Chapter 14- Immunology

How does arachidonic acid produce prostaglandins and leukotrienes?

- cyclooxygenase pathway- prostaglandin D2 - 5-lipoxygenase pathway- leukotriene C4

What determines power of IgE- mediated response?

1. Amount of IgE 2. Amount of allergen 3. Route of allergen entry to body

What important features distinguish antigen receptors on mast cells, basophils, and eosinophils from B cells and T cells?

1. Do not require a phase of cell proliferation and differentiation- immediate response. 2. Cell is not restricted to carrying receptors of one antigen specificity. Can carry a range of IgE. *These combine to quicken and strengthen response. When one antigen enters a tissue, all mast cells in vicinity with enough IgE will be triggered to degranulate immediately.

What percentage of people in develop countries suffer from allergies?

10-40%

What is angioedema?

Activation of mast cells in deeper subcutaneous tissue with more diffuse swelling. Can arise due to allergy of food or drug if allergen gets carried to skin by bloodstream.

What is the antigen/effector mechanism/ and example of a type II hypersensitivity reaction?

Antigen: Cell or matrix associated antigen or cell-surface receptor Mechanism: complement, FcR+ cells (phagocytes, NK cells) or antibody alters signaling Example: drug allergies (penicillin) or chronic uticaria- hives (antibody to FaRIa)

What is the antigen/effector mechanism/ and example of a type IV- CTL hypersensitivity reaction?

Antigen: cell associated antigen Mechanism: cytotoxicity Example: contact dermititis

What is the antigen/effector mechanism/ and example of a type I hypersensitivity reaction?

Antigen: soluble antigen Effector mechanism: mast cell activation Examples: allergic rhinitis, asthma, systematic anaphylaxis

What is the antigen/effector mechanism/ and example of a type III hypersensitivity reaction?

Antigen: soluble antigen Mechanism: complement phagocytes Example: serum sickness, Arthus reaction - rash

What is the antigen/effector mechanism/ and example of a type IV- TH2 hypersensitivity reaction?

Antigen: soluble antigen Mechanism: eosinophil activation Example: chronic asthma, chronic allergic rhinitis

What is the antigen/effector mechanism/ and example of a type IV- TH1 hypersensitivity reaction?

Antigen: soluble antigen Mechanism: macrophage activation Example: contact dermititis, tuberculin reaction (Tb test)

How is an inhaled allergen sensitized?

Antigens are taken up by APCs into mucosa of airways. Activate naive T cells to become TH2 effector cells. TH2 cells secrete IL-4. IL-4 binds to B cells IL-4 receptor. B cell switches isotype to secrete IgE. IgE binds to FCaRI on mast cells. Subsequent exposures are more serious and cause immediate reaction.

What happens with food allergies?

As food is digested it is broken down into small peptides that serve as potential sources of peptides for presenting to TH2 cells. IgE is made against a small portion of digested food produces. Once sensitized to food allergen, and intake can cause an immediate reaction. Histamine release, urticaria, contraction of smooth muscles, cramps, vomiting, diarrhea. Negative outcome: dehydration, weakness because of food and electrolyte imbalance, waste of food.

How is histamine involved in acute allergic reactions?

Binding of histamine to H1 receptor on smooth muscles and endothelial cells of blood vessels. Induces vascular permeability and entry of other cells/molecules causing inflammation. Constricts airways and induces secretion of mucus on muscosa lining.

Do mast cells contribute to innate or adaptive immune responses?

Both because of their capability to express TLRs and FcRs for IgA and IgG.

What chemokines are synthesized after mast cell activation?

CCL3 Attracts monocytes, macrophages, and neutrophils.

What chemokines are released after eosinophil activation?

CXCL8 Promotes influx of leukocytes

Describe type II hypersensitivity (IgG) reactions?

Caused by small molecules that bind covalently to cell-surface components of human cells. Produces modified structures that are seen as foreign to the immune system.

Describe type IV hypersensitivity (T-cell) reactions?

Caused by the products of antigen specific effector T cells. Called delayed-type hypersensitivity or DTH because they only manifest 1-3 days after exposure.

How is breathing restricted in chronic asthma?

Chronic inflammation develops seems to be perpetuated in the absence of further exposure to the allergen. Airway becomes totally occluded by mucus. Hyper activity causes reactions to common irritants (cigarette smoke, etc). Disease is exacerbated by bacterial or viral infections of the respiratory tract.

What is thought to be responsible for chronic allergic inflammation from environmental sources (asthma)?

Constant antigenic stimulation and hypereosinophilia.

How many eosinophils?

Constitute less than 1% of white blood cells.

What is a defining characteristic of mast cells?

Contain 50-200 granules that contain inflammatory mediators.

What is the major allergen responsible for over 20% of allergies in North America?

Cysteine protease derived from Dermatophagoides pteronyssimus (house dust mite).

Describe type III hypersensitivity (IgG) reactions?

Due to small soluble immune complexes formed by soluble protein antigens binding to the IgG made against them. Some complexes are deposited in walls of small blood vessels or alveoli of lungs. Immune complex activates complement and initiates an inflammatory response that damages the tissue, impairing the function.

What has eliminating intestinal helminths in the industrialized world caused?

Eliminated natural T regulatory cell mechanisms that prevent excessive T cell activation. This occurs in IBD, MS, Type-1 diabetes, asthma, and allergies.

What are allergens?

Environmental antigens that induce a state of hypersensitivity.

What are enzymes in eosinophil granules?

Eosinophil peroxidase Poisons parasites by halogenation. Eosinophil collagenase Remodels connective tissue matrix.

Describe the hygiene hypothesis.

Epidemic of allergy was caused by improved hygiene, widespread vaccination, and increased use of antibiotics to terminate infection. Children are exposed to less infections, leading to an underdeveloped immune system.

How is change in BP in systematic anaphylaxis treated?

Epinephrine injection stimulates reformation of tight junctions between endothelial cells. Reduces permeability and prevents fluid loss, diminishes tissue swelling and raises blood pressure. Relaxes constructed bronchial smooth muscle and stimulates heart.

What ligand do basophils express and why?

Express CD40 ligand which binds to CD40 of antigen-stimulated B cells. Drive isotype switching to IgE and IgG4.

What does IgE effect have on GI, airways, and blood vessels?

GI- increased fluid secretion, increased peristalsis- diarrhea and/or vomiting Airways- decreased diameter, increased mucus secretion- expulsion of contents through coughing, sneezing, phelgm BV- increased blood flow, increased permeability- edema and inflammation, increased flow of antigens to lymph and lymph nodes.

Where are eosinophils located?

Generally resident in tissues (epithelia mucosa surfaces) Minority are in peripheral circulation.

What are eosinophils?

Granulocytes whose granules contain arginine-rich basic proteins. Heavily stain with eosin. Activation leads to stages release of toxic molecules and inflammatory mediators. Response is highly toxic and potentially damaging to host. Kept low in healthy individual by restricting production in bone marrow.

What is a side effect seen with penicillin?

Hemolytic anemia and throbocytopenia. Chemically reactive drug molecules bind to surface components of RBCs and platelets and create new epitopes of which immune system is not tolerant. Modified RBCs acquire a coating of complement component C3B. Antigen specific B cells produce antibodies against these modified epitopes. Results in: Red cell lysis Receptor mediated phagocytosis by macrophages.

What is the most prominent inflammatory mediator?

Histamine Exerts physiological effects through its receptors on cell surface (H1, H2, H3)

What are toxic mediators in granules of mast cells?

Histamine and heparin Effect: poison parasites, increase vascular permeability, cause smooth muscle contraction

What do mast cell granules contain?

Histamine, heparin, TNF-a, chondriotin sulfate, neutral proteases, and other degradative enzymes.

What cytokines are released after eosinophil activation?

IL3, IL5, GM-CSF Amplify eosinophl production by bone marrow Cause eosinophil activation

What are cytokines synthesized after mast cell activation?

IL4 and IL13 Stimulate and amplify TH2 cell response. IL3, IL5, and GM-CSF Promote eosinophil production and activation.

What does IgE bind to?

IgE made in primary response will bind to Fc receptors on mast cells. Secondary exposure will cause antigen-mediated linking of IgE. Stimulates mast cell degranulation and activation of inflammatory reactions lessening the parasite load.

When does immediate and late phase response finish in asthma?

Immediate- 1 hour Late- in chronic, up to 6 hours and can be more dangerous.

When is IgE production favored?

Immune system is challenged by small quantities of antigen and IL4 is provided by activated basophils when naive CD4 T cells are presented with antigen.

How do we regulate eosinophil activity?

In resting state, eosinophils do not express FCaRI, do not bind IgE, and can therefore not be induced to degranulate by antigen. Once inflammatory response is set in motion, it will not express FCa and complement receptors.

How is asthmatic response measured?

In terms of breathing capacity: peak expiratory flow rate (PEFR). Measurement of maximum speed that a person can blow air out of their lungs in one burst.

How are eosinophils released into circulation?

Infection stimulation activates TH2 cells and cytokine release triggers bone marrow to quicken production and release into circulation.

Role of basophils?

Initiate TH2 response by secreting TH2 cytokines, IL4 and IL13, at the beginning of the adaptive response. In innate response they are recruited to infected tissue and activated through TLRs and other receptors.

How does predisposition to allergic disease have a genetic basis?

Involves polymorphisms of many genetic loci that contribute to adaptive immune response. Nine loci, six are involved in stimulation of antigen-specific IgE. 1. Higher levels of soluble IgE 2. Higher levels of circulating eosinophils Half of risk is genetic, half is environmental.

What is experimental anti-IgE?

It cross links IgE bound to FCaRI and activates mast cell degranulation. This causes inflammatory response.

What is therapeutic anti-IgE?

It prevents mast cell from acquiring cell-surface IgE. Mast cell cannot be activated through FCzRI. It downregulates its cell-surface expression.

What lipid mediators are synthesized after mast cell activation?

Leukotrienes C4, D4, and E4 Cause smooth muscle contraction, increase vascular permeability, and cause mucus secretion. PAF Attracts leukocytes Amplifies production of lipid mediators Activates neutrophils, eosinophils, and platelets

What lipid mediators are released after eosinophil activation?

Leukotrienes C4, D4, and E4 Smooth muscle contraction, increases vascular permeability, causes mucus secretion PAF Attracts leukocytes Amplifies production of lipid mediators Activates neutrophils, eosinophils, and platelets

What is role of mast cells?

Maintain integrity of tissues they reside Alert immune system of local trauma and infection Facilitate the repair of damage caused by infection or wounds

What are toxic proteins in eosinophil granules?

Major basic protein Poisons parasites and mammalian cells Triggers histamine release from mast cells Eosinophil cationic protein Poisons parasites Neurotoxin Eosinophil-derived neurotoxin Degradation of RNA Antiviral effects

How do mast cells, eosinophils, and basophils work together?

Mast cell degranulation initiates the inflammatory response, which then recruits eosinophils and basophils. Eosinophil degranulation releases major basic protein (MBP) which causes degranulation of mast cells and basophils.

Describe a Type I hypersensitivity (IgE-mediated) - immediate hypersensitivity reaction.

Occur immediately upon exposure to antigen. Highly prevalent and diverse. Commonly caused by inhaled particulate (SOLUBLE) antigens. Results from the binding of antigens to antigen specific IgE bound to its Fc receptor.

What is a hypersensitivity/allergic reaction?

Overreactions of the immune system to harmless environmental antigens.

What are the stages of immune system in parasite-infested and parasite-free populations?

Parasite-infested Superinfection- parasite suppression- immunopathology Parasite-free ALLERGY

What is Hypereosinophilic syndrome?

Presence of abnormally large number of circulating eosinophils, cause damage to tissue (fibrous exudate- mass of cells) from contents released in granules. Cells are not seen in injured endocardium- tissue.

What are three distinct strategies to prevent and treat allergies?

Prevention- modify behavior and environment to avoid allergen, pharmacological- use drugs to reduce impact (antihistamines, corticosteroids) , and immunological strategies- prevent production of allergen-specific IgE. One way is through desensitization (IgE to IgG response). Entails several injections with small dose.

What are some examples of inhaled allergens?

Protein papain used as a meat tenderizer. Chymopapain, used to treat sciatica - can cause systematic anaphylaxis. Protease subtilsin, biological component of laundry detergents.

What are features of inhaled allergens that promote priming of TH2 cells that drive IgE response?

Proteins (induce T cell response) Proteases Low dose (favors activation of IL-4 producing CD4 T cells) Low molecular mass (diffuses out of particle into mucus) High solubility (readily eluted from particle) High stability (survives desiccated particles) Contains peptides that bind host MHC class II (necessary for T cell priming)

What is the end product of mast cell activation and degranulation?

Release of many types of chemical mediators and the attraction of circulating leukocytes (eosinophils, basophils, neutrophils, and TH2 lymphocytes) to the site of mast cell activation.

Where are mast cells located?

Resident in mucosal tissues (mucosal mast cells produce tryptase) and epithelial tissue (connective tissue mast cells produce chymotryptase).

What happens when antigen binds to IgE on surface of a mast cell?

Signal is transmitted that leads to release of preformed granules containing histamine and other inflammatory mediators.

What happens when an allergen enters the blood stream?

Systematic anaphylaxis. Disseminated mast cell activation causes both increase in vascular permeability and widespread constriction of smooth muscle. Fluid leaves blood and causes BP to drop dramatically. Death usually caused by asphyxiation due to constriction of the airways and swelling of epiglottis. Most common cause: allergy to penicillin.

What are the components of a typical adaptive immune response against helminth worms?

T cells: CD4 TH2 cells Cytokines: IL3, IL4, IL5, IL9, IL10, IL13 Antibodies: IgE, IgG1, IgG4 Effector cells: eosinophils, basophils, mast cells

What does the acute response in allergic asthma lead to?

TH2 mediated chronic inflammation. Inflammation causes eosinophils and TH2 lymphocytes to come to area. Activated mast cells and TH2 cells secrete cytokines that augment eosinophil activation and degranulation. This causes further tissue injury and influx. The end result is chronic, that causes irreversible damage to airways.

What are cytokines in granules of mast cells?

TNF (some stored preformed) Effect: promotes inflammation, stimulates cytokine production by many cell types, activates endothelium.

What are basophils?

They are rare granulocytes that initiate TH2 responses and the production of IgE. More closely related to eosinophils with a common stem cell precursor and common growth factors.

What happens when antigen is cleared but IgE molecules have not encountered it?

They bind to receptors on mast cells, basophils, and eosinophils.

What are enzymes in the granules of mast cells?

Tryptase, chymase, cathepsin G, carboxypeptidase Effect: remodel connective tissue matrix

What are the physical parts of an allergic reaction?

Wheal: raised area of skin with injection site at center. Flare: redness (erythema) spreading out from wheal. Involves immediate response and late-phase response (usually spread of swelling to surrounding tissue).

What is the role of IgE?

Work with mast cells, basophils, and eosinophils in controlling parasitic infections, particularly with helminths.