Immuno 16

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Hypersensitivity:

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a state of heightened reactivity to antigen

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Hypersensitivity reactions:

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immune responses to innocuous antigens that lead to symptomatic reactions upon re-exposure

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Hypersensitivity disease:

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damage to host tissue caused by hypersensitivity reactions to typically innocuous antigens

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Coombs and Gel classified hypersensitivity reactions into 4 types based on the types of antigens that are recognized, and the types of immune responses that are involved (

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Type I hypersensitivity

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involves IgE-dependent triggering of mast cells (commonly referred to as allergy)

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Type II hypersensitivity

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involves IgG antibody that is reactive with cell-surface or matrix antigens

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Type III hypersensitivity

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involves the production of antigen:antibody complexes

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Type IV hypersensitivity:

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T cell-mediated hypersensitivity

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Type I hypersensitivity:

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TH2 CD4 cells can induce class switching from IgM to IgE;

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allergens

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antigens that selectively stimulate TH2 cells that drive an IgE response

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most human allergic responses are elicited by a limited number of inhaled protein allergens; since humans inhale many proteins that do not induce allergic responses, there must be something unusual about allergens that leads to stimulation of IgE production

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although it is not known what causes allergens to elicit allergic responses, there are several general features that many allergens have in common

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•• most allergens are small proteins
•• most are highly soluble
•• most are carried on desiccated particles (pollen, mite feces)
•• upon contact with mucosa of airways, soluble antigens elute from the delivery particles and diffuse into the mucosa
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•• these antigens are typically presented to the immune system at very low doses
••• remember: antigens presented to TH0 cells at low doses tend to elicit differentiation into TH2 CD4 cells
••• estimated that the maximum exposure to the common pollen allergens of ragweed is ≤ 1 μg/year/person (many people suffer irritating and even life threatening TH2-driven IgE responses to these antigens)

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important to note that not all people exposed to this allergen produce an allergic reaction

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many common allergens have enzymatic activity not all

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this may be very important: it has been shown that IgE is a very important isotype of antibody in the immune response to parasites; many parasites produce and secrete proteolytic enzymes that break down connective tissues, allowing access of the parasite to host tissues; it is believed that these proteases are particularly strong inducers of TH2-type responses
*** One of the prerequisites for type 1 hypersensitivity is that the initial response to an allergen must be an IgE response.

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How do TH2 cells stimulate class switching to IgE?

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effector TH2 cells deliver several molecular signals that favor class switching in B lymphocytes to IgE; once the TCR of a TH2 cell becomes ligated (by specific peptide antigen presented via MHC class II molecules on the B cell), the TH2 cell:
•• produces and secretes IL-4, IL-5 and IL-13
•• upregulates surface expression of CD40 ligand (CD40L) and CD23 (low affinity receptor for IgE); these costimulatory molecules can bind to their counter receptors (CD40 and CR2) on the presenting B cell
•• the combination of these signals induces class switching to IgE

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Type I hypersensitivity reactions are initiated primarily by mast cells (eosinophils and basophils are also involved)
• all 3 of these cell types express the high affinity IgE receptor (FcRI

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when the IgE bound to these cells is crosslinked by specific antigen, they degranulate; their granules contain a variety of inflammatory mediators (see IS3-Figure 12.9) that initiate inflammatory responses
•• basophils also produce a variety of immunological mediators similar to those produced by eosinophils

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type I hypersensitivity reactions are initiated by

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degranulation of mast cells; the mediators released by mast cells initiate inflammation, and recruit eosinophils and basophils to the site of inflammation; eosinophils and basophils contribute to the inflammatory response by releasing the contents of their granules

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Predisposition to allergy has a genetic basis

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• approx. 40% of the Caucasian population of North America and Europe are more likely to produce IgE responses to common environmental antigens than the rest of the population. This predisposed state is termed atopy by allergists.

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atopic individuals have higher levels of soluble IgE and more circulating eosinophils than non-atopic individuals
• genes encoded on chromosomes 5 and 11 appear to be involved in allergic predisposition

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•• chromosome 11 encodes a gene for the subunit of FcRI (high affinity IgE receptor)
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•• chromosome 5 encodes a cluster of genes that encode IL-3, IL-4, IL-5, IL-9, IL-13, and GM-CSF; all of these proteins are involved in isotype switching, eosinophil survival, and mast cell proliferation
••• an inherited sequence difference in the promoter region of the IL-4 gene has been correlated with elevated IL-4 levels in atopic individuals

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• HLA class II polymorphism also affects the IgE response to certain allergens
•• IgE response to several pollen antigens of ragweed correlate with

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the expression of HLA class II allotype DRB1*1501; this suggests that a certain HLA class II:peptide combination predisposes to stimulation of a TH2 response

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An individual’s sensitivity to a particular allergen can be easily tested:
• a two-step response to allergens injected into the skin can be visually observed

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first step of response

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injection of an allergen into the skin of a sensitive individual produces a characteristic inflammatory reaction known as a wheal and flare at the injection site
••• the wheal and flare reaction is called an immediate reaction because it appears within a few minutes; it is the result of mast cell-degranulation in the skin; released histamine and other mediators cause increased permeability of local blood vessels (fluid enters tissue causing swelling or edema); the swelling produces the wheal; increased blood flow in the area causes redness (flare)
••• immediate reactions last about 30 minutes

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2nd step of response

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6-8 hours post injection, a second reaction (the late phase reaction) occurs at the site of injection
••• consists of more widespread swelling and is mediated by leukotrienes, chemokines, and cytokines produced by mast cells following IgE-mediated activation

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The effects of IgE-mediated allergic reactions vary with the site of mast cell activation

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when a sensitized person is re-exposed to an allergen, the resulting reaction depends on the tissues that come in contact with the allergen; only the mast cells that reside at the site of allergen contact will be induced to degranulate (via IgE crosslinking by allergen)
•• most allergens are either airborne and irritate the mucosa of the respiratory tract, or are food-borne and irritate the mucosa of the gastrointestinal tract
•• some allergens gain access to the connective tissues and blood via insect bites
•• some allergens gain access to the blood via absorption via the gut and respiratory mucosa

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crosslinking of allergen-specific IgE bound to the FcRI receptor on mast cells results in degranulation

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•• degranulation of mast cells induces strong inflammatory responses

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it is widely believed that the IgE response evolved as

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a mechanism of defense against invertebrate parasites (worms); violent expulsions of airways (coughing and sneezing) and contents of stomach (vomiting) and intestines (diarrhea) initiated by mast cells man have developed as a means of expulsion of parasites from the body

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systemic anaphylaxis:

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wide-spread activation of mast cell degranulation causing both an increase in vascular permeability and a widespread constriction of smooth muscle

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Systemic anaphylaxis is caused by allergens in the blood:

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•• fluid leaving the blood causes dramatic reduction of blood pressure (anaphylactic shock)
•• connective tissues swell due to influx of fluid
•• damage can be sustained by many organ systems, impairing their function
•• constriction of airways and swelling of the epiglottis can result in asphyxiation leading to death
•• approx. 160 deaths in the U.S.A. yearly due to anaphylaxis

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anaphylactic shock

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fluid leaving the blood causes dramatic reduction of blood pressure

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anaphylaxis (anti-protection) because instead of being protective, this immune response is fatal; as opposed to prophylaxis (protection)

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potential allergens can be introduced directly into blood (systemic) by insect sting

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•• insect venom-induced anaphylaxis accounts for approx. 25% of anaphylactic fatalities in the U.S.A.

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drug injections can also result in systemic anaphylaxis

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food or drugs taken orally can also induce anaphylaxis if the allergen is absorbed rapidly from the gut into the blood

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•• peanuts and brazil nuts can cause anaphylaxis
•• the most common cause of anaphylaxis is IgE-mediated allergy to penicillin or other drugs (ingestion or injection); 100 fatalities/year in U.S.A.

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anaphalactoid reactions:

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resemble anaphylactic reactions, but do not involve interaction between allergen and IgE

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treatment of anaphylactic and anaphylactoid reactions

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is injection of epinephrine

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epinephrine stimulates reformation of tight junctions between endothelial cells, thus reducing permeability of blood vessels, diminishing tissue swelling, and raising blood pressure; also relaxes constricted bronchial smooth muscle and stimulates the heart

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•• patients with known anaphylactic sensitivity to insect venoms or food are encouraged to carry a syringe full of epinephrine at all times (EpiPen)

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Rhinitis and asthma are caused by inhaled allergens:

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• allergic rhinitis (hay fever):

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mild allergic response characterized by violent bursts of sneezing and runny nose in response to inhaled allergens

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allergic rhinitis

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•• caused by allergens that diffuse across the mucous membranes of nasal passages and activate mucosal mast cells beneath the nasal epithelium
•• characterized by local edema which obstructs nasal airways along with nasal discharge of mucous that is rich in eosinophils
•• histamine release causes a general irritation of the nasal passages as well
•• reaction can extend to the ear and throat leading to accumulation of fluid in the sinuses and Eustachian tubes (conducive to bacterial infections)
•• can also effect the conjunctiva of the eye (allergic conjunctivitis)

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allergic asthma

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a much more serious condition in which allergic reactions to commonly inhaled allergens cause chronic breathing difficulties

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allergic asthma

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•• triggered when submucosal mast cells in the lower respiratory tract are stimulated by allergen/IgE interaction
•• characterized by increase in fluid and mucous secretions into respiratory tract, and bronchial constriction due to contraction of smooth muscle surrounding airways
•• chronic inflammation of the airways involving persistent infiltration of leukocytes (TH2 cells, eosinophils, and neutrophils)
*** overall effect of allergic asthmatic attack is the trapping of air in the lungs making breathing more difficult; can be fatal

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while allergic asthma is initially driven by a response to an allergen, the chronic inflammation that develops can be perpetuated in the absence of further allergen

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•• the airways can be almost totally occluded by mucous plugs
•• a generalized hypersensitivity of the airways develops, and chemical irritants that are commonly present in air, such as cigarette smoke or sulfur dioxide, can trigger asthma attacks
•• asthmatic disease can be exacerbated by immune responses to bacterial or viral infection of the respiratory tract (especially infections that elicit TH2 responses

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***therefore, chronic asthma is considered a type IV hypersensitivity reaction

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Urticaria, angioedema, and eczema are

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allergic reactions in the skin

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urticaria (hives):

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itchy swellings caused by release of histamine by mast cells in the skin (following activation by allergen)
•• reaction is essentially a wheal and flare reaction (discussed previously

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• angioedema:

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inflammation caused by activation of mast cells in deep subcutaneous tissue
•• swelling is more diffuse than observed for urticaria

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** both urticaria and angioedema

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result from food or drug allergens that get carried to the skin via the bloodstream; both can occur during an anaphylactic reaction

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Food allergies can cause systemic effects and gut reactions

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• humans eat a wider variety of foodstuffs than any other living thing; although foods that humans eat are composed of a large number of different proteins (many of which are potentially immunogenic), only a few proteins from foodstuffs elicit IgE Ab responses

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• foods that cause food allergens:

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grains, nuts, fruits, legumes, fish, shellfish, eggs, and milk

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once an individual is sensitized to a food allergen,

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any subsequent intake of that allergen leads to an immediate reaction in the gastrointestinal tract

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•• allergen passes thru the wall of the gut, binds to IgE on mast cells (of the gastrointestinal tract) triggering degranulation
•• histamine causes increase in permeability of blood vessels, leading to accumulation of fluid in the gut lumen
•• contraction of smooth muscles of the stomach walls produces cramps and vomiting, while the same reaction occurs in the intestine to cause diarrhea
• food allergens can also cause allergic reactions in the skin (see urticaria and angioedema above

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There are 3 distinct strategies used to reduce the effects of allergic disease

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1)modification 2)pharmacological approach 3)immunological rxn

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1) modification

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of patients behavior and environment to eliminate contact with the allergen

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) pharmacological approach:

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to use drugs that reduce the impact of contact with an allergen

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•• drugs that block the effector pathways of the allergic response and limit inflammation that results

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••• antihistamines- reduces rhinitis and urticaria by preventing histamine from binding to H1 histamine receptors on vascular endothelium
••• corticosteroids- suppresses leukocyte function; used to treat chronic inflammation of asthma, rhinitis, or eczema
••• cromolyn sulfate- used as a prophylactic inhalant; prevents degranulation of activated mast cells and granulocytes
••• epinephrine-used to reverse anaphylaxis

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3) immunological treatment:

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to prevent the production of allergen-specific IgE

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•• modulate the immune response so that it shifts from an IgE response to an IgG response

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••• desensitization: a series of injections of increasing doses of the allergen; gradually changes a TH2 (IgE) response to a TH1 response in which no IgE is produced; can result in anaphylaxis…must be careful!
••• vaccinate patients with allergen-derived peptides that are known to be presented by HLA class II molecules to TH2 CD4 cells in an attempt to induce anergy

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almost all parasites induce

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very potent immune responses, and usually the immune responses are TH2-driven and large quantities of IgE are produced

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only a small percentage of the IgE that is induced is parasite-specific; the remainder of the IgE is highly heterogeneous and represents the product of a non-specific, polyclonal B- and T-cell activation by the parasite (mechanism is not well understood)

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•• the non-specific IgE out-competes the parasite-specific IgE for binding to the FcRI on mast cells, basophils, and eosinophils; this strategy prevents the parasite from triggering IgE-mediated effector mechanisms; this allows the parasite to evade immune responses

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• as a byproduct of this strategy by parasites, people that live in regions that have high incidence of parasitic infections (and high concentrations of IgE) experience reduced incidence of allergic disease compared to people that live in areas with low incidence of parasitic infections
*** could intentional parasitic infection be a treatment strategy for people that suffer from allergic asthma?????

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type II hypersensitivity reactions are caused

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by antibodies specific for altered components of human cells
•• common examples include hemolytic anemia and thrombocytopenia (caused by destruction of red blood cells or platelets, respectively) following the administration of drugs

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•• type II hypersensitivity reactions can be associated with

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the administration of the drugs penicillin, quinidine (used to treat cardiac arrhythmia), and methyldopa (used to treat high blood pressure)
••• in each case, the chemically active drug binds to the surface of red blood cells or platelets and creates new epitopes to which the immune system is not tolerant

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Penicillin-induced type II hypersensitivity

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the new epitopes generated by penicillin stimulate the production of IgM and IgG antibody specific for the new epitope(s)
•• penicillin-modified RBCs must be coated with complement (side effect of complement activation by infection being treated with penicillin); facilitates phagocytosis by macrophages via complement receptors
macrophages present the newly formed epitopes to naïve CD4+ T cells to produce armed effector TH2 cells (see IS3-Figure 12.27)
•• effector TH2 cells specific for new epitopes supply help to antigen-specific B cells; ultimately, IgG specific for new epitopes is produced
•• IgG antibodies bind to the altered RBCs and stimulate either complement activation or phagocytosis by macrophages
***end result, altered RBCs are destroyed (see IS3-

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Type III hypersensitivity:

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caused by immune complexes formed from IgG and soluble antigens
***antigen:antibody complexes are generated in almost all immune responses, and in most cases, these immune complexes are removed without causing tissue damage
• immune complexes can be very small (single complex of 1 antigen molecule and 1 Ab molecule) or very large (containing millions of antigen and Ab molecules)
• large immune complexes fix complement efficiently, and are readily taken up by macrophages and removed without incident

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Type III hypersensitivity

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smaller immune complexes are less efficient at complement fixing, and they tend to remain in circulation and become deposited along blood vessel walls
•• tissue damage (type III hypersensitivity) occurs when sufficient immune complexes accumulate; once immune complexes accumulate, circulating leukocytes recognize the immune complexes thru their Fc and complement receptors, activating their inflammatory activities
• type III hypersensitivity can be experimentally induced (in an individual that has made IgG specific for a particular antigen) by subcutaneous injection of soluble antigen
•• antigen-specific IgG diffuses from the blood into injection-site tissues and combines with antigen to form immune complexes
•• the complexes activate complement, initiating an inflammatory response known as an Arthus reaction (see IS3-Figure 12.32)

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systemic type III hypersensitivity reactions can be caused by

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intravenous administration of large quantities of antigen (see IS3-Figure 12.33 and IS3-Figure 12.34); examples of such treatments are listed below
•• serum sickness: results from immune responses to non-self material administered into the bloodstream as a treatment for a variety of illnesses; serum sickness is caused by a systemic accumulation of immune complexes (and eventual systemic inflammatory responses), and is characterized by chills, fever, rash, arthritis, vasculitis, and sometimes glomerulonephritis (see Figure 12.34)
••• years ago, immune horse sera was injected into patients to treat life-threatening bacterial infections (diphtheria, tetanus, scarlet fever, etc.)
••• transplant patients often receive large doses of monoclonal anti-T cell antibodies (to prevent rejection of transplanted tissues)
••• heart attack patients receive large injections of the bacterial enzyme streptokinase to help degrade blood clots
••• large i.v. injections of penicillin (which alter RBCs, eliciting Ab responses); can be problematic for people (even those not allergic to penicillin)

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type III hypersensitivity can also result from continual

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inhalation of antigens that elicit IgG instead of IgE antibody responses; continued inhalation of these antigens results in the accumulation of immune complexes in the walls of lung alveoli which leads to inflammatory immune responses
•• the inflammation results in accumulation of fluid, antigen, and immune cells that prevent proper lung function
•• occupations in which workers are exposed daily to the same airborne antigens can lead to this condition; there are a variety of Type III hypersensitivities that result from inhalation of antigens (see Type III Hypersensitities Chart)
••• since farmers are constantly exposed to hay dust and mold spores, this condition is commonly referred to as farmer’s lung
••• Bird-breeder’s disease is also a very common form of type III hypersensitivity of the lungs and is caused by inhalation of avian antigens
*** Although there are many causes for this condition, Farmer’s lung and the various Bird-breeder’s diseases are the most common

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type IV hypersensitivity reactions

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are mediated by antigen-specific effector T cells
•• also called delayed-type hypersensitivity (DTH) reactions because they usually occur 1-3 days after contact with antigen; this is in stark contrast to Ab-mediated hypersensitivities which are usually apparent within minutes of antigen exposure
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•• DTH reactions require 100-1000 fold larger quantities of antigen due to the relative inefficiency of antigen processing/presentation
•• most common antigens that elicit DTH responses are mycobacterial proteins, insect venoms, penadecacatechol (poison ivy), and small metal ions

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the most well studied example of type IV hypersensitivity reaction is the

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the tuberculin reaction (the clinical test to determine if an individual has been infected with Mycobacteria tuberculosis (see IS3-Figure 12.36)
•• to perform this test, a small amount of protein extracted from M. tuberculosis is injected subcutaneously
••• an individual that has produced immune responses to M. tuberculosis produces an inflammatory reaction around the site of injection 24-72 hrs post-injection
••• the inflammatory response is mediated by effector TH1 cells that recognize peptides (presented by MHC class II molecules on macrophages) derived from the injected protein; these cells produce cytokines that activate and recruit macrophages to the site (see IS3-Figure 12.37)

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Poison ivy is the term used to describe

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the type IV hypersensitivity reaction produced against penadecacatechol (a small highly reactive lipid-like molecule that is present in the roots and leaves of the North American “poison ivy” plant, Rhus toxicodendron)
•• upon initial contact with a poison ivy plant, penadecacatechol penetrates the outer layers of the skin and indiscriminately forms covalent bonds with extracellular proteins and skin cell surface proteins, forming new antigens that are recognized as non-self; local antigen presenting cells (macrophages and Langerhans’ cells) take up the new antigens, return to secondary lymphoid tissues, and present peptide antigens on MHC class II to naïve CD4 cells
•• since the penadecacatechol also penetrates cell membranes and modifies intracellular proteins, the modified proteins can be processed and presented via MHC class I molecules to naive CD8+ cells as well
•• the response to initial contact with poison ivy results in production of effector T cells and immunological memory, but little if any inflammatory response
•• each subsequent contact with poison ivy plants results in an unpleasant rash of the skin that is mediated by antigen-specific effector CTLs (which kill cells exposed to penadecacatechol), and antigen-specific effector TH1 cells that produce cytokines that activate macrophages and induce inflammation (see IS3-Figure 12.38)

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poison ivy is an example of contact sensitivity

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because contact of the allergen with the skin is required to initiate the allergic response