Hypersensitivity Reactions Lecture 22 December 7 th 2010.

Hypersensitivity Reactions

Lecture 22 December 7th 2010

Domains of the thymus

In cortex, thymic epithelial cells presents 2X the amount of MHC2 molecules as MHC1 molecules. This

determines the ratio of Th to Tc as 2:1.

They present all the alleles in the persons genome: 6 MHC class 1 molecules and 12 different MHC class 2 molecules. This determines that only T cells with a TCR receptor that recognizes the persons own MHC

survives the cortex.

Delta

Three outcomes with regard to what the TCR chosen sees:

TCR does not recognize any of your own MHCI or MHCII molecules

TCR recognizes but reacts to one of your own MHCI or MHCII molecules by proliferating even

when unoccupied by antigen

TCR recognizes as self one of your own MHCI or MHCII molecules but does not proliferate to the

unoccupied MHC molecule.

Now those T cells that survive the cortex move to the medulla,

they upregulate the number and affinity of their TCRs and become committed as either

CD4 or CD8 positive.

In medulla they express either CD4 or CD8 not both.

Three outcomes with regard to what the TCR chosen sees:

TCR does not recognize any of your own MHCI or MHCII molecules (cortex, positive selection)

TCR recognizes but reacts to one of your own MHCI or MHCII molecules by proliferating even when unoccupied by antigen (medulla, negative

selection)

TCR recognizes as self one of your own MHCI or MHCII molecules but does not proliferate to the unoccupied MHC molecule (only these cells get

out of thymus).

.

Routes of entry

antibody mediated antibody mediated antibody mediated cell mediated

Ig E Ig M or IgG Ig M or IgG T lymphocyte

Immediate Immediate Immediate Delayed

Fastest (sec) 4-6 hrs w/i 4-6 hrs 48-72 hrs.

Type 1 hypersensitivity

• All hypersensitivity reactions require a first asymptomatic exposure to antigen

• Second exposure manifests a exaggerated and extensive reaction

• In type one reactions, these are very fast within secs and usually but not always can resolve not causing permanent damage. They can during the reactive phase however cause death.

Type 1 hypersensitivity

• A. Systemic anaphylaxis• B. Local Anaphylaxis-atopic allergies

– 1. Allergic rhinitis 20% of the population– 2. Asthma– 3. Food allergies– 4. Atopic dermatitis

First exposure

Second exposure

All type 1 Rxs.

A. Systemic anaphylaxis

• Portier and Richet Nobel 1913

• Dogs with jelly fish toxins

• Guinea pigs with penicillin

HS1

Systemic Analyphaxis-Shock• Within secs of second exposure to drugs, venoms or

specific foods (peanuts).• Mast cells degranulate.• GI tract –increased fluid (edema), increased peristalsis

= severe diarrhea and vomiting.• Lungs- this is life threatening . Every time the person

exhales, SMC constrict causing further decreased diameter of bronchi, increased mucous secretion and swelling of connective tissue closes airways completely. Within minutes they cant take a breathe in = asphyxiation.

Upper and lower respiratory

Tract, GI tract, skin reaction.

Severe

Severe

Severe

Severe

constriction

permeability

secretion

Histamine release

At multiple sites simultaneously-

GI tract, upper and lower respiratory tract, skin

1. Processing of antigen

3. 2- 10 X more mast cells

2. T help that produces a Ig E response

4. Mast cells with 10 x higher affinity receptors

What is different about an allergic individual and a non-allergic individual.

5. Mast cells with 10-100 x more histamine per cell

7. Mast cells with 10 x higher affinity receptors

6. More and higher histamine receptors on SMC

If you suspect that you or someone you are with is having an anaphylactic reaction, inject epinephrine immediately. The shot is given into the outer thigh and can be administered through light fabric. Rub the site to improve absorption of the drug. An Epi Pen kit is shown.

Epinephrine antagonist of histamine and causes EC tight junction to re-formation and SMC relaxation.

Type 1 hypersensitivity

Systemic anaphylaxis-severe. • Local Anaphylaxis-mild-severe

– Allergic rhinitis 20% of the population.hay fever, animal dander.

– Asthma (Extrinsic not Intrinsic)-pollen, dust mites, fumes, insect products.

– Food allergies-hives, anaphylaxis.– Atopic dermatitis-fabric softeners, wool.

Milder forms of HS1. Upper airways only.Ragweed 16 tons of pollen per sq. mileAntigens are complex. Enzymes break them down. 5 fractions 2 are allergens

E and K – 95% of HS1 RA3, RA4 and RA 5 5-20% of HS1 rhinitisAllergic individuals process the antigen in a different way.

Animal dander is a protein deposited on hair.

B. Local anaphylaxisB. Local anaphylaxis1. Allergic rhinitis1. Allergic rhinitis

Upper respiratory onlyUpper airways only

Local not systemic Type 1 Hypersensitivity reactions

The first generation antihistamines (e.g., trade names Benadryl, Chlor-Trimetron, and Dimetapp)

bind to histamine receptors, preventing the allergic response. Dosages vary depending on

the medication.

Type 1 hypersensitivity

Systemic anaphylaxis-severe. Local Anaphylaxis-mild-severeAllergic rhinitis 20% of the population:

hay fever, animal dander.– Asthma (Extrinsic not Intrinsic)-pollen,

dust mites, fumes, insect products.– Food allergies-hives.– Atopic dermatitis-fabric softeners, wool.

Asthma Asthma

• Mild to severe –lower airways .• Can cause permanent damage because of

eosinophil involvement in lower bronchi. Eosinophils also possessing high affinity receptors for Ig E.

• Eosinophils produce leukotrines which recruit and activate neutrophils to make proteases that carve up and damage tissue.

Lower bronchi only

Eosinophils cause permanent damage to bronchi

The prevalence of asthma has been increasing since the early 1980s for all age, sex and racial groups.• higher among children than adults • higher among girls than boys • higher among blacks than whites

BRONCHODILATORS dilate the small airways to increase airflow. Long-acting bronchodilaors are given prophylactically to prevent asthma attacks, and may last up to 12-hours. Rapid-acting bronchodilators have effects that last 3-4 hours and are used to relieve a sudden attack. Rapid-acting bronchodilators may also be used as a preventative in some cases, as before exercising to prevent exercise induced asthma.

ANTI-INFLAMMATORY medications are used to prevent and/or relieve airway inflammation, thus reducing the patient's susceptibility to a sudden attack. Most of these medications are steroids, although there are some widely used non-steroidal anti-inflammatory medications.

LEUKOTRIENE MODIFIERS are oral medications that interrupt the body's allergic response, thus preventing attacks in some patients. They are more effective in patients with allergies than in those with chemical sensitivity.

NEBULIZERS and NEBULIZED MEDICATIONS are used not only by EMS and medical facilities, but are not uncommon in home use. Basically the same medications as are supplied in inhalers, nebulization usually results in a more rapid response to the medications

antibody mediated antibody mediated antibody mediated cell mediated

Ig E Ig M or IgG Ig M or IgG T lymphocyte

Immediate Immediate Immediate Delayed

Fastest (sec) 4-6 hrs w/i 4-6 hrs 48-72 hrs.

Allergic rhinitis

Anaphylaxis

Asthma (extrinsic)

Blood transfusions

rH disease of newborn

Pernicious anemia

Post Strep infection

Arthus reaction

Pigeon Fanciers Syn.

Poison Ivy

Tuberulin Test

Allograft Rejection

Type 1 diabetes

Multiple sclerosis

Immediate

6-8 hrs.

6-8 hrs.

48-72 hrs.

Blood transfusions

rH disease of newborn

Pernicious anemia

A, B O blood group antigens are T cell independent antigens.

If transfused with different blood, immediate response because you have been exposed to A, B due to symbiotic microorganisms in gut possessing isohemaglutinins on surface.

Effects of Mis-matched blood transfusion

• Ig M binds to RBC and complement or innate cells lyse the RBCs in mass.

• Free hemoglobin goes to kidney and is converted to bilirubin.

• Bilirubin is toxic and is deposited in skin and liver and brain capillaries.

• Jaundice, severe anemia, liver failure and coma can result.

rH disease of the

newborn occurs

Most often

with mothers married to

husbands with

same ABO blood type

as them. Severity only seen

After mother has had a first

Preqnancy whether it goes to

Term or not.

In rH disease, a Ig G is produced. How ?

Dr. Vincent Freda

• Took Sing Sing prisoners (male) and injected them with different blood types.

• Identified a D antigen, a minor antigen that is T cell dependent and evokes a Ig G response, but only if Ig M to major blood group antigens hasn’t occurred.

• Developed Rhogam , recombinant Ig G to D antigen. Injected after each pregnancy.

Vitamin B12 cannot be absorbed through the small intestine unless complexed to Intrinsic Factor (IF) which transports it across the intestinal mucosa. Pernicious anemia (PA) is associated with circulating antibodies to intrinsic factor (IF). IF antibodies bind to IF on the surface of gut epithelial cells and blocks binding of vitamin B12 to IF in the stomach. This brings about a deficiency in vitamin B12 that prevents RBC production and thus causes anemia.

Pernicious

Anemia:

If penicillin becomes bound to RBC membrane.

Arthus reaction

Post Streptococcal Glomerulonephritis

Pigeon Fanciers Syndrome- excess of dried pigeon fecal protein.

Farmers Lung- excess of thermophilic actinomycetes from moldy hay.

Arthus Reaction

Antigen in excess and in solution when it binds antibody; then becomes associated to tissue.

Tissue damaged by complement

Poststreptococcal glomerular nephritis

Rheumatoid arthritis – rheumatoid factor = immune complexes

Poison Ivy

Tuberculin Test

Leprosy

Contact reactions

Leprosy, Tuberculin test

Leprosy

Cannot be grown in the laboratory. In vivo, it is one of the slowest growing of all organisms and incubations periods in humans with a minimum of 3-5 years. The organism is an obligate, intracellular parasite of peripheral nerves, skin cells, and nasal mucosa.

US Marine contracting Leprosy in Australian after getting a tattoo there.