Hypersensitivity reactions (asthma and allergy)

Question 1

Identify the four different types of hypersensitivity reactions

Answer 1

1) Type 1, immediate hypersensitivity:

• Allergen triggers the production of IgE, which binds to mast cells and basophils.
• Upon re-exposure to the allergen, these cells degranulate and release inflammatory mediators such as histamine
• Leading to itching, ↑membrane permeability = inflammation, broncho-constriction (asthma) or systemic anaphylaxis
• Hay fever, food allergies and asthma

2) Type 2, antibody-mediated or cytotoxic hypersensitivity

• Involves IgG and IgM antibodies against antigen present on the surface of cells or extracellular material, leading to cell damage and destruction. Via:
• Complement-mediated lysis, opsonisation and phagocytosis or ADCC (antibody-dependent cell-mediated cytotoxicity)
• Autoimmune hemolytic anaemia, Goodpasture’s syndrome and rheumatic fever

3) Type 3, immune complex-mediated hypersensitivity:

• antigen-antibody complex (IgG and IgM) are formed in large quantities and get deposited in various tissues, inducing an inflammatory response
• The deposited immune complexes can trigger complement activation and recruit neutrophils, causing tissue damage
• Systemic lupus erythematosus (SLE), post-streptococcal glomerulonephritis and serum sickness

4) Type 4, delayed-type or cell-mediated hypersensitivity

• T-cell mediated, either CD4+ or CD8+ and takes 24-72 hours to develop
• Unlike the first 3, these reactions are not antibody-mediated, instead, occur when T cells become activated in response to an antigen and either release cytokines that recruit and activate macrophages by CD4+ or directly kill target cells by CD8+
• contact dermatitis (poison ivy rash), tuberculin skin test reaction and granulomatous inflammation (tuberculosis)

Question 2

Describe and explain the production of allergen-specific IgE

Answer 2

1) Allergen Exposure and Antigen-Presenting Cells:

• APCs like dendritic cells in the tissue takes up and process the allergen to present the allergen-derived peptides on their surface using MHC 2 molecules

2) Activation of Helper T Cells:

• The APCs then travel to the nearest lymph node where they present the allergen-peptide complex to naive helper T (Th0) cells
• MHC 2-allergen peptide complex with TCR + additional co-stimulatory signals, triggers the activation of these Th0 cells

3) Differentiation into Th2 Cells:

• Activated Th0 cells differentiate into Th2, driven by the cytokine environment, with IL-4 promoting development

4) B Cell Activation and Class Switching:

• Th2 cells then interact with B cells that can specifically recognise the same allergen
• Through the release of cytokines like IL-4 and IL-13, then Th2 cells stimulate the B cells to undergo class switching, from producing IgM to IgE

5) Production of Allergen-Specific IgE:

• The B cells then differentiate into plasma cells that secrete large amounts of allergen-specific IgE
• These antibodies circulate in the bloodstream and bind to high-affinity IgE receptors on the surface of mast cells and basophils

6) Sensitisation:

• The binding of IgE to mast cells and basophils completes the sensitisation process
• Upon subsequent exposure to the same allergen, the allergen cross-links the bound IgE on most cells or basophils, triggering these cells to degranulate and release histamine and other inflammatory mediators to cause symptoms of an allergic reaction

Question 3

Describe and explain the role of cells and inflammatory mediators in the allergic immune response

Answer 3

Mast Cells and Basophils:

• The primary effector cells involved in allergic responses
• Express high-affinity IgE receptors (FcεRI) on their surface
• When an allergen cross-links the allergen-specific IgE bound to these receptors, it triggers mast cell and basophil degranulation, resulting in the release of inflammatory mediators like histamine

Histamine:

• One of the main mediators released by mast cells and basophils
• Causes vasodilation and increased vascular permeability, leading to typical allergic symptoms such as redness, swelling and itching

Cytokines:

• Mast cells and basophils also release various cytokines, including tumour necrosis factor (TNF), interleukins (IL-4, IL-5, IL-13), and chemokines
• These cytokines contribute to the recruitment and activation of other immune cells, such as eosinophils, and can promote chronic inflammation and tissue damage

Eosinophils:

• IL-5 released by activated Th2 cells and mast cells is crucial for the recruitment and activation of eosinophils
• Activated eosinophils release toxic granules that can cause tissue damage and contribute to chronic inflammation
• Also produce leukotrienes and prostaglandins, which contribute to bronchoconstriction, mucus secretion and sustained vascular leakage
• T Lymphocytes:
• Th2 cells produce cytokines like IL-4, which promotes B cell class-switching to IgE production
• and IL-5 which recruit and activate eosinophils

B Lymphocytes:

• B cells produce the allergen-specific IgE
• Once activated and class-switched by Th2 cells, differentiate into plasma cells that secrete the IgE antibodies

Neutrophils:

• Recruited to the site of inflammation by chemokines released by mast cells
• Contribute to inflammation and tissue damage during severe allergic reactions like anaphylaxis

Question 4

Describe and explain asthma in the context of allergy

Answer 4

Asthma Overview:

• Chronic obstructive respiratory disorder, characterised by recurrent episodes of wheezing, shortness of breath chest tightness and coughing
• Caused by inflammation and constriction of the airways, leading to increased airway resistance and reduced airflow

Allergic/Atopic Asthma:

• Immune system reacts to harmless allergens, leading to an inflammatory response in the lungs
• APCs like dendritic cells take up and process the allergen to present the allergen-derived peptides on their surface using MHC 2 molecules, activating naive T helper cells with additional co-stimulatory signals. Differentiation into Th2 with cytokines like IL-4. Th2 cells promote B cells that can recognise the allergen to class switch (mediated by IL-4 and IL-13) to produce IgE resulting in sensitisation

Role of IgE

• The process begins when an individual sensitised to an allergen (pollen, dust mites or animal dander) inhales that allergen
• Sensitisation involves the production of allergen-specific IgE antibodies by B cells, facilitated by Th2 cells producing IL-4
• These IgE molecules bind to high-affinity IgE receptors (FcεRI) on the surface of mast cells and basophils in lung tissues

Mast Cell Activation

• Subsequent exposure to the same allergen leads to cross-linking of the allergen-specific IgE on mast cells, triggering their degranulation
• Resulting in the release of preformed mediators such as histamine, which cause immediate bronchoconstriction, increased vascular permeability and mucous production - asthma attack symptoms

Late-phase Reaction and Chronic Inflammation:

• Mast cells in addition, also release cytokines such as IL-4, IL-5 and IL-13, leading to late-phase reaction that occurs several hours after the initial allergen exposure
• These cytokines recruit and activate other immune cells like eosinophils, which cause further tissue damage and inflammation
• Over time, this chronic inflammatory response can lead to structural changes in the airways, aka airway remodelling, which exacerbates the severity of asthma

Treatments:

• Inhaled corticosteroids to reduce inflammation, bronchodilators to relieve symptoms and allergen avoidance strategies
• Therapies that target IgE (omalizumab) or specific cytokines (mepolizumab for IL-5)

Question 5

Describe and explain the basic concept of the ‘hygiene hypothesis

Answer 5

A theory proposed to explain the increase in allergic and autoimmune diseases observed in developed countries. It suggests that reduced exposure to microbes and infections during early childhood may lead to improper development of the immune system

Th1 and Th2 Response Balance:

• Immune system has two main types of responses: Th1 and Th2
• Th1 responses are typically involved in fighting bacterial and viral infections
• Th2 responses are more associated with responses to parasites and allergic reactions
• These two types of responses counter-regulate each other, meaning the predominance of one can suppress the other
• In a less hygienic environment, regular exposure to infections would favour a Th1 response, keeping the Th2 response in check and lowering the risk of allergies
• Vice versa, in a more hygienic environment, less exposure to infections = less stimulus for Th1 response. Lack of Th1 stimulation leave to a relative overactivity of TH2 responses, thereby increasing the risk of allergies

Additional Factors and Developments:

• Early exposure to a diverse array of gut microbes is thought to play a significant role in the development of a balanced immune response.
• The Old Friends Hypothesis is an extension of the Hygiene Hypothesis, arguing that it’s not just exposure to infections but also exposure to certain harmless microbes (our “old friends”) that have co-evolved with humans, which is crucial for proper immune system development