Hypersensitivity Reactions

altered immunological response to an antigen that results in disease or damage to host

Hypersensitivity reaction

How can hypersensitivity reactions be classified?

1. The mechanisms that cause the disease (Type I-IV)

2. the source of the antigens: allergy, autoimmunity, alloimmunity (rxns against tissues of another person ex. blood transfusion/organ transplant)

Type I hypersensitivity reactions

-IgE mediated (attaching to mast cells)

-immediate reaction

- allergies

Degranulation mechanism of allergic response

1. allergin binds IgE/FceR1 on mast cell surface

2. cross links 2 IgE to activate degranulation signal

3. Ca2+ influx

4. degranulation & release of inflammation mediators

immediate phase events

- release of histamine and cytokines by Mast cells

- immediate

Late phase events

- synthesis of eicosanoids, cytokines and chemokines

- immune cells infiltrate (eosinophils, etc)

- SM contraction, edema

- can last hours-days, can lead to chronic inflammation

mediators of allergic response (type I)

Primary:

Histamine, proteases, chemotactic factors (ECF, NCF)

Secondary:

Luekotrienes & Prostaglandin

Sensitization (mechanism of allergic response)

refers to class switching of Abs

Effector stage (mechanism of allergic response)

binding of IgE to mast cell surface (& basophils, eosinophils)

Type I HSR; Localized anaphylaxis

- targeted organ responds to direct contact with allergens

ex. lung -> asthma -> pollen, dust -> wheezing

nose/eyes -> pollens -> runny nose/itchiness

skin -> food/meds -> itchiness/blisters

Gi tract -> food -> diarrhea/vomitting

Systemic anaphylaxis (anaphylactic shock)

- systemic vasodilation & SM contraction leading to severe bronchiole constriction, edema, and hypotension (shock)

- tachycardia, arrhythmia & cardiac arrest can occur

-medical emergency

Type I HSR; atopy

- associated with genetic predisposition for localized anaphylaxis

- have higher levels of IgE and eosinophils

- polymorphic genes related to atopy:

- il-4R, Il-4, FceR, MHC II, inflammation genes

Type II HSR

- IgG/M mediated (inappropriate binding to tissue cell surface)

- cytotoxic reactions; Ab binds causes C' MAC or ADCC

- onset = hours-days

ex. mistakes in blood transfusions, autoimmune disease

What happens if the wrong blood types are transfused

surface Ag + opposing Ab = agglutination and hemolysis

type III HSR

- IgG/M mediated

- immune complex diseases

- onset = Hrs to weeks

Immune complex disease (ICD) (Type III HSR)

formation of immune complexes (IC) made by Ag-Ab complexes in circulation (IgG/M)

- IC found in circulation, not effectively removed - get trapped in tissues and cause degranulation of phagocytes

- inflammation/injury where IC are depositied (kidneys, joints, endo-cells)

Systemic Lupus - type of ICD (autoimmune) // Type III HSR

- Ab against dsDNA from apoptotic cells form IC

- IC deposited in kidneys glomerular structures & blood vessels

-> eventually leads to immune-mediated tissue inflammation & damage

Type IV HSR

- T-cell mediated

- delayed type hypersensitivity (DTH)

- onset = 2-3 days (only memory TCs)

delayed type hypersensitivity (DTH) // Type IV HSR

- classified by macrophage APC & TC activation that results in tissue damage

- can be the result of chronic infection or exposure to Ags

- can be autoimmune

Contact dermatitis // type IV HSR// DTH

- response to poison ivy

- Ag taken up by APCs & presented to Th1 cells

- during secondary exposure, Th1 memory cells become activated to CD8 TCs to cause DTH

Note: Ags can also be heavy metals and latex

autoimmune disorder causes

1. breakdown in immune tolerance against self Ags

2. molecular mimicry of infectious microbe's Ags resembling self Ags

3. neo-Ag creation (through hapten-binding to cellular proteins & somatic mutations altering protein structure)

risk factors of autoimmune disorders

-genetic predisposition

-sex, X-inactivation (more common in women)

- infections in susceptible individuals (immunocompromised)

- Age: loss of immune system self-regulatory capacity

Guillain-Barre is a type ___ HSR

Type II HSR

- targets PNS; gangliosides on nerve cells

- molecular mimicry, Abs produced recognize self-Ag

Graves disease is a type ___ HSR

II

- targets the thyroid; TSH receptor

- Auto Ab against TSH, increases thyroid hormone production

myasthenia gravis is a type ___ HSR

II

- targets skeletal muscles; nicotinic AChR

- blocks/destroys AChR at NMJ, prevents contractions

rheumatoid arthritis is a type ___ HSR

III

- targets synovial membrane/other organs

- autoimmunity & IC in joints/other organs

systemic lupus erythematosus is a type ___ HSR

III

- production of anti-nuclear Ab

- systemic attack on skin, joints, kidneys, heart, blood & lungs

Celiac disease is a type ___ HSR

IV

- targets small intestine; gliadin-enterocytes

- TC response in genetically susceptible ppl

Multiple Scelerosis is a type ___ HSR

IV

- targets CNS; myelinated axons

- demyelination of nerve cells

Type 1 diabetes is a type ___ HSR

IV

- targets pancreas; beta cells (insulin producing)

- Auto Abs against beta-cells persists after diabetes onset