Class hypersensitivity

Hypersensitivity

The term hypersensitivity is used to describe immune responses which are damaging rather than helpful to the host.

The term hyper sensitivity or allergy denotes a condition in which an immune response results in exaggerated or inappropriate reactions that are harmful to the host

Allergies

• Allergies are exaggerated (hypersensitive) responses– To certain antigens called allergens

• A state of altered reactivity in which the body reacts with an exaggerated immune response to a foreign agent.

• An acute allergic response sometimes leads to anaphylactic shock– A whole-body, life-threatening reaction that can occur

within seconds of exposure to an allergen

Hypersensitivity

These reactions occur after the second contact with the specific antigen [allergen]

Gell and Coombs proposed a classification scheme which defined 4 types of hypersensitivity reactions.

The first 3 are mediated by antibody, the fourth by T cells.

Hypersensitivity• 4 types of HS (Gell & Coombs)

– Type I: IgE-mediated degranulation of mast cells → acute anaphylactic response

– Type II: IgG / IgM on cells– Type III: Immune complexes → c’ activation,

inflammation

– Type IV: TDTH activate macs → chronic inflammation

Hypersensitivity Reactions

• The allergic response

IgE antibodies produced in response to initial exposure to an allergen bind to receptors or mast cells.

1 On subsequent exposure to the same allergen, IgE molecules attached to a mast cell recog-nize and bind the allergen.

2 Degranulation of the cell,triggered by cross-linking of adjacent IgE molecules, releases histamine and other chemicals, leading to allergysymptoms.

3

1

2

3

Allergen

IgE

Histamine

GranuleMast cell

Type I Hypersensitivity

• This describes the rapid (‘immediate') allergic reaction.

• The symptoms produced by exposure of a sensitized person to antigen depend upon the site of contact. Hay fever, allergic rhinitis, eczema, asthma and urticaria all result from type I hypersensitivity.

• It is caused upon contact with antigen against which the host has pre-existing IgE antibody.

• IgE is present in very low levels in serum in most people (i.e. 5 × 10 8gm) per ml.

Type – I • Its' life in serum is only 2-3 days• Most of the IgE in the body is bound with

high affinity receptors (Fc epsilonRI), in the bound state and its life is ~3 weeks.

• The high affinity Fc epsilonRI receptors are found on mast cells and basophils.

• Each cell has a high density of these receptors (40-250,000 per cell) .

• The cells are activated by cross-linking of Fc epsilonRI receptors via antigen binding to the bound IgE molecules.

Contd..

Such cross-linking leads to rapid degranulation (60-300 secs) of the mast cells and the release of primary inflammatory mediators stored in the granules.

These mediators cause all the normal consequences of an acute inflammatory reaction - increased vascular permeability, smooth muscle contraction, and extra vasodialation etc

Mast cell activation via Fc epsilonRI also leads to the production of two other types of mediators. These secondary mediators.

molecule SOME SPACES effects

Primary mediators

HistamineVascular permeability,

sm contraction

Serotoninvascular permeability,

sm contraction

Secondary mediators

Leukotrienesvascular permeability,

sm contraction

Prostaglandinsvasodilation, sm

contraction, platelet activation

Bradykininvascular permeability,

sm contraction

Figure 18.1

The type I response has an early and a late component.

A very rapid early response occurs when you are challenged with an antigen to which you are sensitised which is apparent within a few minutes and maximal after about 20 minutes

If the challenge is cutaneous it produces the so-called 'wheal and flare' - raised patch surrounded by a pink effusion.

• The late response seen after some hours is characterised by cellular infiltrate which gives a hard but barely pigmented nodule in the case of skin.

ATOPY

• Some 20-30% of the population exhibit type I hypersensitivity or atopic allergy to common environmental substances.

• Some individuals have multiple and severe allergies, typically both hayfever and eczema; these individuals are termed atopic.

• They have raised total serum IgE levels (10 -100 × normal). There is a correlation between total [IgE] and atopy.

• Atopic hypersensitivity disorders exhibit strong familial predisposition and are associated with IgE level.

• Predisposition to atopy is totally genetic but symptoms are induced by exposure to specific allergens.

• These allergens are typically environmental ex. Respiratory allergy to pollens, rag weeds or house dust. Or sometimes some foods ex. Intestinal allergy to shellfish.

• Clinical manifestation includes hay fever, eczema, etc.

Allergens

Numerous ideas have been put forward as to what property might distinguish antigens which stimulate a sufficient IgE response to generate type I hypersensitivity (allergens) from those antigens which rarely or never do so.

However no common property has yet been found.

Below is a list of common allergens.

Figure 10-1

– Inhaled allergens that are small may reach the lungs

• Causes asthma• Characterized by wheezing, coughing, excessive

production of mucus, and constriction of the smooth muscles of the bronchi

– Some foods may contain allergens • Cause diarrhea and other gastrointestinal signs and

symptoms– Local dermatitis

• Produces hives, due to release of histamine and other mediators into nearby skin tissue and the leakage of serum from local blood vessels

Clinical Signs of Localized Allergic Reactions

• Type I hypersensitivity reactions are usually mild and localized

• Site of the reaction depends on the portal of entry– Inhaled allergens may cause hay fever, an upper

respiratory tract response• Marked by watery nasal discharge, sneezing, itchy

throat and eyes, and excessive tear production• Commonly caused by mold spores, pollens, flowering

plants, some trees, and dust mites

Clinical Signs of Localized Allergic Reactions

• Degranulation of many mast cells at once causes the release of large amounts of histamine and inflammatory mediators

• Acute anaphylaxis or anaphylactic shock can result• Clinical signs are those of suffocation

– Bronchial smooth muscle contracts violently– Leakage of fluid from blood vessels causes swelling of the larynx

and other tissues– Contraction of the smooth muscle of the intestines and bladder

• Must be treated promptly with epinephrine

Clinical Signs of Systemic Allergic Reactions

Identifying HS-I: Allergy Testing

• skin test: small doses of allergen– look for wheal & flare

• measure IgE levels

Treatment for HS-I Disorders• avoid allergen• drugs

– anti-histamines (not Abs) compete with histamine for receptors. Anti histamine drugs can block histamine receptor sites and are effective.

– epinephrine – best immediate treatment for anaphyl. shock• reverses effects of granules (vasoconstriction,

relaxes muscles)• quick acting, but short duration

– cortisone blocks histamine synthesis

Treatment for HS-I Disorders• immunological treatment

– hyposensitization – rpt injections of allergen• may work by shifting from IgE to IgG production

– MAb anti-IgE that binds mIgE on B cells

Type II Hypersensitivity

The second class of damaging reactions is caused by specific antibody binding to cells or tissue antigens.

The antibodies are of the IgM or IgG classes and cause cell destruction by Fc dependent mechanisms either directly or by recruiting complement via the classical pathway.

It involves binding of antibodies (IgG or IgM) to cell surface antigen or extracellular matrix molecules.

Antibody directed to cell surface antigens can activate complement to damage the cells.

The antibody (IgG or IgM) attaches to the antigen via the Fab and act as a bridge to complement via Fc region.

The result may be complement mediated lysis as occurs in haemolytic anemia, ABO transfusion reactions.

• Drugs such as Penicillin and quinidine can attach to surface proteins on red blood cells and initiate antibody formation.

• Certain pathogens like Mycoplasma pneumoniae can induce antibodies that cross react with red cell blood antigen resulting in haemolytic anemia.

• The classic ABO incompatibility reaction is a type II, with IgM antibodies causing complement lysis of erythrocytes.

Hypersensitivity ReactionsHypersensitivity Reactions

Binding of antibody to antigenBinding of antibody to antigenComplement fixationComplement fixationActivation of complementActivation of complementLysis of antigen by complementLysis of antigen by complementPhagocytosis and degradation by Phagocytosis and degradation by

phagocytesphagocytes• Results when cells are

destroyed by an immune response, often due to the combined activities of complement and antibodies

• Blood group antigens are the surface molecules of red blood cells

• The ABO blood group consists of two antigens designated A antigen and B antigen

• Each person’s red blood cells have either A antigen, B antigen, both antigens, or neither

• Transfusion reaction can result if individual receives blood of a different blood type

• Donor’s blood group antigens may stimulate the production of antibodies in the recipient that bind and eventually destroy the transfused cells

ABO System and Transfusion Reactions

• If recipient has preexisting antibodies to foreign blood group antigens– Immediate destruction of donated blood cells

can occur by two mechanisms • Antibody-bound cells may be phagocytized by

macrophages and neutrophils• Hemolysis- antibodies agglutinate cells, and

complement ruptures them• Can result in kidney damage, blood clotting and

stress on the liver

Transfusion Reactions

• If recipient has no preexisting antibodies to foreign blood group antigens– Transfused cells circulate and function normally

for a while– Eventually recipient’s immune system mounts a

primary response against the foreign antigens that destroys them

• Happens over a extended period such that severe symptoms and signs don’t occur

Transfusion Reactions

ABO Blood Group Characteristics and

Donor/Recipient Matches

Table 18.2

• Based on the rhesus, or Rh, antigen– Antigen that is common to the red blood cells of humans

and rhesus monkeys

• Rh positive (Rh+) individuals have the Rh antigen on their red blood cells while Rh- individuals do not

• 85% of population is Rh positive. Those who are Rh negative can be sensitized to destroy Rh positive blood cells.

– Hemolytic disease of newborn: Fetal cells are destroyed by maternal anti-Rh antibodies that cross the placenta.

RH System and Hemolytic Disease of the Newborn

Hemolytic Disease of Newborn (HDN)• involves Rh blood group system

– 3 genes C, D, E: D most immunogenic

• HDN (erythroblastosis fetalis)– Rh(D) negative mom with Rh+ fetus makes

Abs vs baby rbc that enter mom circ. at birth– next pregnancy: IgG Abs cross placenta,

destroy fetal rbc → jaundice, brain damage

• Due to the formation of antigen-antibody complexes, also called immune-complexes

• Can cause systemic or localized reactions– Systemic

• Systemic lupus erythematosus• Rhematoid arthritis

– Localized• Hypersensitivity pneumonitis• Glomerulonephritis

Type III (Immune-Complex Mediated) Hypersensitivity

Type III hypersensitivity is mediated by immune complexes essentially of IgG antibodies.

When antibody combines with specific antigen, immune complexes are formed.

Normally they are promptly removed by reticulo-endothelial system.

Occasionally, they persist and deposit in tissues resulting in disorders.

• In persistent microbial or viral infections, immune complexes may be deposited in organs eg. Kidneys - resulting in dysfunction.

• Sometimes, they deposit in joints which causes arthritis.

• It causes vasculitis in blood vessels.

• Wherever the immune complexes are deposited, they cause inflammation and tissue injury

The Arthus reaction• The Arthus reaction is the name

given to a local type III hypersensitivity reaction.

• When a low dose of antigen is injected, an immune complex is formed locally involving IgG antibodies are involved.

• The resultant activation of complement leads to enhanced vascular permeability.

• It occurs in 4 – 10 hours.

Arthus Rx• intradermal injection of Ag• complexes deposit on blood vessel walls,

kidney, etc• damage mech: C’ activ. → inflammation• examples of Arthus-type Rx

– insect bite– pneumonitis / farmer’s lung

Figure 18.8

• Glomerulonephritis– Immune complexes circulating in the bloodstream are deposited on the

walls of glomeruli (small blood vessels in the kidney’s)– Damage to the glomerular cells impedes blood filtration– Result is kidney failure and ultimately death

SERUM SICKNESS• generalized HS-III – circulating immune complexes• induced by injection of foreign proteins (antitoxin)• complex deposit in capillary beds

Localized Type III Hypersensitivity Reactions

Type IV Hypersensitivity• This is the only class of hypersensitive

reactions to be triggered by antigen -specific T lymphocyte cells (not anti bodies)

• It occurs after sensitisation with simple chemicals, (eg nickel & formaldehyde), plant materials (Ivy poison, Oak poison), topically applied drugs (sulfonamides & neomycin), some cosmetics and soaps.

• In all cases, small molecules enter the skin which is attached to the body protein to serve as an antigen.

Contd ..

• Cell mediated hypersensivity is induced mainly in skin.

• When skin again comes in contact with those agents, the sensitized person develops erythema, itching, eczema or necrosis within 12 – 48 hours.

• Subsequent avoidance of the material can prevent recurrence.

• The Langerhans cell in the epidermis interacts with CD 4 T cells to cause contact sensitivity.

• 4 examples– Tuberculin response– Allergic contact dermatitis– Graft rejection– Graft versus host disease

Type IV (Delayed or Cell-Mediated) Hypersensitivity

• Skin of an individual exposed to tuberculosis or tuberculosis vaccine reacts to an injection beneath the skin of tuberculin

• Used to diagnose contact with antigens of M. tuberculosis– No response when tuberculin injected into the

skin of a never infected or vaccinated individual– A red hard swelling develops when tuberculin is

injected into a previously infected or immunized individual

Tuberculin Response

– The tuberculin response is mediated by memory T cells• When first infected with M. tuberculosis, the resulting cell-mediated

response generates memory T cells that persist in the body

• When sensitized individual is injected with tuberculin, dendritic cells migrate to the site and attract memory T cells

• T cells secrete cytokines that attract more T cells and macrophages to produce a slowly developing inflammatory response

• Macrophages ingest and destroy the tuberculin, allowing the tissue to return to normal

Tuberculin Response

• A cell-mediated immune response resulting in an intensely irritating skin rash

• Response triggered by chemically modified skin proteins that the body regards as foreign– Can happen when a hapten, such as the oil from poison

ivy and related plants, binds to proteins on the skin

• In severe cases, TC cells destroy so many skin cells that fluid-filled blisters develop

• Other haptens include formaldehyde, cosmetics, and chemicals used to produce latex

• Can be treated with corticosteroids

Allergic Contact Dermatitis