Hypersensitivity

immune response which harms the host

what is hypersensitivity?

• responses to foreign antigens become deregulated or uncontrolled

• responses are directed against self antigens (autoimmunity)

when may hypersensitivity occur?

anaphylactic hypersensitivity

what is type I immediate hypersensitivity also known as?

cell-bound antibodies react with antigen to release active substances

what characterizes Type I immediate Hypersensitivity?

Antibody-Mediated Cytotoxic Hypersensitivity

what is Type II Antibody-Mediated Diseases also known as?

free antibody reacts with antigen on cell surface

what characterizes type II Antibody-mediated dieases?

antibody reacts with soluble antigen; complexes precipitate in tissues

what characterizes type III hypersensitivity?

immune complex-mediated diseases

what is type III hypersensitivity?

T-cell mediated diseases

what is type IV hypersensitivity?

sensitized T cells responsible for symptoms

what characterizes type IV hypersensitivity?

• antibody mediated— type I, type II and type III

• symptoms develop within minutes to hours

what characterizes immediate type hypersensitivity?

• cell-mediated—type IV

• symptoms occur 24-48 hours after contact with antigen

what characterizes delayed type hypersensitivity?

• hay fever

• asthma

• hives

• food allergies

• anaphylactic shock

what are examples of type I hypersensitivity?

atopic antigens

what triggers the formation of IgE?

allergens

what is another name for atopic antigens?

inherited tendency to response to naturally occurring allergens with continued production of IgE

what is atopy?

HLA DR2, DR4 and DR7

what do atopic antigens have evidence for?

• atopic individual

• IgE

• mast cell/basophil

what are the key participants of type I hypersensitivity?

a person that usually can make increased amounts of IgE in spite of small amount of antigen

what is an atopic individual?

Th2

what regulates IgE production?

• histamine and heparin

• cytokines that increase IgE production

what do mast cell granules contain?

vasodilation and permeability, smooth muscle contraction

what is the function of histamine and heparin released from mast cells?

1. allergen activates B cells to form IgE secreting plasma cells

2. IgE antibodies binds to high-affinity receptors on mast cell and coat the cell (sensitization)

3. subsequent exposure to the same allergen leads to crosslinking of bound IgE antibodies

4. results in release of granules from cell

5. chemical mediators are released

6. synthesis and secretion of other products

what is the sequence of events for type I hypersensitivity?

stored in granules and released at mast-cell activation

what are primary mediators?

• skin manifestations

• Wheal and Flare reactions

• smooth muscles contract

• increased vascular permeability

what does a release of histamine cause?

• redness; wheal and flare

• appearance of an erythematous area at the site of injury

• development of a flare surrounding the site— “the redness”

• wheal forms at the site as fluid leaks under the skin— “the bump”

what are the skin manifestations of primary mediator release?

formed after the mast cell undergoes degranulation

what are secondary mediators?

• prostaglandins

• leukotrienes

• cytokines

• platelet-activating factor

what are some secondary mediators?

mimics effects of histamine

what is the function of prostaglandins?

some act like histamine, but more potent

what is the function of leukotrienes?

induce local inflammation

what is the function of cytokines?

acts on platelets, PMNs, eosinophils, smooth muscles, and vasculature

what is the function of the platelet-activating factor?

• systemic reaction

• most severe type of response

what characterizes anaphylaxis?

• bronchospasm

• swelling

• urticaria

• diarrhea

• vomiting

• shock

what are the clinical signs of anaphylaxis?

• sneezing

• nasal congestion

• itching of eyes and nose, etc

what characterizes rhinitis?

recurrent airway obstruction; breathlessness

what characterizes asthma?

anti-histamine

what is the treatment for allergic rhinitis?

bronchodilators and corticosteroids

what is the treatment of asthma?

systemic reactions

what is epinephrine a treatment of?

allergy shots to build up IgG/T cell mediated suppression

what is hyposensitization?

omalizumab

what is recombinant anti-IgE?

binds to the IgE which blocks its actions

what is the function of omalizumab?

inject antigen and inspect wheal and flare in 15-30 minutes

what are skin tests?

• readioimmunosorbent assay

• radioallergosorbent

what are the in vitro testing methods?

total IgE

what does RIST test for?

Sandwich EIA

what immunoassay is RIST?

patient and family history

what does RIST interpretation depend on?

ELISA; microarray

what type of test is RAST?

level of specific IgE

what does RAST test for?

1. allergen molecules bound to cellulose disk

2. serum of the patient to be tested for allergy. If he is allergic, it would contain allergen-specific IgE molecules

3. patient’s serum is mixed with allergosorbent

4. after washing, IgE molecules remaining stick to allergosorbent. The net stage is the mix radio labeled anti-IgE

5. Radiolabeled anti-IgE sticks to IgE molecules. The amount of radioactivity measured gives the levels of IgE in patient’s blood.

what are the steps to RAST?

1. solid-phase anti-human IgE

2. Capture IgE in patient serum

3. detect captured IgE with radiolabeled anti-IgE

what are the steps to RIST?

• cost efficient

• high sensitivity

• less invasive

• less painful

what are advantages to microarray tests?

antibodies binding to cell antigens or to tissue antigens and inducing inflammation

what causes type II hypersensitivity?

1. antibodies stimulated by cell antigens

2. antibodies attach to antigen and fix complement

3. possible effects:

   • opsonization and subsequent phagocytosis

   • binding of C’ and lysis of cell antigen

   • antibody dependent cell cytotoxicity by some WBCs

   • antibody binds to tissue—destroyed

what are the sequence of events for type II hypersensitivity?

• transfusion reaction

• hemolytic disease of the newborn

• autoimmune hemolytic anemia

what are examples of type II hypersensitivity?

systemic response of incompatible blood

what causes a transfusion reaction?

mother exposed to baby blood group antigens

• mother makes IgG antibodies that cross the placenta and destroy fetal RBCs

what causes hemolytic disease of newborns?

fetus may be aborted, stillborn, or born with jaundice

what can happen with hemolytic disease of newborns?

D antigen

what is the most common antigen involved in severe reactions?

Rh blood group

what is the D antigen a member of?

the mother is Rh= and the baby is Rh+

how is hemolytic disease of newborns induced?

• cold agglutinins

• warm autoimmune hemolytic anemia

• idiopathic autoimmune hemolytic anemia

• autoimmune or idiopathic thrombocytopenic purpura

what are the autoimmune hemolytic anemias?

IgM against I/i blood group

what usually causes cold agglutinins?

adverse reactions

what type of reactions are seen when a person with cold agglutinins is exposed to cold?

IgG

which immunoglobulin is responsible for Warm Autoimmune Hemolytic Anemia?

unknown

what is the cause of idiopathic autoimmune hemolytic anemia?

antibodies formed to platelets which are destroyed

what is the mechanism of autoimmune thrombocytopenic purpura?

children following respiratory viral illness

who does autoimmune thrombocytopenic purpura occur mainly in?

• blood group antibodies

• ITP: platelet antibodies

• other autoimmune diseases: often test for specific antibody

• Goodpasture’s syndrome—immunofluorescent stain of IgG to glomeruli basement membrane

what is the testing of type II hypersensitivity?

antibodies bind to cell antigens or bind to tissue antigens

what causes type III hypersensitivity?

IgM or IgG antibodies bind to soluble antigens and form small immune complexes that are deposited in small vessels which activates the C’ system and causes localized destruction

what classifies type III hypersensitivity?

contact with allergen produces IgE antibodies that bind to mast cells/basophils and cells release inflammatory mediators when IgE antibodies are cross-linked

what classifies type I hypersensitivity?

IgM or IgG antibodies bind to cell-bound antigens present on various cell types leading to their destruction

what classifies type II hypersensitivity?

sensitized CD4+ T cells have contact with the same antigen which leads to release of cytokines and activation of CTL followed by tissue destruction

what classifies type IV hypersensitivity?

antibody reacts with soluble antigen; complexes precipitate in tissues; antigen-antibody complexes induce inflammation that interferes with cellular functions

what also causes type III hypersensitivity?

vasculitis, arthritis, and nephritis

how is type III hypersensitivity often manifested?

1. production of IgM or IgG stimulated by soluble antigen

2. antigen-antibody complexes formed and deposited in tissues (normally cleared by macrophages)

3. complement binds to immune complexes

4. phagocytosis enhanced by C3b

5. target cells are too large

what is the sequence of events of type III hypersensitivity?

anaphylatoxins:

• C5a

• C3a

• C4a

what are the mediators of type III hypersensitivity?

increase vasodilation, vasopermeability and attract macrophages and neutrophils

what is the function of the anaphylatoxins of type III hypersensitivity?

• arthus reaction

• serum sickness

• autoimmune diseases

• immune complex diseases associated to pathogens

what are examples of type III hypersensitivity?

an experimental model for immune complex disease—skin reactions

what is the Arthus reaction?

1. animal immunized with antigen and produces antibodies

2. challenge animal with intradermal injection of antigen

3. antigen-antibody complexes form which activate C’

4. activated C’ causes increased permeability, edema, and accumulation of neutrophils

what are the steps of the Arthus reaction?

one day

how long does an Arthus reaction typically last?

1. human passively immunized with animal serum to treat infection

2. human makes antibody to animal serum proteins and form immune complexes

what are the steps to serum sickness?

• headache

• nausea

• vomiting

• joint pain

• lymphadenopathy

what are the symptoms of serum sickness?

urticarial rash in child 10 days after cefaclor for sore throat—associated with antibiotics

what is an example of serum sickness?

• Rheumatoid arthritis

• systemic lupus erythematosus

what autoimmune diseases are a part of type III hypersensitivity?

• rheumatoid factor

• joints affected

what characterizes Rheumatoid arthritis?

• antibodies against DNA and nucleohistones

• multiple organs affected

what characterizes systemic lupus erythematosus?

• post-streptococcal glomerulonephritis

• polyarteritis nodosa

what are the immune complex diseases associated to pathogens, that are part of type III hypersensitivity?

• arteries inflamed

• cause unknown

• more commonly seen in patients with HBV infection

what characterizes polyarteritis nodosa?

• look for specific antibody

• detection of immune complexes in tissue

• measure C’ levels

what is the testing done to determine type III hypersensitivity?

sensitized T cells have a major role

• first exposure: sensitization —1-2 weeks

• subsequent exposure: symptoms peak 24 to 48 hours after exposure to antigen

what characterizes type IV hypersensitivity?

1. antigen processed by macrophages and Langerhans (dendritic) cells and presented to T helper cells

2. T helper (Th1) cells activated and release cytokines that promote inflammation

3. cytotoxic T cells are activated and destroy antigen-coated target cells

4. hapten binds to glycoproteins on skin cells

5. Langerhans cells and macrophages process antigen and present to T cells

6. T cells become sensitized; takes several days and may last for years

7. upon repeat exposure, skin eruption

what the sequence of events for type IV hypersensitivity?

• poison ivy

• poison oak

• poison sumac

• nickel

• rubber

• latex

• topical medications

what are common causes of contact dermatitis?

• contact dermatitis

• hypersensitivity pneumonitis

• tuberculin-type IV hypersensitivity

• granulomatous hypersensitivity

what are examples of type IV hypersensitivity?

using latex gloves—can be type I or type IV hypersensitivity

what can also cause contact dermatitis?

• if area is small, can be treated with topical steroid

• systemic corticosteroids may be needed in severe cases

• avoid contact with allergen

how is contact dermatitis treated?

mediated sensitized T cells responding to inhaled allergens

what causes hypersensitivity pneumonitis?

inflammation of lower respiratory tract

what does hypersensitivity pneumonitis cause?