Immuno 17: Type III Hypersensitivity

Antigen-antibody (immune) complexes

Type III hypersensitivity reactions occur when ___ form in tissues or in the circulation.

Local reaction

Triggered by subcutaneously injected (skin) or inhaled (lung) soluble antigens

Systemic reaction

Triggered when large amounts of soluble antigens (foreign or self) are in the blood circulation and form immune complexes that are not adequately cleared, leading to tissue deposition in vessels, joints, and kidneys

Vasculitis

Injury to blood vessels

Arthus reaction (subcutaneous or muscle tissue), hypersensitivity pneumonitis (lung)

Examples of diseases caused when the soluble antigen is localized in a tissue or organ

Arthus reaction

1. Painful, localized swelling and inflammation under the skin that occurs when the immune system reacts to a booster vaccination or repeated antigen exposure

2. Involves the degradation of mast cells via the anaphylatoxin C5a and binding of IgG to Fc-gamma-RIII

C5a, Fc-gamma-RIII

The Arthus reaction involves the degranulation of mast cells via the anaphylatoxin ___ and binding of IgG to ___.

Farmer’s lung

Occupational exposure:

1. Inhalation of Ags from moldy hay

2. Cause:

   1. Repeated sensitization to spores of Saccharopolyspora rectivirgula (a thermophilic actinomycetes)

   2. Immune complexes form in the walls of alveoli in the lungs

Pulmonary reactions:

1. Hypersensitivity pneumonitis

Also reported in cattle and horses

Site of immune complex deposition/formation, amount of Ag and Ab, Ag:Ab ratio

What is the pathology and intensity of the systemic type III hypersensitivity reaction determined by?

Small complexes, large complexes

___: Not cleared from the circulation

1. Type III hypersensitivity

___: Cleared from the circulation by phagocytosis in the liver

C’ receptor 1 (CR1)

Normally, ___ on erythrocytes helps clear immune complexes from the circulation

Soluble antigens

Immune complexes formed between ___ (such as proteins or viruses free in the blood) are in excess relative to the antibodies (IgG)

Immune complex vasculitis, cutaneous small vessel vasculitis

1. In ___, immune complexes are deposited in the vascular endothelium or in capillary beds, such as those found in the skin, joints, kidneys, or lungs

2. A common manifestation of this syndrome in the skin is called ___ and is clinically manifested as a rash, hemorrhages, and in horses as purpura hemorrhagica

3. Common causes are either medications (e.g., penicillin, sulfonamides, or cephalosporins), foreign substance, or during bacterial and viral infections

Relative lower abundance of Ab, abundance and persistence of Ag, formation of small Ag-Ab complexes that do not fix C’ and are not cleared from the circulation, does not develop as intensely without mast cells

Factors that contribute to the development of Type III hypersensitivity when the Ag is in the blood

Serum sickness, mediated by infectious agent, autoimmune diseases

Categories of syndromes that develop when Ag is in bloodstream

Feline infectious peritonitis (FIP), blue-eye, porcine circovirus type II (PDNS)

Examples of diseases mediated by an infectious agent that develop when Ag is in bloodstream

Systemic lupus erythematosus, rheumatoid arthritis

Examples of autoimmune diseases that develop when Ag is in bloodstream

7-10 days after the injection of Ag

Disease onset of serum sickness

Large, small

___ immune complexes are normally cleared, while ___ immune complexes cause serum sickness.

Cause smooth muscle contraction, histamine release from mast cells, and enhanced vascular permeability; mediate chemotaxis and activation of neutrophils and monocytes/macrophages; promote inflammation and generation of cytotoxic oxygen radicals

Function of anaphylatoxins in systemic type III HST

Granulocytes (neutrophils, eosinophils, basophils), monocytes, mast cells

What are C3a and C5a chemotactic for?

Neutrophils

Play a major role in the development of vasculitis in systemic type III hypersensitivity

1. Immune complex (IC) bind to Fc-gamma-Rs on the neutrophil surface, triggering their activation

2. Activated neutrophils produce reactive oxygen species (ROS)

3. Release of proteases and NETs

Mechanism of neutrophil extracellular trap (NET) formation in immune complex-mediated diseases

Neutrophil extracellular traps (NETs)

1. Characterized as extracellular DNA fibers comprised of decondensed chromatin, histones, and cytoplasmic granule proteases

2. Provide a scaffold for protein and cell binding

   1. Protein binding to these further activates the coagulation system, which participates in thrombosis

3. Can also damage the tissues due to the toxic proteins they carry

Neutrophil extracellular traps (NETs)

Many studies have suggested that the excessive formation of ___ may contribute to a range of diseases, including thrombosis, atherosclerosis, autoimmune diseases, sepsis, and pulmonary thrombosis in COVID-19 pneumonia.

Thrombosis

Release of neutrophil extracellular traps (NETs) activates the coagulation system, resulting in ___, which plays a major role in the pathogenesis of type III hypersensitivity.

Tissue factor (TF)

Triggers immunothrombosis through the intrinsic and extrinsic coagulation pathways

Vasculitis

Type III hypersensitivity develops when immune complexes are formed and either locally or systemically produce ___.

C3a, C5a

Trigger the degranulation of mast cells, attract neutrophils, and increase vascular permeability

Neutrophil extracellular traps (NETs)

Released from neutrophils

Activate FXII– intrinsic blood coagulation cascade (immunothrombosis)

Fibrinoid necrosis

1. Seen in immune reactions involving blood vessels

2. Deposition of immune complexes (antigen antibody complex) + leaking fibrin deposits = fibrinoid in arterial walls

3. Deposits of “immune complexes + fibrin” result in a bright pink and amorphous appearance in H&E stains called “fibrinoid” (fibrin-like)

Systemic lupus erythematosus

Canine

Systemic inflammatory disease (joints, kidneys, skin)

Rheumatoid arthritis

Canine

Erosive arthritis

Polymyositis

Canine

Myositis (muscle fiber degeneration)

Strangles

1. Characterized by abscessation of the lymphoid tissue of the upper respiratory tract

2. Remains one of the most common infectious diseases of horses worldwide

Purpura hemorrhagica

Form of nonthrombocytopenic purpura that often is a sequela of an earlier Streptococcus equi respiratory infection

1. Mediated by immune complexes of Ab and streptococcal Ag (M protein) in vascular basement membranes

False

True or false?:

The mutated feline coronavirus that causes FIP can be transmitted from cat to cat.

Less than 2 years old, multi-cat environment

Typical signalment of FIP cats

Feces, saliva, inhalation, trans-placenta

How is FIP transmitted?

Effusive (“wet”), non-effusive (“dry”)

What are the two forms of FIP?

FIP

Which replicates in monocytes more efficiently: FeCoV or FIP?

Feline enteric coronavirus (FeCoV)

Most cats with this common virus either stay healthy or show only a mild enteritis

Only a proportion of cats infected with this virus will develop FIP

Feline infectious peritonitis

Pyogranulomatous vasculitis that a proportion of FeCoV-infected cats develop

Viral load, immune response of cat

What two factors determine whether FIP will develop in a cat?

Viral genetics, host immunity

What plays a role in the development of FIP?

Effusive (wet)

Form of FIP characterized by polyserositis (simultaneous inflammation of multiple serous membranes; e.g., thoracic and abdominal effusion) and vasculitis (type III hypersensitivity)

Non-effusive (dry)

Form of FIP characterized by pyogranulomatous lesions in organs (type IV hypersensitivity)

Protein, cellularity, macrophages, neutrophils

1. FIP effusions (in the effusive/wet form of FIP) typically have a very high ___ content (>35 g/L) but a low ___ (<5000 nucleated cells/mL) with a dominance of ___ and ___

2. When sufficient cells are present, the demonstration of viral Ag in macrophages confirms the diagnosis of FIP

Effusive (wet)

These are the clinical signs of which form of FIP?:

1. Ascites (fluid buildup in abdomen)

2. Bright or dull

3. Anorexic or eating well

4. Mild fever

5. Weight loss

6. Dyspnea

7. Palpable abdominal mass

Non-effusive (dry)

These are the clinical signs of which form of FIP?:

1. Vague clinical signs

2. Fever

3. Weight loss

4. Dullness

5. Anorexia

6. Dyspnea

7. Uveitis (uvea inflammation), iritis (iris inflammation), retinitis (retina inflammation)

Ab (humoral), cellular (Th1)

In the wet form of FIP, the immune response to the virus is dominated by a strong ___ immune response and a weak ___ response.

Cell-mediated, humoral

Cats that mount an intermediate level of ___ immunity to FIP virus and an intermediate level of ___ immunity will develop the dry form of FIP.

Cell-mediated

Clinical recovery from FIP is dependent on a strong ___ immune response and a reduced level of virus in the body and its eventual elimination.

Strength of cell-mediated immunity (CMI), viral load

The outcome of FIP is determined by what two factors?

Strong cell-mediated immune response

Activates the resistance of macrophages to virus infection curtailing virus replication

Humoral immunity

Provides no protection from FIP infection but rather appears to enhance infection

Cell-mediated

Cats that mount a strong ___ immune response to FIP from the start of infection are generally resistant to either form of the disease.