Allergy: Inflammation and Immune Response

Introduction to Allergy

• The lecture covers inflammation, the adaptive immune system, its activation, and different types of allergies, including chemical sensitivity, classic allergies, and food intolerances.

Body's Environment and Defense Mechanisms

• The body provides a warm, wet, and nutritious environment suitable for cells, both beneficial and harmful organisms.
• Skin acts as a barrier, forming a bag to retain water and keep invaders out.
• The immune system is the second line of defense activated once the skin is compromised, consisting of a diffuse set of cells stationed or wandering throughout the body.
• The immune system must defend an area equivalent to approximately 1.5 tennis courts.

Inflammation and Mast Cells

• Mast cells are located around the surface of the skin, approximately 25 per mm\u00b2, and are chief activators of the inflammatory response.
• Chronic conditions will increase cell density
• Mast cells are activated by immune processes, chemicals (toxins, venom, cleaning products), and physical injury (trauma, temperature extremes, UV radiation).
• Mast cells contain granules with signal molecules that release during activation, including histamine.
• Mast cell degranulation results in inflammation of surrounding tissue and accompanying symptoms.

Steps and Functions of Inflammation

• Acute inflammatory response follows mast cell degranulation and release of cellular contents.
• Inflammation causes redness (increased blood flow), swelling (extra-vascular fluid and immune cell infiltration), heat (increased blood flow and pyrogens), and pain (tissue destruction and nerve irritation).
• Inflammation destroys unwanted substances, walls off infected areas, stimulates the immune response, and promotes healing.

Immune Cells and Cytokines

• Neutrophils are immune cells attracted by inflammation, acting as killers by spraying oxidants like hydrogen peroxide, and form pus when they die in large numbers.
• Neutrophils and other immune cells release cytokines, a family of hormones.
• Pro-inflammatory cytokines (PICs) like IL1, TNFα, and IL6, give rise to flu-like symptoms at high concentrations.
• Sustained inflammation, including allergic reactions can cause PICs to increase over time
• Hydrogen peroxide is great for killing invaders and cleaning wounds, but it can also damage healthy tissue, oxidize cholesterol, and mutate DNA.

Adaptive Immune System Overview

• Chronic diseases show a risk factor of low-grade inflammation
• The adaptive immune system tags perceived threats for targeted immune responses.
• Antibodies, or immunoglobulins, are proteins that serve as tags.
• The adaptive immune system can be very selective to minimize damage to the body.
• Creating antibodies requires approximately 1 billion combinations

Antibody Production and Activation

• B-cells, educated in the bone marrow to recognize self and non-self, produce antibodies.
• Naïve or virgin B cells leave the bone marrow and reside in tissues until needed.
• Virgin B cells display antibodies on their surface and require more than one antibody to bind a complementary antigen for activation.
• To be fully activated, B cells also need to interact with a 'helper T cell,' confirming the body is at war.

B Cell Specialization and Antibody Types

• T helper cells instruct B cells on the type of threat.
• B cells will respond by changing the form of antibody that it produces
• There are five types of antibodies: IgM (virgin type), IgD (non-functional), IgA (secreted), IgG (blood), and IgE (skin).
• IgA neutralizes invaders before they enter and is the most common antibody found in secretions including mother's milk.
• IgE defends against parasites and induces inflammation in the skin using mast cells, and cocktail of toxins including hydrogen peroxide.
• IgG counters systemic infections in the blood or throughout intersitial fluid.

T Helper Cells and B Cell Memory

• Th1 cells indicate infections are in the tissues, leading B cells to produce IgG antibodies.
• Th2 cells are on the surface on skin guarding mucosal membranes directing B cells to produce IgA or IgE .
• Activated B cells become plasma cells (secreting antibodies) or memory cells (remembering the war's signs), allowing for quicker immune responses upon reinfection.
• Inflammation is used as B cell activation and reproduction require 2 days

Allergy Types and Chemical Sensitivity

• Three types of allergy include chemical sensitivity, classic allergy (IgE mediated), and non-classic allergy (non-IgE mediated), such as food intolerance, they are not mutually exclusive.
• Chemical sensitivity involves acquired intolerance to airborne chemicals like combustion products, perfumes, cleaning products, pesticides, food additives, and paints.
• Chemical sensitivity mechanisms are still unclear.
• Chemical sensitivity symptoms are similar to allergies.
• Mildly disabling
• Chemical sensitivity often involves multiple organ systems like the respiratory and nervous systems.

Classical Allergy and Mechanism

• Classical allergy, Type 1 Hypersensitivity, induced by IgE route is the most common
• Classical allergies are known as type I hypersensitivity. They range from hay fever to food allergies, are an acquired condition mediated by IgE and induce inflammation via histamine release from mast cells.
• Classical allergies can be atopic (immediate) or non-atopic (delayed).
• An allergy prone person will come across a food allergen -> it stimulates plasma cells to make large amounts of IgE antibodies to that food antigen -> these IgE molecules attach themselves to mast cells -> when the person eats the food again the IgE primed mast cells degranulate and release powerful chemical mediators such as histamine and cytokines into the local environment -> these chemical mediators cause characteristic symptoms of allergy.

Allergy Symptoms and Anaphylaxis

• Allergic reactions manifest in various ways such as allergic rhinitis (atopic hypersensitivity), allergic asthma (bronchoconstriction), allergic gastroenteropathy (localized IgE reactions), urticaria (diffuse hives), and angioedema (tissue swelling).
• Anaphylaxis is a sudden, severe allergic reaction occurring within minutes of exposure, marked by swelling, hives, and breathing trouble, and can be fatal within 15 minutes.
• IgE-mediated anaphylaxis involves an initial sensitizing exposure, IgE coating of mast cells, and chemical mediator release upon re-exposure.
• Non-IgE-mediate Anaphylaxis is used when reactions produce the same symptoms although IgE is not required.

Allergy Testing and Development

• Skin prick testing, elimination/challenge diets, antibody testing, hydrogen breath tests (lactose), and coeliac tests (gut biopsy) are methods used for IgE allergy testing.
• IgE and atopic allergies develop in childhood and are related to the hygiene hypothesis.
• Babies have Th2 cell rich immune systems which drive IgE antibody production.
• Babies immune systems can down regulate Th1 cells by passing antigens to the mother from placenta
• In most cultures kids are exposed to lots of micro-organism from birth stimulating Th1 cells to develop and thus restoring the Th1/Th2 balance
• Th2 cells direct the B-cell antibody type.
• Clean environments limit stimulation of Th1 cells are thus increase allergic reactions
• Breast feeding is thought to "educate" the baby's immune system by exposing it to a diverse array of 'safe' food antigens in breast milk.

Th1/Th2 Imbalance and Desensitization

• In adults, Th1 and Th2 cells differentiate from virgin/naive T-helper cells (Th0).
• Frequent type 1 hypersensitivity is a process by which low levels of Th1 cells results in more systemic infections that is bronchitis
• Mast cells and memory B cells are very long lived
• Allergies tend to reappear even after long term excusion of allergenic food
• Desensitization should only be done under clinical subervision, which helps by using a very small dose of food
• Desensitization is a process in which people give the sufferer a dose where it is small enough not to cause a reaction
• Scientific articles show, this can lead to an increase in T reg cells -> desensitization can stop reactions if a quantity of allergens is encountered
• However, to take allergenic food every day would maintain the effects, but further publication suggested this to not be the case
• Doses must be administered by trained allergy specialists

Food Intolerance Overview

• Food intolerances can be non-allergy or IgG based.
• Non-allergy intolerance implies a lack of necessary digestive enzyme and lactose that pass down to lower gut to get digested
• Symptoms from intolerances can range from feelings of being off to illness.
• Allergy-related food intolerance is identified by antibodies to the food allergen, and the release of histamines and other chemicals into the blood.
• Food sensitivities and intolerances may involve IgG antibodies, immune complexes or cell-mediated reactions and the reactions can be quick or delayed for 2 to 72 hours.

IgG Allergies and Food Intolerance Expression

• IgG allergies have atopic symptoms and are similar to IgE antibody reactions.
• IgG is the most common and smallest antibody where only immunoglobulin can cross the placenta
• IgG allergies involve fighting of disease
• IgG antibodies bind to mast cells (causing anaphylaxis) as well as macrophages, monocytes and polymorphonuclear leukocytes.
• Reactions are often less intense and only result in the person feeling rough
• If large amounts of any type of food is eaten that gets in to the body (via leaky gut for instance) then any virgin B cells reacting to the food could be activated
• Allergens can be influenced by physical factors such as physical exertion, stress, and inflammation as well as permeability of the gut
• Some food intolerances are not necessarily fixed, such as IgG-mediated reactions.
• The body can be supported by good gut bacteria (probiotics), 10 billion living cells and at least 71 of that bacteria