Type III (Immune Complex) Hypersensitivity- Mechanism, Examples

Hypersensitivity is a term that describes an abnormal or excessive immune response to an antigen, resulting in tissue damage or disease. There are four types of hypersensitivity reactions, classified by Gell and Coombs according to the mechanism and the type of antigen involved.

Type III hypersensitivity, also known as immune complex hypersensitivity, occurs when antibodies bind to soluble antigens in the circulation and form immune complexes that are not cleared by the innate immune system . These immune complexes can deposit in various tissues and organs, such as the skin, kidneys, joints, lungs, and blood vessels, and trigger an inflammatory response that causes tissue damage .

Type III hypersensitivity can be divided into two forms: local and systemic. Local immune complex disease, or Arthus reaction, occurs when immune complexes are formed locally in the tissues, usually as a result of repeated exposure to an antigen by injection or inhalation . Systemic immune complex disease occurs when immune complexes are formed in the blood and circulate throughout the body, depositing in different organs and causing widespread inflammation . Some examples of systemic immune complex diseases are systemic lupus erythematosus (SLE), post-streptococcal glomerulonephritis, serum sickness, and farmer`s lung .

Type III hypersensitivity is mediated by IgG and IgM antibodies that activate the classical pathway of complement . The complement activation produces anaphylatoxins (C3a and C5a) that attract neutrophils and monocytes to the site of immune complex deposition . These cells attempt to phagocytose the immune complexes but fail to do so because they are bound to the tissue . Instead, they release inflammatory mediators such as lysosomal enzymes, prostaglandins, and reactive oxygen species that damage the surrounding tissue . In addition, the Fc region of the antibody in the immune complex can bind to Fc receptors on platelets and cause aggregation and thrombosis .

Type III hypersensitivity is a serious condition that can lead to chronic inflammation, tissue necrosis, organ failure, and death if not treated promptly. The diagnosis of type III hypersensitivity is based on clinical features, laboratory tests (such as serum complement levels, anti-nuclear antibodies, anti-streptolysin O titers), and histopathology (such as vasculitis, glomerulonephritis, granulomas) . The treatment of type III hypersensitivity depends on the underlying cause and the severity of the symptoms. It may include anti-inflammatory drugs (such as corticosteroids), immunosuppressive drugs (such as cyclophosphamide), plasmapheresis (to remove circulating immune complexes), and supportive care (such as dialysis) .

In this article, we will explain the mechanism of type III hypersensitivity in more detail and describe some examples of local and systemic immune complex diseases. We will also discuss how type III hypersensitivity can be prevented and treated.

Type III hypersensitivity is a type of immune reaction that occurs when antibodies bind to soluble antigens and form immune complexes. Immune complexes are clusters of antigens and antibodies that can trigger inflammation and tissue damage.

The mechanism of type III hypersensitivity can be divided into four steps:

1. Formation of immune complexes: When an antigen enters the body, it can stimulate the production of antibodies by B cells. These antibodies can bind to the antigen and form immune complexes. The size and shape of the immune complexes depend on the ratio and affinity of antigens and antibodies. Some immune complexes are small and soluble, while others are large and insoluble.
2. Circulation and deposition of immune complexes: The immune complexes that are formed in the blood or tissues can circulate throughout the body. Depending on their size, charge, and shape, some immune complexes can be cleared by the liver, spleen, or phagocytic cells. However, some immune complexes can escape clearance and deposit in various tissues, such as the skin, joints, kidneys, lungs, or blood vessels. The factors that influence the deposition of immune complexes include blood flow, vascular permeability, tissue charge, and complement binding.
3. Activation of complement system: The immune complexes that are deposited in tissues can activate the classical pathway of the complement system. The complement system is a group of proteins that can enhance the immune response by opsonizing pathogens, attracting inflammatory cells, and forming membrane attack complexes. The activation of the complement system by immune complexes results in the generation of several fragments, such as C3a, C4a, C5a, C3b, and C5b-9. These fragments have different functions in mediating inflammation and tissue damage.

4. Inflammation and tissue damage: The complement fragments that are produced by the activation of the complement system can cause inflammation and tissue damage in several ways. For example:

   • C3a, C4a, and C5a are anaphylatoxins that can bind to receptors on mast cells and basophils and induce degranulation. Degranulation is the release of histamine and other inflammatory mediators that can increase vascular permeability, smooth muscle contraction, and mucus secretion.
   • C5a is also a chemotactic factor that can attract neutrophils and monocytes to the site of immune complex deposition. These cells can try to phagocytose the immune complexes but fail to do so because they are bound to tissues. Instead, they release reactive oxygen species, proteases, and other cytotoxic substances that can damage the surrounding tissues.
   • C3b is an opsonin that can coat the immune complexes and facilitate their phagocytosis by macrophages. However, this process can also lead to the release of inflammatory cytokines and prostaglandins that can amplify the inflammatory response.
   • C5b-9 is a membrane attack complex that can insert into cell membranes and create pores that disrupt the integrity and function of cells.

The inflammation and tissue damage caused by type III hypersensitivity can manifest as various clinical conditions depending on the location and extent of immune complex deposition. Some examples of type III hypersensitivity diseases are discussed in later points.

A local immune complex disease or Arthus reaction is a type of type III hypersensitivity reaction that occurs when immune complexes are formed and deposited in the tissues, usually the skin, after repeated exposure to an antigen. This can happen after vaccination, such as tetanus or diphtheria booster, or after multiple insect bites .

The mechanism of Arthus reaction involves the following steps:

• The injected antigen binds to the circulating antibodies (usually IgG) that were produced by previous exposure to the same antigen.
• The antigen-antibody complexes accumulate around and within the small blood vessels of the skin, causing inflammation and damage to the vessel walls.
• The complement system, which is part of the innate immune system, is activated by the immune complexes and enhances the inflammatory response by attracting neutrophils and monocytes to the site of deposition.
• The neutrophils try to phagocytose the immune complexes, but fail to do so because they are attached to the tissues. Instead, they release various substances, such as prostaglandins, lysosomal enzymes, and free oxygen radicals, that cause further tissue damage and necrosis.
• The antibody-bound immune complexes may also activate platelets, causing aggregation and blood clots that block the blood flow and lead to hemorrhages.

The signs and symptoms of Arthus reaction usually develop within 24 hours after exposure to the antigen and include redness, swelling, pain, induration (hardening of the area), and sometimes hemorrhage or ulceration at the site of injection or bite. The reaction may last from a week to a few months and usually resolves without scarring.

Systemic immune complex disease occurs when soluble antigens combine with antibodies in the vascular compartment, forming circulating immune complexes that are trapped nonspecifically in the vascular beds of various organs. These antigens may be derived from microbial infections or from autoantigens produced by the body itself. The immune complexes activate the complement system and recruit inflammatory cells, leading to tissue damage and organ dysfunction.

Some of the organs that are commonly affected by systemic immune complex disease are:

The diagnosis of systemic immune complex disease is based on the clinical presentation, laboratory tests (such as serum complement levels, anti-nuclear antibodies, anti-DNA antibodies), and biopsy of the affected tissues. The treatment of systemic immune complex disease depends on the underlying cause and the severity of the condition. It may include immunosuppressive drugs (such as corticosteroids, cyclophosphamide, azathioprine), anti-inflammatory drugs (such as nonsteroidal anti-inflammatory drugs), plasmapheresis (removal of plasma containing immune complexes), and supportive care (such as dialysis for renal failure).

Systemic immune complex disease is a serious and potentially life-threatening condition that can affect multiple organs and systems. It is important to identify and treat the underlying cause of the immune complexes and to prevent further tissue damage and complications.

The principle feature that separates type III hypersensitivity from other types of hypersensitivity reactions is that in type III reactions, the antigen-antibody complexes are pre-formed in the circulation before their deposition in tissues. These complexes can be formed by exogenous antigens (such as microorganisms or drugs) or endogenous antigens (such as self-antigens in autoimmune diseases).

There are two major forms of immune complex-mediated hypersensitivity:

• Local Immune Complex Disease or Arthus Reaction: The immune complexes are formed locally, that is, directly in the tissues, mostly seen in the skin and pulmonary diseases resulting from inhaled antigen . For example, farmer`s lung and bird fancier`s disease are caused by inhalation of bacterial spores and avian serum/fecal proteins, respectively.
• Systemic Immune Complex Disease: Systemic disease occurs when soluble antigens combine with antibodies in the vascular compartment, forming circulating immune complexes that are trapped nonspecifically in the vascular beds of various organs . For example, systemic lupus erythematosus and post-streptococcal glomerulonephritis are caused by immune complexes with autoantigens and streptococcal antigens, respectively.

The mechanism of both types can be summarized as follows:

1. Antigen-antibody complexes are formed when antibodies bind to antigens.
2. If the complex is not cleared by normal processes of phagocytosis, the immune complexes persist in the circulation.
3. The immune complexes subsequently deposit in tissues.
4. The tissue-deposited complexes activate the classical complement cascade.
5. The complement fragments (e.g., C3a and C5a) that form during complement activation activate a variety of potent mediators of inflammation, causing an influx of neutrophils and monocytes to the site of deposition .
6. The attracted neutrophils attempt to engulf the immune complexes. Since the complexes are deposited over the tissues, the neutrophils do not succeed.
7. Consequently, the neutrophils release a number of substances like prostaglandins, lysosomal enzymes, and free oxygen radicals over the complexes, causing damage to the tissues at the site of immune complex deposition .
8. Additionally, the binding of the Fc region of antibody in the immune complex may bind to the Fc receptor on platelets, causing aggregation, blood clots, and blockage of blood vessels leading to hemorrhages at the site.

Type III hypersensitivity reactions can affect various organs and tissues, depending on where the immune complexes deposit. Some examples of diseases caused by type III hypersensitivity are:

• Systemic Lupus Erythematosus (SLE): This is an autoimmune disease in which antibodies are made against various self-antigens, such as nuclear proteins, DNA, and phospholipids. These antibodies form immune complexes that deposit mainly in the kidneys, skin, and joints, causing inflammation and damage .
• Post-streptococcal Glomerulonephritis: This is a kidney disease that occurs after an infection with Streptococcus bacteria, such as strep throat or impetigo. The bacteria produce antigens that cross-react with glomerular antigens, forming immune complexes that lodge on the glomerular membrane. This triggers complement activation and inflammation, leading to reduced kidney function .
• Drug-induced Serum Sickness: This is a condition that occurs when a person is exposed to a foreign protein or a hapten (a small molecule that binds to a carrier protein) from a drug or biological agent. The immune system produces antibodies against the drug-protein complex, resulting in immune complexes that circulate in the blood and deposit in various tissues. The symptoms include fever, rash, joint pain, and lymphadenopathy .
• Farmer`s Lung and Bird Fancier`s Disease: These are examples of local immune complex diseases that affect the lungs. They are caused by inhalation of antigens from organic dusts, such as fungal spores or avian proteins. The antigens form immune complexes with antibodies in the alveoli, causing inflammation and fibrosis of the lung tissue .

These are some of the common examples of type III hypersensitivity reactions. However, there are many other diseases that involve immune complex-mediated mechanisms, such as rheumatoid arthritis, polyarteritis nodosa, and cryoglobulinemia . Therefore, it is important to recognize the signs and symptoms of type III hypersensitivity and perform appropriate diagnostic tests to identify the underlying cause.

Systemic lupus erythematosus (SLE) is the most common and serious form of lupus, a chronic autoimmune disease that causes inflammation and tissue damage in various organs of the body. SLE affects about 70% of people with lupus and can involve the joints, skin, brain, lungs, kidneys, blood vessels, and other tissues.

The exact cause of SLE is unknown, but it is believed to be influenced by genetic, environmental, and hormonal factors. SLE occurs when the immune system produces antibodies that attack the body`s own cells and tissues, forming immune complexes that deposit in different organs and trigger inflammation and damage. SLE is more common and severe in women than men, especially during childbearing years. It is also more prevalent and severe in certain ethnic groups, such as African Americans, Asian Americans, Hispanics/Latinos, and Native Americans.

The signs and symptoms of SLE vary widely depending on the organs involved and the severity of the disease. Some of the common symptoms include:

• Fatigue
• Fever
• Joint pain and swelling
• Skin rashes, especially a butterfly-shaped rash across the cheeks and nose (malar rash)
• Sensitivity to sunlight
• Hair loss
• Mouth ulcers
• Chest pain or shortness of breath
• Kidney problems
• Nervous system problems, such as headaches, seizures, or psychosis
• Blood disorders, such as anemia, low platelets, or low white blood cells

SLE is a complex and unpredictable disease that can have periods of flares (worsening of symptoms) and remissions (improvement of symptoms). There is no cure for SLE, but treatments can help control the symptoms and prevent complications. The treatment options depend on the type and severity of the symptoms, and may include:

• Anti-inflammatory drugs, such as ibuprofen or naproxen, to reduce pain and swelling in the joints and skin
• Steroid creams, such as triamcinolone or fluocinolone, to reduce skin rashes
• Corticosteroids, such as prednisone or methylprednisolone, to suppress the immune system and reduce inflammation in severe cases
• Antimalarial drugs, such as hydroxychloroquine or chloroquine, to modulate the immune system and treat skin rashes, joint pain, and fatigue
• Immunosuppressants, such as azathioprine, methotrexate, or mycophenolate, to inhibit the immune system and prevent organ damage in severe cases
• Biologic agents, such as belimumab or rituximab, to target specific molecules involved in the immune response in severe cases

People with SLE also need regular monitoring of their organ function and blood tests to check for potential complications. They may also benefit from lifestyle changes, such as avoiding sun exposure, wearing sunscreen and protective clothing, quitting smoking, eating a balanced diet rich in calcium and vitamin D, exercising regularly, managing stress, and getting enough rest.

SLE can have a significant impact on the physical, mental, and social functioning of people with the disease. It can also increase the risk of developing other conditions, such as infections, osteoporosis, cardiovascular disease, kidney failure, or cancer. Therefore, early diagnosis and effective treatment are essential to improve the quality of life and prognosis of people with SLE.

Post-streptococcal glomerulonephritis (PSGN) is a rare kidney disease that can develop after a group A streptococcus (GAS) infection, such as strep throat, scarlet fever, or impetigo. PSGN is not a direct infection of the kidneys, but an immune-mediated complication that occurs when antibodies against GAS form immune complexes that deposit in the glomeruli. The glomeruli are the tiny filters in the kidneys that remove excess fluid and waste from the blood.

The mechanism of PSGN is as follows:

• After a GAS infection, the body produces antibodies to fight off the bacteria.
• Some of these antibodies bind to antigens on the surface of GAS or to antigens that are released by the bacteria into the bloodstream.
• These antigen-antibody complexes circulate in the blood and get trapped in the glomeruli, where they activate the complement system, a part of the immune system that enhances inflammation and cell lysis.
• The complement activation attracts neutrophils and monocytes, which are white blood cells that try to engulf and destroy the immune complexes.
• However, since the immune complexes are attached to the glomerular basement membrane, the white blood cells cannot remove them effectively and end up releasing enzymes and reactive oxygen species that damage the glomeruli and surrounding tissues.
• The glomerular damage leads to proteinuria (protein in the urine), hematuria (blood in the urine), hypertension (high blood pressure), edema (swelling), and reduced urine output.

PSGN usually develops about 10 days after a strep throat or scarlet fever infection, or about 3 weeks after an impetigo infection. The symptoms of PSGN may include dark or cola-colored urine, foamy or bubbly urine, swelling in the face, hands, feet, and abdomen, fatigue, nausea, vomiting, and muscle cramps . PSGN is more common in children than adults, especially in young school-age children .

PSGN is diagnosed by medical history, physical examination, urinalysis, blood tests, and sometimes kidney biopsy. The treatment of PSGN focuses on managing the swelling, blood pressure, and infections with medications such as diuretics, antihypertensives, and antibiotics. Most people with PSGN recover completely within a few weeks or months, but some may develop chronic kidney disease or end-stage renal disease that require dialysis or transplantation.

The main way to prevent PSGN is to prevent GAS infections by practicing good hygiene, such as washing hands frequently, covering coughs and sneezes, and avoiding sharing utensils or personal items with others. People with strep throat or impetigo should seek medical attention and complete the prescribed course of antibiotics to prevent complications.

Drug induced serum sickness is a type of serum sickness-like reaction (SSLR) that occurs when a person has an immune response to certain medications that contain non-human proteins or haptens. Haptens are small molecules that can bind to tissue proteins and trigger an immune reaction. Some examples of drugs that can cause serum sickness are beta-lactam antibiotics, ciprofloxacin, sulfonamides, bupropion, streptokinase, metronidazole, carbamazepine, insulin detemir, and some monoclonal antibody therapies .

The mechanism of drug induced serum sickness is similar to that of classic serum sickness. The drug or its metabolites act as antigens that combine with antibodies in the blood, forming immune complexes. These complexes can deposit in various tissues, such as the skin, joints, kidneys, and blood vessels, and activate the complement system. This leads to inflammation, tissue damage, and the release of mediators that cause fever, rash, itching, and joint pain.

The symptoms of drug induced serum sickness usually appear 1 to 2 weeks after the first exposure to the drug, or sooner if the person has been exposed to the same drug before. The symptoms typically last for a few days to a few weeks after stopping the drug. The most common symptoms are hives, itching, rash, fever, arthritis, and swollen lymph nodes . In some cases, more severe complications can occur, such as glomerulonephritis (inflammation of the kidneys), vasculitis (inflammation of the blood vessels), neuropathy (nerve damage), or anaphylaxis (a life-threatening allergic reaction).

The diagnosis of drug induced serum sickness is based on the history of drug exposure, the clinical features, and the exclusion of other causes of similar symptoms. There is no specific laboratory test for drug induced serum sickness, but some tests may show evidence of inflammation, such as elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), or complement levels .

The treatment of drug induced serum sickness involves discontinuing the offending drug and avoiding it in the future. Symptomatic relief can be achieved with antihistamines, nonsteroidal anti-inflammatory drugs (NSAIDs), or corticosteroids. In severe cases, intravenous immunoglobulin (IVIG) or plasmapheresis (a procedure that removes antibodies from the blood) may be required .

Drug induced serum sickness is a rare but potentially serious adverse reaction to some medications that contain non-human proteins or haptens. It is important to recognize the signs and symptoms of this condition and to stop the offending drug as soon as possible. Most cases resolve spontaneously within a few weeks with supportive care and avoidance of re-exposure .

Farmer’s lung and bird fancier’s disease are two examples of local immune complex disease or Arthus reaction. They are caused by repeated or intense exposure to antigens that are inhaled from the environment and form immune complexes in the lungs. These antigens can be proteins from bird feathers or droppings, or dust from moldy hay, straw, or grain.

The immune complexes activate the complement system and attract inflammatory cells to the lung tissue. The inflammation damages the alveoli, the tiny air sacs where gas exchange occurs, and causes symptoms such as cough, shortness of breath, fever, and chest pain. The symptoms usually appear 4 to 8 hours after exposure to the antigen.

If the exposure to the antigen is not stopped, the inflammation can become chronic and lead to pulmonary fibrosis, a condition where scar tissue replaces normal lung tissue and reduces lung function. Pulmonary fibrosis can cause irreversible damage to the lungs and increase the risk of infections and respiratory failure.

The diagnosis of farmer’s lung and bird fancier’s disease is based on the history of exposure to the antigen, the clinical symptoms, and the radiological findings. Chest X-rays or CT scans may show a “ground glass” appearance or patchy infiltrates in the lungs. Lung biopsy may reveal granulomas, which are clusters of immune cells that form around the immune complexes. Blood tests may show elevated levels of antibodies against the specific antigen.

The treatment of farmer’s lung and bird fancier’s disease involves avoiding further exposure to the antigen and taking anti-inflammatory drugs such as corticosteroids to reduce the inflammation. In some cases, oxygen therapy or lung transplantation may be needed if the lung damage is severe. The prognosis depends on the extent of lung injury and the response to treatment. Early diagnosis and avoidance of exposure can prevent permanent lung damage and improve the outcome.

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