Overview

• Type III hypersensitivity reactions are mediated by IgG (or IgM) antibody-antigen complexes; recall that these responses occur 1-3 hours after antigen exposure.
• Normally, antibody-antigen complexes, aka, immune complexes, are removed by phagocytes of the spleen and lymph nodes.
• However, persistent complexes can concentrate and cause tissue damage via complement and immune cell activation.
• This most commonly occurs where blood or plasma is filtered through fenestrated capillaries; for example, in the synovial joints and renal glomeruli.

Pathogenesis of immune complex-mediated hypersensitivity:

• Immune complexes become deposited on the vessel wall (or, in some cases, in the tissues).
• As a result, complement and neutrophil activation occurs, leading to the release of pro-inflammatory cytokines, enzymes, and reactive oxygen species.
• Increased vessel permeability allows the inflammatory molecules to cause additional tissue damage outside of the vessel.

Examples

• Vasculitis, which is inflammation of the vessel walls, is a common manifestation of type III hypersensitivity. In the image, we can see small purple lesions in the skin.
  — In the histological sample showing fibrinoid necrosis of a vessel, highlight where immune complex deposits promote cell death and excessive fibrin synthesis.
• Arthritis occurs when immune complexes deposit in the synovial joints.
• Post-infectious glomerulonephritis, which involves inflammation of the renal glomeruli, is associated with Staphylococcus bacterial infection (and, increasingly, Streptococcus infections).
  — In the histological sample of a glomerulus, show that antibody-antigen complexes aggregate in the basement membrane, and, that neutrophils infiltrate the glomerulus and damage the renal filtration system.

Local Arthus Reaction

• Produces localized vasculitis and tissue necrosis; rarely, it is associated with tetanus or diphtheria-containing vaccines.
• It can be produced by re-injecting antigens too soon after initial exposure:
  — The antigens form immune complexes with circulating IgG antibodies.
  — Then, the immune complexes activate complement and recruit inflammatory cells, including neutrophils and mast cells.
  — Inflammatory cell degranulation releases cytokines, enzymes, and other molecules that produce local inflammation at the injection site, which is marked by pain, swelling, and redness that typically subsides after a few days.
• As an additional clinical correlation, write that hypersensitivity pneumonitis, aka, allergic alveolitis, is a type III hypersensitivity reaction that takes place in the lungs (we discuss this in more detail in the hypersensitivity essentials tutorial).

Systemic Serum Sickness

• Manifests throughout the body.
• Serum sickness can be induced by older vaccines that used antibodies from other species, such as horses and rabbits; though rare, it can also occur after transfusions. Anti-venom reactions can occur when, for example, anti-snake venom treatment is administered to a previously sensitized individual. Newer anti-venom treatments avoid this reaction.
• Graphically:
  — X-axis = “Time in Days”; Y-axis = “Plasma levels”
  — At time 0, show that plasma levels of foreign proteins spike immediately after administration, then slowly decline for a period; Initially, plasma antibody concentration is low.
  — Then, show that as production of plasma antibodies increases, immune complexes are formed; thus, the concentration of foreign protein is rapidly reduced.
  — Furthermore, show that the appearance of serum sickness symptoms coincides with immune complex formation, and typically resolve on their own.
• Common manifestations of serum sickness include: blotchy skin rashes, joint pain, peripheral edema, and fever.

Systemic Lupus Erythematosus (SLE)

• Genetically-influenced disorder caused by autoantibodies that target self-antigens.
• SLE is associated with a wide variety of autoantibodies, some of which are specific to the disorder; furthermore, some of the autoantibodies are correlated with specific outcomes.
  — Some key autoantibodies include:
  Antinuclear antibodies, which target components of host nuclei; these are non-specific to SLE.
  Anti-double stranded DNA antibodies, which are specific for SLE and may be associated increased renal damage;
  Anti-sm antibodies, also specific to SLE, may be associated with increased pulmonary arterial hypertension;
  Antiphospholipid antibodies, which are non-specific and are associated with thrombosis, hemolytic anemia, and, possibly, problematic pregnancies.
  Anti-Ro and anti-La antibodies are commonly found in SLE patients, but are not-specific; importantly, anti-La antibodies may cross the placenta and interfere with fetal heart development.
• Clinical manifestations of autoantibody actions include:
  — Lupus nephritis, of which there are 6 patterns of glomerular damage;
  Here, we indicate that the most common includes widespread destruction characterized by thickened “wire loops” and necrosis; often, crescent-shaped damage in Bowman’s capsule is also visible.
  — SLE produces specific rash patterns; the malar rash pattern, also known as the “butterfly rash,” and, “discoid rash,” which is disc-shaped and tends to be scalier.
  — The cardiovascular system may also be affected. Here, show Libman-Sacks endocarditis, in which sterile vegetations form along the margins of the valve leaflets; recall that sterile vegetations are especially prone to breaking free and embolizing.
  — Pericarditis and/or peritonitis are also common, though not shown here.
• Common environmental triggers for SLE flares include: ultraviolet light, some medications, cigarette smoking, and certain viral infections.
• Some of the immune-complex mediated symptoms of systemic lupus erythematosus can be treated with hydroxychloroquine (originally used to treat malaria) and corticosteroids, such as Prednisone, which dampen the immune response.