Immuno Exam 3 - Lec 30 Type III

When does Type III Hypersensitivity develop?

When antigens and antibodies combine to form immune complexes, which if deposited in large amounts in tissues, trigger severe inflammation with damage caused mostly by neutrophils

Antigens and antibodies combine to form what in Type III Hypersensitivity?

Immune Complexes

What is triggered if large amounts of immune complexes are deposited in tissues?

Severe inflammation with damage caused mostly by neutrophils

What needs pre-exposure with development of antibodies?

Type III Hypersensitivity

When considering Type III Hypersensitivity - what is the prerequisite for the development of immune complex disease?

The persistent presence of soluble antigen and antibody

What is formed as a result of the presence of soluble antigen and antibody?

Insoluble immune complexes that become trapped on the basement membrane of small blood vessels

What are the most frequently affected sites with immune complex disease?

- Skin
- Lungs
- Kidneys
- Joints
- Brain
(where large capillary beds exist)

What is the timing of the clinical manifestation of immune complex disease?

6-8 hours after exposure

What is this describing?
- Immune complexes lodged in tissues
- Activate classical complement pathway
- Generates chemotactic peptides that attract neutrophils (gets frustrated - can't phagocytize (too big))
- Neutrophils release oxidants and enzymes anyways
- Acute inflammation and tissue destruction
- Healing

Type III Hypersensitivity

What are the cells and mediators involved in Type III Hypersensitivity?

> *Neutrophils - granule contents
> Macrophages - phagocyte
> Mast Cells - granule contents
> Complement - Anaphylatoxins (C3a, C5a)

What are C3a and C5a also known as?

Why?

- Anaphylatoxins

- When injected in sufficient amounts, they can kill an animal in a manner similar to anaphylaxis by causing mast cells to release histamine granules = pro-inflammatory

What are the 2 major forms of Type III Hypersensitivity?

Localized and Generalized

What happens during localized Type III Hypersensitivity?

- Immune complexes are deposited in tissues and the reaction is seen at the site of the antigen entry
- The antigen is introduced into the tissue and preformed antibody in circulation binds to the antigen
- Immune complexes stay localized

What happens during generalized Type III Hypersensitivity?

- There is excess antigen in circulation
- Antibody in circulation (IgG) binds to circulating antigen and forms free-floating immune complexes in the blood
- Immune complexes circulate and get deposited in blood filtration points

If an antigen is injected subcutaneously (or inhaled) into an animal that already has a very high level of antibodies in its blood stream - acute inflammation will develop at the injection site in the skin within 1-2 hours - what is this known as?

Arthus Reaction

What follows Arthus Reaction?

- Starts a red edematous swelling
- Eventually local hemorrhage and thrombosis occur, and if severe it results in local necrotic tissue destruction

What are some examples of Local Type III Hypersensitivity?

- Insect Bite
- Booster Vaccination
- Farmer's Lung
- Chronic Obstructive Pulmonary Disease in horses (Heaves)
- Blue Eye in dogs

The activation of Mast Cells is different in Type III than Type I - what happens instead?

- Instead of IgE - receptors are stimulated by complement intermediates (C3a, C5a) or IgG
- Not fully activated, only some granules are released

What is Blue Eye in dogs attributable to?

Natural infection with Canine Adenovirus Type I or vaccination with the live modified virus (CAV1 vaccine no longer used - only CAV2 in vaccine)

T or F: CAV1 vaccine is no longer used - only CAV2 is in the vaccines.

True

How does Blue Eye in dogs appear?

Diffuse clouding of the cornea and opacity with anterior uveitis

When dealing with Blue Eye in dogs - what does the immune complex formation result from?

What does it bring about?

- Release of virus especially from infected corneal endothelial cells

- Endothelial corneal damage and hence corneal edema

When does Blue Eye develop?

When/How does it resolve?

- 1-3 weeks after onset of infection

- Spontaneously

What does degranulation in Local Type III Hypersensitivity lead to?

Death of neutrophils and mast cells

What is it known as when a Type III Hypersensitivity reaction occurs in the lungs when sensitized animals inhale antigens like molds, dust and chemicals?

Hypersensitivity Pneumonitis

When considering Hypersensitivity Pneumonitis - what are cattle and horses housed during the winter exposed to?

Dusty feeds and moldy hay

What is the most important thermophilic actinomycetes that makes very small spores that can be inhaled and penetrate as fas as alveoli?

Saccharopolyspora rectivirgula

When considering Hypersensitivity Pneumonitis - what do spore antigens encounter when inhaled?

What does this lead to?

- Antibodies within alveolar walls, resulting immune complexes and complement activation

- Pneumonia

Hypersensitivity Pneumonitis also occurs in people exposed to Saccharopolyspora rectivirgula spores from moldy hay - what is this known as?

Farmer's Lung

What type of condition is Farmer's Lung?

Why?

- Aseptic

- Not an infection, antibody immune response to mold particles - get complexes

What are the clinical features of Farmer's Lung?

- Pneumonia (within 5-10 hours of acute exposure to grossly moldy hay
- Difficulty breathing
- Severe cough

What else occurs with Farmer's Lung other than the clinical signs?

- Acute alveolitis with vasculitis and exudation of fluid into the alveolar spaces
- The alveolar septa is thickened and entire lesion infiltrated with inflammatory cells

What can Farmer's Lung be treated with?

Corticosteroids

T or F: Generalized Type III Hypersensitivity has the same sequence just occurring systematically.

True

Who is Generalized Type III Hypersensitivity triggered in?

Sensitized individuals to a soluble antigen

How does the antigen get into circulation in Generalized Type III Hypersensitivity?

Injected

Where do immune complexes form in Generalized Type III Hypersensitivity?

The blood stream

When considering Generalized Type III Hypersensitivity - where are immune complexes deposited?

At sites of plasma filtration

When considering Generalized Type III Hypersensitivity - what does accumulation of immune complexes cause?

Inflammation - same as local, just occurring systematically

What factors influence deposition of immune complexes?

- Size and amount of the circulating immune complex
- Ability of the host to clear the immune complexes from circulation
- Anatomic and hemodynamic factors

What are some common locations (occur at filtration points) for deposition of immune complexes?

- Blood Vessels
- Glomeruli
- Synovia
- Choroid Plexus

T or F: If the immune complex is small, it cannot be cleared by phagocytes.

False

T or F: If the immune complex is large, it can't phagocytose.

True

What is caused by a large amount of passively administered serum from a different species (anti-toxin)?

Acute Serum Sickness

When does the reaction to Acute Serum Sickness occur?

About 10 days later

What is seen with Acute Serum Sickness?

- Generalized vasculitis with erythema
- Edema
- Urticaria
- Neutropenia
- Lymph node enlargement
- Joint swelling
- Proteinuria

What can cause all 4 types of Hypersensitivity?

Penicillin

What is Chronic Drug Exposure such as IgG-mediated penicillin drug reaction or Sulphanamides an example of?

Generalized Type III Hypersensitivity

What does Methimazole inhibit?

By interfering with what?

- Thyroid hormone synthesis

- Iodine incorporation

Where can adverse reactions occur due to a Methimazole reaction?

- Skin
- Arthralgias
- GI
- Polyarthritis
- Agranulocytosis

What is Methimazole drug reaction believed to be due to?

Immune complex disease

What occurs in a Methimazole Drug Reaction?

- Sensitized patients develop antibodies to drug/hapten
- Excess of antigen leads to immune complex disease, lodges in the skin and is attacked by neutrophils

T or F: Discoid lupus in dogs is confined to the skin and is not systemic.

True

What are autoimmune diseases such as systemic lupus erythematous (SLE), mediated by self-nuclear antigens, the antigen is in constant supply - immune system sees DNA after cell dies and generates anti-DNA Ig an example of?

Generalized Type III Hypersensitivity

Generalized Type III Hypersensitivity can be caused by infectious agents - especially those that what?

Have a large # of persistent circulating antigen

What is it known as when immune complexes deposit in the glomeruli causing basement membrane thickening and stimulate glomerular cells to proliferate?

Glomerulonephritis

What are the 3 cells in the glomerular cell population?

- Epithelial
- Endothelial
- Mesangial

Any of the 3 glomerular cell population can proliferate - what is the lesion called?

Membrano-proliferative glomerulonephritis

How many different forms of Membrano-proliferative Glomerulonephritis are there?

3

What do all types of Membrano-proliferative Glomerulonephritis have?

- Capillary endithelial proliferation
- Mesangial proliferation
- Capillary wall thickening

What types of Membrano-proliferative Glomerulonephritis have immune complexes containing IgG, IgM, IgA and C3?

Type I and Type III

What types of Membrano-proliferative Glomerulonephritis have dense deposits within glomerular basement membrane and do not contain Ig but do contain C3?

Type II

What regions are Type I Membrano-proliferative Glomerulonephritis seen in?

Mesangial and Subendothelial regions

What regions are Type III Membrano-proliferative Glomerulonephritis seen in?

Subepithelial region

What is Type I Membrano-proliferative Glomerulonephritis associated with?

Infectious Diseases

What is Type II Membrano-proliferative Glomerulonephritis associated with?

Dense Deposits

What is Type III Membrano-proliferative Glomerulonephritis associated with?

Very small immune complexes

What types of Membrano-proliferative Glomerulonephritis are most commonly seen?

Types I and II

What is Purpura Hemorrhagica in equines related to?

- Prior bouts of 'strangles' and vaccine (Streptococcus equi)

- Upper respiratory infection

What is seen with Purpura Hemorrhagica in equines?

- Swelling of blood vessels of the head, legs and underbelly
(Usually mild)
- Red spotting on gums and other mucous membranes, bleeding and seeping from the skin

What happens in severe cases of Purpura Hemorrhagica?

Skin dies and sloughs

What else can be affected by Purpura Hemorrhagica?

What can this cause?

- Lungs, Muscles and Kidneys

- Lameness, Laminitis, Colic, Weight Loss, Neurological Signs, May die or need to be put down

What is Purpura Hemorrhagica due to?

An improper immune response (inflammation) to Ag-Ab complexes

What is formed when antigens and antibodies combine?

Immune Complexes

What can immune complexes trigger?

Severe inflammation when deposited in large amount in tissues

What is caused by local deposition of immune complexes in the lungs following inhalation of antigenic dusts?

Hypersensitivity pneumonitis

Immune complexes formed in the bloodstream are deposited where?

What do they cause?

- Glomeruli of the kidney

- Membrano-proliferative glomerulonephritis

Type III Hypersensitivity is a feature of what?

Many viral and some bacterial diseases, especially if not neutralized by antibodies and large amount of immune complexes are generated