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Hypersensitivity
Robert Beatty
MCB
Type I IgE Mediated Classic Allergy Type II IgG/IgM Mediated rbc lysis Type III IgG Mediated Immune complex Disease Type IV T cell Delayed Type Hypersensitivity Gel and Coombs classification of hypersensitivities.
TYPE I Hypersensitivity
Classic allergy
Mediated by IgE attached to Mast cells.
The symptoms resulting from allergic responses
are known as anaphylaxis.
- Includes: Hay fever, asthma, eczema, bee stings, food allergies.
Allergens
Allergens are nonparasite antigens that can
stimulate a type I hypersensitivity response.
Allergens bind to IgE and trigger
degranulation of chemical mediators.
Allergens
In the US --- 36 million people said to have hay fever!
Characteristics of allergens
Small 15-40,000 MW proteins.
Specific protein components
Low dose of allergen
Mucosal exposure.
Most allergens promote a Th2 immune.
Allergens
Dermatophagoides pteronyssinus (common dust mite) Example: Der P Der P1 is an enzyme allergen from the fecal pellets of the dust mite. Allergen is easily aerosolized and inhaled. Der P1 breaks down components of tight junctions which helps it to cross mucosa.
Der P1 Allergen
Atopy
Atopy is the term for the genetic trait to have a
predisposition for localized anaphylaxis.
Atopic individuals have higher levels of IgE and
eosinophils.
Genetic Predisposition
Type I hypersensitivity
Candidate polymorphic genes include:
- IL-4 Receptor.
- IL-4 cytokine (promoter region).
- FcεRI. High affinity IgE receptor.
- Class II MHC (present peptides promoting Th2 response).
- Inflammation genes.
Mechanisms of allergic response
Sensitization
Repeated exposure to allergens initiates
immune response that generates IgE
isotype.
Th2 cells required to provide the IL-
required to get isotype switching to IgE.
Mechanisms of allergic response
Sensitization
Th2/B cell interaction
IL-
IL-4R
CD
Drive B cell
Activation and IgE
isotype switch.
Busse and Lemanske NEJM Feb 2001. 344:
Immediate vs Late Effects
(early mediators) Early/Late Effect on lung airflow OR Wheezing
Mediators of Type I Hypersensitivity
Primary Mediators
Pre-formed mediators in granules
Histamine
Cytokines TNF-α, IL-1, IL-6.
Chemoattractants for Neutrophils and
Eosinophils.
Enzymes
- tryptase, chymase, cathepsin.
- Changes in connective tissue matrix, tissue breakdown. Type I Hypersensitivity Secondary mediators Mediators formed after activation
Leukotrienes
Prostaglandins
Th2 cytokines- IL-4, IL-5, IL-13, GM-CSF
Continuation of sensitization cycle
Mast cells control the immediate response.
Eosinophils and neutrophils drive late or
chronic response.
More IgE production further driven by
activated Mast cells, basophils, eosinophils.
Continuation of sensitization cycle
Eosinophils
Eosinophils play key role in late phase
reaction.
Eosinophils make
- enzymes,
- cytokines (IL-3, IL-5, GM-CSF),
- Lipid mediators (LTC4, LTD4, PAF)
Eosinophils can provide CD40L and IL-
for B cell activation.
Localized anaphylaxis
Target organ responds to direct contact with allergen.
Digestive tract contact results in vomiting,
cramping, diarrhea.
Skin sensitivity usually reddened inflamed
area resulting in itching.
Airway sensitivity results in sneezing and
rhinitis OR wheezing and asthma.
Systemic anaphylaxis
Systemic vasodilation and smooth muscle
contraction leading to severe bronchiole
constriction, edema, and shock.
Similar to systemic inflammation.
Treatment for Type I
Pharmacotherapy
Drugs.
- Non-steroidal anti-inflammatories
- Antihistamines block histamine receptors.
- Steroids
- Theophylline OR epinephrine -prolongs or increases cAMP levels in mast cells which inhibits degranulation.
Treatment for Type I
Immunotherapy
- Desensitization (hyposensitization) also known as allergy shots.
- Repeated injections of allergen to reduce the IgE on Mast cells and produce IgG.
Treatment for Type I
Effect of allergy shots Allergen Specific Antibodi es Change in amount of each isotype from more IgE to more IgG. TYPE II Hypersensitivity Antibody mediated cytotoxicity
Blood Transfusion reactions
Innocuous antigens on red blood cells. EXAMPLE: ABO blood group antigens A and B carbohydrate antigens
Antibody against rbc antigen binds and
mediates killing of rbcs via C’or ADCC
causes systemic inflammation.
ABO Blood Groups Quex: Why do we have antibodies to these innocuous antigens even before we get blood transfusion?
TYPE III Immune Complex Disease
Localized disease
Deposited in joints causing local inflammation =
arthritis.
Deposited in kidneys = glomerulonephritis.
TYPE III Immune Complex Disease
Serum sickness from large amounts of antigen
such as injection of foreign serum.
Serum sickness is usually transient immune complex disease with removal of antigen source.
Serum Sickness
Systemic immune complex disease
Days after Antigen Injection Large amounts of antigen such as injection of foreign serum. Delayed type hypersensitivity Th1 cells and macrophages
DTH response is from:
- Th1 cells release cytokines to activate macrophages causing inflammation and tissue damage.
- Continued macrophage activation can cause chronic inflammation resulting in tissue lesions, scarring, and granuloma formation. Delayed is relative because DTH response arise 24- hours after exposure rather than within minutes.
Stages of Type IV DTH
Sensitization stage
Memory Th1 cells against DTH antigens
are generated by dendritic cells during the
sensitization stage.
These Th1 cells can activate macrophages
and trigger inflammatory response.
Stages of Type IV DTH
Effector stage
Secondary contact yields what we call DTH.
Th1 memory cells are activated and produce
cytokines.
- IFN-γ, TNF-α, and TNF-β which cause tissue destruction, inflammation.
- IL-2 that activates T cells and CTLs.
- Chemokines- for macrophage recruitment.
- IL-3, GM-CSF for increased monocyte/macrophage
Stages of Type IV DTH
Effector stage
Secondary exposure to antigen
Inflamed area becomes red and fluid filled can
form lesion.
- From tissue damage there is activation of clotting cascades and tissue repair.
Continued exposure to antigen can cause chronic
inflammation and result in granuloma formation.
Type IV DTH
Contact dermatitis
The response to poison oak is a classic Type IV.
- Small molecules act as haptens and complex with skin proteins to be taken up by APCs and presented to Th cells to get sensitization.
- During secondary exposure Th1 memory cells become activated to cause DTH.
Contact dermatitis
Delayed type hypersensitivity
(DTH)
DTH is a type of immune response classified by Th1 and macrophage activation that results in tissue damage. DTH can be the result of Chronic infection or Exposure to some antigens. Granuloma Formation from DTH Mediated by Chronic Inflammation
Drug reactions can be any Type
of Hypersensitivity
