5). These eosinophils release granular proteins including major basic protein and eosinophilic cationic protein. These produce chemicals (hypochlorous acid, hypobromous acid) that are toxic to parasites (helminthes, protozoa) and the human host.

Describe food allergies/anaphylaxis in terms of Type I hypersensitivity

Food allergy anaphylaxis is an immediate-onset severe systemic type I hypersensitivity reaction in response to a food allergen that the individual is sensitized to. It consists of cutaneous symptoms, including hives and non-dependent asymmetric tissue edema (angioedema); larynogospasms, bronchospasm, and low blood pressure (hypotension). Examples of allergens include peanut, shrimp, milk, or egg allergy. - Incidence has increased from 21/100,000 from 1983-1987 to 49.8/100,000 from 1990/2010 - Rapid onset, 5-20% biphasic - may be localized (single organ) or generalized - potentiall fatal - food can induce anaphylaxis, but majority of the most severe reactions triggered by peanut and tree nuts

What is the role of T-lymphocytes in Type I reactions?

Helper T lymphocytes (Th) recognize allergen presented within the MHC class II located on antigen presenting cells, most notably dendritic cells but also B cells. The Th2 lymphocytes respond by becoming activated and preferentially produce cytokines (e.g. IL-4 to class switch to the ε heavy chain) associated with type I hypersensitivity. These activated, skewed Th-lymphocytes are called Th2 lymphocytes. They also use CD40 to stimulate class switching in B-cells

What does histamine do in Type I hypersensitivity?

Histamine is released from mast cells and basophils. Released histmaine binds to one of four histamine receptors on a wide range of tissues. Histamine binding to these receptors on endothelial cells induce vasodilation, vascular leak, and smooth muscle contraction. This smooth muscle contraction in the airways is responsible for bronchoconstriction which leads to wheezing and reduced air movement. In the GI tract, smooth muscle contraction leads to hypermotility, leading to nausea, vomiting, and diarrhea.

What is the purpose of immediate hypersensitivity?

It is thought to be to protect against parasites and helmiths (worms).

How do leukotriene receptor antagonists work?

Leukotrienes are generated from arachidonic acid and involved in asthma and allergic rhinitis Oral meds are effective in treating asthma and allergic rhinitis. It can be used as an alternative or add on therapy

What does leukotriene do in Type I hypersensitivity?

Leukotrienes are preformed mediators that are derived from the phospholipid bilayer. Leukotrienes are generated by a series of enzymes, including cyclooxygenase (the enzyme targeted by aspirin and other non-steroidal anti-inflammatories). Leukotrienes are released extracellularly where they bind to multiple receptors. Binding to one of these receptors (cysteinyl leukotriene receptor 1) is blocked by Montelukast (Singulair), which is used in the treatment of allergic rhinitis and asthma.

What is the role of mast cells in Type I reactions?

Mast cells are mostly found within the tissue. Mast cells bind the secreted IgE via its high affinity IgE receptor (FcεRI). Once the allergen specific IgE molecule bound to the mast cells recognizes the allergn again, it induces the mast cell to degranulate. The preformed mediators in these granules include histamine, tryptase, leukotrienes, and prostaglandins. On re-exposure, recognition and crosslinking of IgE molecules on mast cells, the mast cells degranulates

What are treatments for asthma related to type I hypersensitivity?

Short term (acute) treatment includes β-adrenergic agonists (albuterol). Long term (chornic) treatment includes inhaled corticosteroids, leukotriene receptor antagonists, and omalizumab (Xolair), a humanized monoclonal anti-IgE antibody.

What is the body reacting to/what is used in the response?

The antigen in an immediate reaction is also called an allergen. After exposure, the allergen is recognized by immunoglobulin E (IgE), which is bound to the high-affinity IgE receptor located on the surface of mast cells and basophils.

What types of epitopes can the IgE bind to?

The epitope can be an amino acid sequence (linear epitope) or a shape of a portion of the allergen (conformational epitope)

Which phase of mediators are responsible for the clinical manifestation typical of type I hypersensitivity reactions?

The immediate and late phase response These are inappropriate immune responses

What happens once FcεRI receptor is bound?

The immediate reaction. The signal is transduced into the cell, causing enzymatic modification of arachidonic acid and following the path of the COX, leading to vascular dilation, smooth muscle contraction, tissue damage, and inflammation.

What happens after the immedate reaction?

There is a late phase reaction that is due to new synthesis of cytokines (e.g. TNF). The immediate and late phase reactions together provide the two componenets of the bimodal distribution that is classic for Type I hypersensitivity reactions. Inhibiting the mediators of these responses explain the clinical utility of medications used to treat these Type I hypersensitivity reactions.

What are some treatments for food allergies/anaphylaxis?

Treatment includes prompt administration of epinephrine and β-adrenergic agonists (albuterol) for bronchosapsm. Antihistimines and corticosteroids can be given to assist in management.

What does tryptase do in Type I hypersensitivity?

Tryptase is one of the preformed mediators of type I hypersensitivity reactions. Clinically, it is useful to determine if there has been mast cell degranulation.

How do you counter asthma (and other allergics)?

Understand the inflammatory pathway. Leukotriene antagonists to counteract bronchial constriction Epinephrine to contract smooth muscle to increase cardiac output and counter shock

What is involved in the allergen response?

Upon binding of IgE to the IgE receptor of basophils and mast cells, these two cells rapidly degranulate vasoactive amines (e.g. histamines), enzymes (e.g. tryptase, chymase), and lipid mediator (e.g. leukotrienes, prostaglandins). These released immediate released mediators work in concert to cause vasodilation, vascular leak, bronchoconstriction, intestinal hypermotility, and tissue damage.

What happens after mast cell degranulation?

Within minutes after mast cell degranulation - Blood vessels dilate (leading to vascular congestion) - Endothelial cells contract (leading to edema from the fluid escaping in to the interstitial space.