Type III Hypersensitivities: Videos & Practice Problems

Type III hypersensitivities involve immune complexes—antibody-antigen clusters—that, when small and soluble, evade phagocytosis and deposit in tissues like kidneys or joints. This activates the complement system, triggering inflammation and tissue damage, as seen in diseases like glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus. These immune complex-mediated reactions can be localized, such as Arthus reaction, or systemic, like serum sickness. Understanding immune complex formation, complement activation, and neutrophil degranulation is crucial for grasping the pathogenesis of autoimmune and inflammatory disorders linked to adaptive immunity and immune dysregulation.

Type III (Immune Complex-Mediated) Hypersensitivity

Type III hypersensitivity reactions, also known as immune complex-mediated hypersensitivities, play a significant role in autoimmune and inflammatory conditions such as rheumatoid arthritis, lupus, and glomerulonephritis. These reactions are triggered by immune complexes, which are clusters of antibodies bound to antigens. The formation of immune complexes depends on specific antibody-antigen ratios, similar to precipitation reactions in immunology.

Immune complexes are a normal part of immune function and are typically cleared efficiently by phagocytic cells. However, problems arise when these complexes persist and are not adequately removed. The antigens involved can be foreign, such as microbial components, or self-antigens, but the critical factor in disease development is the persistence of these immune complexes rather than the antigen type.

The size and solubility of immune complexes influence their clearance. Large immune complexes are more readily phagocytosed and removed, preventing tissue damage. In contrast, small, soluble immune complexes can evade phagocytosis, circulate in the bloodstream, and deposit in various tissues, including the kidneys, joints, or blood vessel walls. Once deposited, these complexes activate the complement system, a cascade of proteins that promotes inflammation and tissue injury.

For example, in glomerulonephritis, immune complexes lodge in the capillary walls of the kidney glomeruli, triggering complement activation and inflammation that damages kidney tissue. This mechanism illustrates how type III hypersensitivity can lead to organ-specific pathology. Despite advances in understanding, the precise reasons why immune complexes preferentially deposit in certain tissues, such as joints in rheumatoid arthritis or kidneys in glomerulonephritis, remain unclear and are an active area of research.

Understanding the dynamics of immune complex formation, clearance, and tissue deposition is essential for grasping the pathophysiology of type III hypersensitivities. The complement system’s role in mediating inflammation highlights the interconnectedness of immune responses and tissue damage in these conditions.

Type III hypersensitivity is caused by the immune system’s reaction to immune complexes. Immune complexes are made of aggregates of which of the following?

• A. Immunohemagglutinins and foreign RBCs.
• B. AB antigens and Rh antigens found in RBCs.
• C. Antigens bound to antibodies in tissues and blood.
• D. Multiple complement system proteins binding to form a membrane attack complex.

Answer: (C)

Why are small immune complexes damaging to the body?

• A. They can enter endothelial cells & damage them from the inside.
• B. They often “clump” together in blood vessels, which can lead to blood clots.
• C. They can weaken our immune system by damaging phagocytes.
• D. They can escape phagocytosis, deposit in tissues/between cells, & cause a damaging inflammatory response.

Answer: (D)

Steps of Immune Complex- Mediated Hypersensitivity

Type III hypersensitivity, also known as immune complex-mediated hypersensitivity, involves a series of immune responses that can lead to conditions such as rheumatoid arthritis, which primarily affects joints including those in the knuckles. This hypersensitivity reaction occurs in three key steps. Initially, immune complexes form when antibodies bind to antigens under specific conditions, particularly when the ratio of antibodies to antigens is optimal. These immune complexes are a normal part of immune function; however, their size plays a crucial role in their clearance. Large immune complexes are typically cleared efficiently by phagocytes, whereas small soluble immune complexes can evade phagocytosis, persist in circulation, and deposit in tissues.

Once these small immune complexes deposit in tissues, such as the synovial joints in rheumatoid arthritis, they activate the complement system. This activation attracts inflammatory cells, notably neutrophils, to the site of deposition. Neutrophils respond by degranulating, releasing enzymes and other cytoplasmic granule contents that cause tissue inflammation and damage. This inflammatory response is responsible for the pain, swelling, and joint damage characteristic of rheumatoid arthritis.

Understanding the dynamics of immune complex formation, deposition, and the subsequent inflammatory cascade is essential for grasping the pathophysiology of immune complex-mediated hypersensitivities. The complement system plays a pivotal role by amplifying inflammation and recruiting immune cells, while neutrophil degranulation directly contributes to tissue injury. This mechanism highlights the delicate balance between immune defense and immune-mediated tissue damage.

Type III Hypersensitivities Example 1

Type III hypersensitivity, also known as immune complex-mediated hypersensitivity, involves a sequence of events beginning with the formation of immune complexes. These complexes form when soluble antigens in the blood bind to antibodies, creating small immune complexes that are particularly prone to causing this reaction. The initial step is the formation of these small immune complexes, which then must evade phagocytosis to persist in circulation.

Once these immune complexes avoid clearance by phagocytes, they deposit in various tissues, triggering the activation of the complement system. Complement activation plays a crucial role by recruiting neutrophils to the site of immune complex deposition. These neutrophils, in turn, release hydrolytic enzymes that cause damage to the surrounding tissues, leading to inflammation and tissue injury characteristic of type III hypersensitivity reactions.

This process highlights the importance of immune complex size and clearance mechanisms in the pathogenesis of immune complex-mediated hypersensitivity. The complement system acts as a bridge between immune complex deposition and the inflammatory response, emphasizing its role in recruiting neutrophils and amplifying tissue damage. Understanding this cascade is essential for grasping how immune complexes contribute to diseases such as systemic lupus erythematosus and certain forms of vasculitis.

Which of the following statements about immune complexes is false regarding hypersensitivity reactions?

• A. Small immune complexes that evade phagocytosis are more problematic than large immune complexes.
• B. Immune complexes are often removed from the body by phagocytosis.
• C. Immune complexes directly damage tissues & cells by releasing hydrolytic enzymes.
• D. Immune complexes are an aggregate of antibodies bound to antigens.

Answer: (C)

Examples of Disorders Caused by Type III Hypersensitivities

Type III hypersensitivity disorders arise from immune complex formation, where antigen-antibody complexes trigger inflammation and tissue damage. These disorders can be categorized as either organ-specific, affecting localized areas, or systemic, impacting multiple body systems. Some of these conditions also overlap with autoimmune diseases, where the immune system mistakenly targets the body's own antigens.

Glomerulonephritis is an example of an organ-specific disorder involving inflammation of the kidney's glomeruli. Immune complexes, formed with either foreign or self antigens, can deposit in the glomeruli, leading to inflammation and impaired kidney function. When self antigens are involved, glomerulonephritis may also be classified as an autoimmune disorder. The persistence of small, soluble immune complexes that evade phagocytosis is a key factor in this condition.

The Arthus reaction is a localized type III hypersensitivity that occurs when a foreign antigen is injected into tissues, such as during booster vaccinations or antivenom administration. Here, immune complexes form directly at the injection site, causing redness, swelling, and pain. Although uncomfortable, Arthus reactions are typically self-limiting and not life-threatening.

Serum sickness represents a systemic form of type III hypersensitivity, where immune complexes circulate in the bloodstream and affect multiple organs. This condition can arise after exposure to certain medications like penicillin, leading to widespread symptoms such as rashes on the neck, torso, and legs. Serum sickness is usually temporary, resolving once the antigen is cleared and immune complex formation ceases.

Rheumatoid arthritis is a chronic autoimmune disorder characterized by persistent joint inflammation due to immune complexes accumulating in the joints. Unlike osteoarthritis, which results from mechanical wear and tear, rheumatoid arthritis involves the immune system attacking self antigens, causing ongoing pain, swelling, and stiffness, especially in the hands and wrists. While there is no cure, treatments focus on managing symptoms and inflammation.

Systemic lupus erythematosus (SLE) is another chronic autoimmune disease marked by autoantibodies targeting various self antigens, particularly nuclear components like DNA. The formation of immune complexes with these nuclear antigens leads to widespread inflammation and tissue damage across multiple organs. Symptoms vary widely but often include joint pain and systemic organ involvement.

Understanding the mechanisms behind type III hypersensitivities highlights the role of immune complexes in both localized and systemic inflammatory disorders. These conditions underscore the delicate balance of the immune system in distinguishing self from non-self and the consequences when this balance is disrupted.

Which of the following is a systemic type III hypersensitivity involving immune complexes against DNA that damage multiple organs?

• A. Rheumatoid arthritis.
• B. Systemic lupus erythematosus (SLE).
• C. Glomerulonephritis.
• D. Arthus reactions.

Answer: (B)

Here’s what students ask on this topic:

What are type III hypersensitivities and how do immune complexes contribute to tissue damage?

Type III hypersensitivities are immune complex-mediated reactions where clusters of antibodies bind to antigens, forming immune complexes. Normally, these complexes are cleared efficiently by phagocytes. However, when small, soluble immune complexes persist and evade clearance, they deposit in tissues such as kidneys or joints. This deposition activates the complement system, triggering inflammation. Complement activation attracts inflammatory cells like neutrophils, which release enzymes through degranulation, causing tissue damage. This process underlies diseases like glomerulonephritis, rheumatoid arthritis, and systemic lupus erythematosus. The key problem is the persistence and tissue deposition of these immune complexes, leading to chronic inflammation and organ damage.

What are the main steps involved in the development of type III hypersensitivity reactions?

The development of type III hypersensitivity involves three main steps. First, immune complexes form when antibodies bind antigens in specific ratios. These complexes can be large or small; large complexes are usually cleared by phagocytes, while small, soluble complexes evade clearance. Second, these small immune complexes deposit in tissues such as joints or kidneys. Third, the deposited complexes activate the complement system, leading to recruitment of inflammatory cells like neutrophils. Neutrophils degranulate, releasing enzymes that cause tissue inflammation and damage. This sequence explains the pathology seen in diseases like rheumatoid arthritis and glomerulonephritis.

What diseases are caused by type III hypersensitivities and how do they differ?

Type III hypersensitivities cause both localized and systemic diseases. Localized examples include the Arthus reaction, which occurs at the site of antigen injection, causing redness and swelling, often after booster vaccines. Systemic diseases include serum sickness, where immune complexes circulate and affect multiple tissues, causing rashes and systemic symptoms. Chronic autoimmune diseases like rheumatoid arthritis and systemic lupus erythematosus (SLE) also involve type III hypersensitivity. Rheumatoid arthritis primarily affects joints with ongoing immune complex deposition, causing chronic inflammation. SLE involves autoantibodies against nuclear antigens like DNA, leading to widespread tissue damage. These diseases differ in antigen type, tissue involvement, and chronicity.

How does the size of immune complexes influence their clearance and pathogenicity in type III hypersensitivities?

The size of immune complexes critically affects their clearance and potential to cause disease. Large immune complexes are more easily recognized and removed by phagocytes, preventing tissue deposition and damage. In contrast, small, soluble immune complexes evade phagocytosis and remain in circulation longer. These small complexes can deposit in tissues such as the glomeruli of kidneys or joint spaces. Once deposited, they activate the complement system, leading to inflammation and tissue injury. Therefore, small immune complexes are more pathogenic and central to the development of type III hypersensitivity diseases.

What role does complement activation and neutrophil degranulation play in type III hypersensitivity reactions?

Complement activation is a key event in type III hypersensitivity reactions. When immune complexes deposit in tissues, they trigger the complement cascade, producing components that attract inflammatory cells like neutrophils. Neutrophils migrate to the site and undergo degranulation, releasing enzymes and reactive oxygen species. These substances damage surrounding tissues, causing inflammation, pain, and dysfunction. This mechanism explains the tissue injury seen in diseases such as rheumatoid arthritis and glomerulonephritis. Thus, complement activation and neutrophil degranulation are central to the pathogenesis of immune complex-mediated hypersensitivity.