Type III Hypersensitivity

What is Type III Hypersensitivity?

Immune complexes are generated by the interaction of antibody with antigen. Typically, this complexing of antigen with antibody enhances antigen removal by phagocytic cells.

Large levels of immune complexes can cause tissue-damaging type III hypersensitivity reactions in certain instances. The extent of the reaction depends on the quantity and distribution of immunological complexes within the body.
A localised reaction develops when the complexes are deposited in tissue very close to the site of antigen entrance. When complexes are generated in the blood, they might cause a reaction wherever they are deposited.

Complex deposition is typically detected on blood artery walls, synovial membranes of joints, glomerular basement membranes of the kidney, and the choroid plexus of the brain.
This complex deposition causes a response that recruits neutrophils to the location. As a result of neutrophil granule release, the affected tissue is damaged.
Immunological complexes activate the complement system’s variety of immune effector molecules, resulting in Type III hypersensitivity reactions.

The C3a, C4a, and C5a complement split products are anaphylatoxins that cause localised mast-cell lysis and an increase in local vascular permeability.
Additionally, C3a, C5a, and C5b67 are chemotactic factors for neutrophils, which can amass in huge numbers at the site of immune-complex deposition.
Smaller immune complexes may penetrate through the basement membrane and be deposited in the subepithelium.

The type of lesion that occurs relies on the location of complicated deposition. The release of lytic enzymes by neutrophils attempting to phagocytose immune complexes contributes significantly to tissue damage in type III reactions.
The C3b complement component coats immune complexes with opsonin. A neutrophil binds to a C3b-coated immunological complex by means of the C3b-specific type I complement receptor.
Because the immune complex is deposited on the surface of the basement membrane, phagocytosis is inhibited, and lytic enzymes are generated during the neutrophil’s futile attempts to consume the adhering immune complex.

Additional activation of the complement system’s membrane-attack mechanism can potentially contribute to tissue damage.
In addition, complement activation can cause platelet aggregation, and the subsequent release of clotting factors can result in the production of microthrombi.

Mechanism of Type III Hypersensitivity

Once ICs become extensive enough to become insoluble, they collect in tiny blood arteries or bodily channels, where they “become stuck.”

In the instance of a blood vessel, the presence of accumulated ICs generates inflammation that causes the endothelial cell layer to become permeable, so permitting the ICs to enter the tissues beneath.
The presence of ICs in the tissues initiates complement activation via the classical pathway. The anaphylatoxins generated during the complement cascade attract neutrophils and mast cells to the site of immunoglobulin (IC) deposition.
The same processes mediating type II HS reactions against fixed tissues then result in cellular damage. In other words, mast cells and neutrophils degranulate and release enzymes and mediators that lyse local tissue cells and promote inflammation.

The surrounding blood arteries are stimulated to widen more, enhancing the availability of ICs to tissues and the influx of leukocytes at the location. Activation of the complement also results in the deposition of C3b on ICs and adjacent tissue cells.
Since neutrophils are equipped with C3b receptors, they attempt to phagocytose cells that have become stuck in solid tissues at the site of IC deposition.
When engulfment fails, “frustrated” neutrophils release lytic chemicals that result in hypersensitivity-related damage. Moreover, the presence of C3b on host cells enhances the synthesis of MAC, which leads to the lysis of those cells.

As expected for processes relying on classical complement activation, certain antibody isotypes, including IgM, IgG3, and IgG1 in humans and IgM, Ig2a/b, and IgG3 in mice, are the primary culprits in type III HS.
Type III HS reactions also involve cells activated by the binding of their FcRs to the many Fcs trapped in deposited ICs. FcRI and FcRIII readily aggregate on local macrophages, DCs, LCs, NK cells, neutrophils, and mast cells, triggering intracellular signals that result in pro-inflammatory cytokine production, respiratory burst, and degranulation (depending on the cell type bearing the receptor).
FcR aggregation plays a crucial role in the development of type III HS reactions, as indicated by studies on Fc-receptor-deficient knockout mice. For instance, when FcyR/ mice were exposed to experimental regimens that typically induce type III HS reactions, the mice exhibited significant decreases in edoema, bleeding, and neutrophil infiltration.

**Mechanism of Type III Hypersensitivity** – Inflammatory responses to immune complexes that concentrate in limited bodily channels cause Type III HS. Antigen–antibody pairings in the blood (1) produce an insoluble immunological complex (IC) that “gets stuck” in a small capillary (2). The deposited IC activates complement, causing C3b deposition on the IC and inflammation that destroys the endothelial cells, so allowing the deposited IC to infiltrate the underlying tissue (3). The presence of IC stimulates complement activation (4), resulting in the production of anaphylatoxins that recruit mast cells and neutrophils (5) to the site of IC deposition. When the cytokine milieu stimulates mast cell degranulation, mediators are subsequently released to destroy host cells (6). In addition, tissue-damaging chemicals are generated by “frustrated” neutrophils and macrophages (7) that attach to the IC via C3b-CR1 or Ig-FcR interactions but are unable to phagocytose it due to its size. NK cells activated by Ig/FcR interactions release lytic mediators as well (8). In conclusion, complement activation initiated by the IC leads to the coating of surrounding host cells with C3b (9) and their death by the production of MAC.

Pathophysiology of Type III Hypersensitivity

After 4-10 days following antigen exposure, an individual’s immune system produces antibodies. The antibody reacts with the antigen to create immunological complexes that circulate and can diffuse into the vascular walls, where they may trigger complement fixation and activation. These immune complexes, together with complement, induce an influx of polymorphonuclear leukocytes at the location, where proteolytic enzymes cause tissue injury. The procedure consists of three steps:

1. Immune complex formation

Antibody production is triggered by antigen exposure, whether endogenous or exogenous. Exogenous antigens are foreign proteins, such as those found in pathogenic microorganisms and pharmaceuticals.
Autoantibodies are produced in response to endogenous antigens, which are self-antigens (autoimmunity).

In both instances, antigens bind to antibodies, generating immune complexes that migrate out of plasma and deposit in host tissues.

2. Immune complex deposition

The ratio between antigen and antibody influences the pathogenicity of immune complexes.
The complexes are insoluble, do not circulate, and are phagocytosed by macrophages in the lymph nodes and spleen when there is an excess of antibody.

However, when there is an overabundance of antigen, the aggregates become smaller. In organs where the blood is changed into fluids such as urine and synovial fluid, they freely filter out of circulation. Immune complexes therefore influence glomeruli and joints.

3. Inflammatory reaction

Inflammatory damage to tissues is triggered by the recruitment of macrophages and neutrophils following the deposition of immune complexes, which is followed by the activation of the classical pathway and the release of C3a and C5a.
Symptoms can manifest as vasculitis (inflammation of the blood vessels), arthritis (inflammation of the joints), or glomerulonephritis (inflammation of the kidney glomeruli).

Examples Of Type III Hypersensitivity

Clinical symptoms of type III HS responses are used to categorise reactions into two groups: those affecting a single site (localised type III HS) and those affecting several sites (systemic type III HS).

Type III Reactions Can Be Localized

An acute Arthus reaction is mediated by the development of localised immunological complexes within 4-8 hours after intradermal or subcutaneous injection of an antigen into an animal with high levels of circulating antibody specific for that antigen.
Examining the tissue under the microscope reveals neutrophils sticking to the vascular endothelium and moving into the tissues at the site of immune complex deposition.

As the reaction progresses, fluid (edoema) and red blood cells (erythema) accumulate at the location due to localised tissue and vascular damage. The reaction might range in intensity from minor redness and swelling to tissue necrosis.
It is possible for someone allergic to insects to have a fast, localised type I reaction at the site of an insect bite. Around 4-8 hours later, the location typically develops the characteristic erythema and edoema of an Arthus reaction.
Pneumonitis and alveolitis can also be caused by an intrapulmonary Arthus-type reaction triggered by bacterial spores, fungal spores, or dry faecal proteins.

A variety of popular names, each corresponding to a certain type of antigen, have come to be associated with these reactions. For instance, “farmer’s lung” occurs when an individual breathes in thermophilic actinomycetes from mouldy hay, while “pigeon fancier’s sickness” is caused by breathing in a serum protein in dust made from dried pigeon excrement.

Type III Reactions Can Also Be Generalized

Circulating immune complexes are formed when a substantial amount of antigen reaches the circulation and binds to an antibody. When there is an abundance of antigen, tiny complexes form; these are difficult for phagocytic cells to remove, and they can trigger tissue-damaging type III responses in numerous locations.
Historically, antitoxins containing foreign serum, such as horse anti tetanus or anti diphtheria serum, frequently induced systemic type III reactions after their administration.

Foreign antiserum causes the receiver to produce antibodies against the foreign serum proteins, which subsequently combine with the foreign antigens to create circulating immune complexes.
After being exposed to foreign serum antigens, it usually only takes a few days or weeks for a person to start showing symptoms that are collectively known as serum sickness.
Fever, weakness, a generalised vasculitis (rash) characterised by edoema and erythema, lymphadenopathy, arthritis, and occasionally glomerulonephritis are all symptoms that may be present.

Serum sickness manifests differently depending on the number of immune complexes generated and the size of the complexes, which in turn determines where the complexes are deposited.
Although complexes can be deposited in a variety of different locales, they tend to collect in tissues that filter plasma, as was noted above. Because of this, it’s clear why serum sickness is associated with such a high rate of glomerulonephritis (complex deposition in the kidney), vasculitis (complex deposition in the arteries), and arthritis (complex deposition in the synovial joints).
Multiple diseases and disorders, not just serum sickness, are influenced by the formation of circulating immune complexes. Among these are the following:
- Autoimmune Diseases
  - Systemic lupus erythematosus
  - Rheumatoid arthritis
  - Goodpasture’s syndrome
- Drug Reactions
  - Allergies to penicillin and sulfonamides
- Infectious Diseases
  - Poststreptococcal glomerulonephritis
  - Meningitis
  - Hepatitis
  - Mononucleosis
  - Malaria
  - Trypanosomiasis
Skin rashes, joint pain, and kidney inflammation are only some of the type III hypersensitivity reactions that have been linked to antibody-antigen complexes from bacteria, viruses, and parasites.
In the case of post-streptococcal glomerulonephritis, for instance, the glomeruli are damaged when antibody-streptococcal antigen complexes circulating in the blood are deposited in the kidney.

Several autoimmune disorders can be traced back to antibodies that have formed complexes with self-proteins, glycoproteins, or even DNA and are circulating in the bloodstream.
Complexes of DNA and anti-DNA antibodies accumulate in the synovial membranes of people with systemic lupus erythematosus, causing arthritic symptoms, or on the basement membrane of the kidney, causing progressive kidney damage.