Lecture 17 - Type III Hypersensitivity

What causes type III hypersensitivity?

It is caused by the deposition of antigen-antibody complexes (immune complexes) in tissues

What mediates a type III hypersensitivity?

IgG

What is the antigen in a type III hypersensitivity?

Soluble antigens

What are the mediators in a type III hypersensitivity?

Immune complexes (Ag-Ab complexes)

Typical onset of a type III hypersensitivity

1-3 weeks

What is the effector mechanism in a type III hypersensitivity?

Activates FcR+ effector cells and complement, causing inflammation

What are the two subtypes of type III hypersensitivity?

Local reactions and systemic reactions

Describe the local reaction in type III hypersensitivity.

It is triggered by subcutaneously injected antigens or inhaled antigens, occurring rapidly within hours

Describe the systemic reaction in type III hypersensitivity.

It is triggered by large amounts of foreign or self-antigens in the blood, leading to immune complexes depositing in vessels, joints, and kidneys, with a slower onset of 1-2 weeks

What conditions are associated with a local type III hypersensitivity?

Arthus reaction

Farmer's lung

What conditions are associated with a systemic type III hypersensitivity?

Serum sickness

Systemic lupus erythematosus

Purpura hemorrhagica

Vasculitis, nephritis, arthritis

What type of hypersensitivity is characterized by the Arthus reaction?

Local type III hypersensitivity

What triggers the Arthus reaction?

Ag injection into the skin, such as vaccines or boosters

In the Arthus reaction, what is the site of immune complex deposition?

Perivascular area

What type of antibodies are involved in the Arthus reaction?

Individuals have IgG antibodies against the injected antigen

What happens during the Arthus reaction?

Circulating antibodies diffuse into the skin and form immune complexes locally

Immune complexes activate mast cells and complement, causing local inflammation

What severe outcomes can occur due to the Arthus reaction?

Vessel occlusion and tissue necrosis

What is the pathogenesis of the Arthus reaction?

Locally injected antigen in immune individual with IgG antibody

Local immune complex formation activates complement

C5a binds to and sensitizes the mast cell to respond to complexes

Activation of mast cells -> degranulation

Local inflammation, increased fluid and protein release, phagocytosis, and blood vessel occlusion

How does IgG activate complement in a type III hypersensitivity?

IgG binds to soluble multivalent antigen

C1q binds to soluble immune complex and initiates complement activation

No MAC formation!!!

Can make C3a, C3b, C5a, C5b

How does IgG activate complement in a type II hypersensitivity?

IgG binds to antigens on bacterial surface

C1q binds to two or more IgG to initiate complement

MAC formation occurs

Can make C3a, C3b, C5a, C5b

What is farmer's lung?

A local type III hypersensitivity reaction caused by occupational exposure to moldy hay

What causes farmer's lung?

Repeated sensitization to spores of Saccharopolyspora rectivirgula, a thermophilic actinomycetes

Immune complexes form in the walls of alveoli in the lungs

In farmer's lung, what is the site of immune complex deposition?

Alveolar/capillary surface

What pulmonary reaction is associated with farmer's lung?

Hypersensitivity pneumonitis

What causes serum sickness?

It is caused by the injection of a large amount of foreign antigens

What are some symptoms of serum sickness?

Symptoms include fever, vasculitis, arthritis, or nephritis

Hemorrhage

What are antivenins derived from?

Serum from sheep or horses immunized with snake venoms

What type of antibodies are now common in treatment?

Humanized monoclonal antibodies

What are the determinants of the pathogenic potential of immune complexes in serum sickness?

Amount of foreign antigens

Size of immune complexes

Amount, affinity, and isotope of antibodies

Why is the immune complex size important in determining pathogenic potential in serum sickness?

Large complexes (Ag < Ab, Ag = Ab) fix complement and are cleared by

phagocytosis

When Ag is in excess (Ag > Ab), small complexes form, evade phagocytosis, and are deposited in tissues (vessels, joints, or kidneys), leading to local inflammation

What determines the size of immune complexes?

The ratio of antigen to antibody

How are large immune complexes cleared?

AG/Ab complex forms in circulation and activates complement

Complex is coated with covalently bound C3b

CR1 on RBC surface binds C3b-tagged complex

RBC carries immune complex to liver or spleen, where it is detached and taken up by a macrophage

Explain the time course of serum sickness.

Disease onset is 7-10 days after the IV injection (time required to produce Abs)

Self-limiting because at some point the Ag and Ab are at equivalence, and complex size will be large enough to be cleared normally

Pathogenesis of serum sickness

Immune complexes adhere to wall of blood vessel

Immune complexes activate complement and inflammatory cells

Enzymes released from neutrophils damage endothelial cells

What causes systemic type III hypersensitivity in Systemic Lupus Erythematosus (SLE)?

Overproduction and/or defective clearance of immune complexes

What occurs in SLE?

Chronic IgG antibody production against nucleoprotein antigens (self-antigens)

Large quantities of antigens, causes large amounts of small immune complexes

Name three types of nucleoprotein antigens targeted in SLE.

Nucleosome subunits of chromatin, splicesomes, and small cytoplasmic ribonucleoprotein complexes

Fragments from dead cells/a biological process, these are not normally antigens outside of this disease

Where do immune complexes deposit SLE?

Immune complex deposition in small blood vessels of kidneys, joints, and other organs

Diagnostic tools for SLE

ID of a "lupus band" on cytology between the epidermis and dermis

Joint tap analysis of WBC count

Antinuclear Ab (ANA) test

Clinical appearance/characteristics of SLE

Inflammation - leukocytosis of joints, kidney, skin, etc

Skin lesions

Thickening of glomerular basement membrane with dense protein and IgG deposits - glomerulonephritis

What is the pathogenesis of SLE?

Nucleic acid containing immune complexes generated from dying cells activate plasmacytoid DCs to produce IFN-alpha

IFN-alpha stimulates myeloid cells to produce BAFF, which enhances the survival and autoantibody production of auto reactive B cells

What is purpura hemorrhagica?

Induced by Streptococcus equi infection in young adult or geriatric horses

A pathogen that should be cleared but is not, the pathogen is forming immune complexes that can circulate in the blood and accumulate in blood vessels

What are common clinical signs of purpura hemorrhagica?

High fever, mucopurulent nasal discharge, depression, and enlarged lymph nodes in the head region

Vasculitis, bleeding, hemorrhage

Abscesses in lymph nodes, hemorrhages on oral mucosa

What complications can arise from purpura hemorrhagica?

Enlarged lymph nodes may interfere with breathing and swallowing

Lymph nodes can rupture and release purulent material into the environment which is highly contagious

What is the mechanism of purpura hemorrhagica?

M protein is surface Ag on bacterial fibrils that functions as an antiphagocytic virulence factor

Inhibits complement activation

Promotes immune complex formation