Hypersensitivity

Table of contents

Introduction

Hypersensitivity is an exaggerated or inappropriate immune response to an antigen (allergen) that leads to tissue damage and pathological conditions.
These responses occur when the immune system reacts too strongly or against harmless substances.
Hypersensitivity reactions can be classified into four distinct types, each characterized by the underlying immune mechanisms and the resulting clinical manifestations.
These reactions can range from mild allergic responses to life-threatening conditions.

The classification of hypersensitivity is based on the type of immune mechanism involved, as defined by Coombs and Gell in 1963. The four types of hypersensitivity reactions are:

Type I: Immediate Hypersensitivity (IgE-mediated)
Type II: Cytotoxic Hypersensitivity (Antibody-mediated)
Type III: Immune Complex-mediated Hypersensitivity
Type IV: Delayed-type Hypersensitivity (Cell-mediated)

Each type of hypersensitivity has distinct immune responses and clinical outcomes, and understanding these differences is key to diagnosing and managing these reactions.

Types of Hypersensitivity Reactions

Type I: Immediate Hypersensitivity (IgE-mediated)

Type I hypersensitivity is the most common form of hypersensitivity and involves immunoglobulin E (IgE)-mediated immune responses. This immediate reaction typically occurs within minutes of exposure to an allergen. It is also known as an allergic reaction or anaphylactic reaction.

Pathophysiology of Type I Hypersensitivity

The process begins when an individual is exposed to an allergen for the first time.
The immune system of a genetically predisposed person produces IgE antibodies specific to that allergen.
These IgE antibodies bind to mast cells and basophils, abundant in the skin, lungs, and gastrointestinal tract.
Upon subsequent exposure to the same allergen, the allergen binds to the IgE antibodies on the surface of mast cells and basophils, triggering the release of various mediators such as histamine, leukotrienes, prostaglandins, and cytokines.
These mediators are responsible for the clinical symptoms of allergic reactions, such as vasodilation, increased vascular permeability, smooth muscle contraction, and inflammation.

Clinical Manifestations of Type I Hypersensitivity

The symptoms of Type I hypersensitivity vary depending on the organ system involved:

Allergic Rhinitis: This is the most common manifestation and involves symptoms such as sneezing, nasal congestion, itchy eyes, and a runny nose. Pollen, dust mites, animal dander, and mold often trigger it.
Asthma: In allergic asthma, exposure to an allergen causes bronchoconstriction, wheezing, cough, shortness of breath, and chest tightness. It is commonly associated with respiratory allergens such as pollen and pet dander.
Anaphylaxis: This is the most severe form of Type I hypersensitivity and can lead to life-threatening consequences. Anaphylaxis involves widespread vasodilation, smooth muscle contraction, and airway obstruction, leading to shock, respiratory failure, and potentially death. Common triggers include insect stings, certain foods (e.g., peanuts), and medications (e.g., penicillin).

Diagnosis of Type I Hypersensitivity

The diagnosis of Type I hypersensitivity is primarily clinical, supported by laboratory tests such as:

Skin Prick Test (SPT): A common method for diagnosing allergies in which small amounts of allergen extracts are applied to the skin, and the reaction is observed.
Serum IgE Levels: Elevated total serum IgE levels or allergen-specific IgE antibodies in the blood can confirm sensitization to specific allergens.
Challenge Testing: In some cases, patients may be exposed to suspected allergens in a controlled setting to observe the immune response.

Treatment of Type I Hypersensitivity

Treatment of Type I hypersensitivity primarily focuses on preventing allergen exposure and managing symptoms. Some common approaches include:

Antihistamines: These drugs block the effects of histamine, alleviating symptoms like itching, sneezing, and runny nose.
Corticosteroids: These are used to reduce inflammation, particularly in conditions like asthma or allergic rhinitis.
Beta-agonists: Inhalers containing beta-agonists, such as albuterol, can help dilate the airways in asthma patients.
Immunotherapy (Allergy Shots): In some cases, allergen immunotherapy is used to desensitize the patient to specific allergens gradually. This involves regular injections of the allergen over time, which can reduce the severity of the allergic response.
Epinephrine: In cases of anaphylaxis, epinephrine is the first-line treatment. It works by reversing bronchoconstriction and vasodilation and increasing blood pressure.

Type II: Cytotoxic Hypersensitivity (Antibody-mediated)

Type II hypersensitivity reactions involve antibodies (usually IgG or IgM) that bind to antigens on the surface of cells, leading to cell damage or destruction. This type of hypersensitivity is also known as cytotoxic or antibody-mediated hypersensitivity because the antibodies directly target and cause damage to the body’s cells.

Pathophysiology of Type II Hypersensitivity

In Type II hypersensitivity, antibodies bind to specific antigens on the surface of cells, such as red blood cells, platelets, or other tissue cells. This binding activates the complement system, which destroys the targeted cells through various mechanisms, including:

Complement-mediated lysis: The complement cascade is activated, forming membrane attack complexes (MACs) that cause cell lysis.
Phagocytosis: Antibody-coated cells are recognized by phagocytic cells (e.g., macrophages), leading to the ingestion and destruction of the cells.
Antibody-dependent cell-mediated cytotoxicity (ADCC): Natural killer (NK) or other cytotoxic cells recognize and destroy antibody-coated cells.

Clinical Manifestations of Type II Hypersensitivity

Type II hypersensitivity can result in various clinical conditions, including:

Autoimmune Hemolytic Anemia (AIHA): In this condition, antibodies target red blood cells, destroying them. This results in symptoms such as fatigue, pallor, jaundice, and an increased risk of infections.
Goodpasture Syndrome: In this rare autoimmune disorder, antibodies target the basement membrane in the kidneys and lungs, leading to kidney failure and pulmonary hemorrhage.
Transfusion Reactions: If a patient receives the wrong blood type, antibodies against the foreign red blood cells can cause hemolysis, leading to fever, chills, and hemoglobinuria.
Graves’ Disease: In this autoimmune disorder, antibodies bind to the thyroid-stimulating hormone (TSH) receptor, leading to overproduction of thyroid hormones (hyperthyroidism).

Diagnosis of Type II Hypersensitivity

Diagnosis is typically confirmed through laboratory tests such as:

Direct Coombs Test (Direct Antiglobulin Test): This test detects antibodies or complement bound to the surface of red blood cells, characteristic of autoimmune hemolytic anemia.
Indirect Coombs Test: This test detects circulating antibodies against red blood cells in the serum.
Serologic Testing: Specific autoantibodies can be detected in diseases like Graves’ disease or Goodpasture syndrome.

Treatment of Type II Hypersensitivity

The management of Type II hypersensitivity depends on the specific condition involved. Common treatment strategies include:

Immunosuppressive Drugs: Medications like corticosteroids or azathioprine can suppress the immune response and reduce the production of harmful antibodies.
Plasmapheresis: This procedure removes antibodies from the blood plasma and is often used in severe cases, such as Goodpasture syndrome.
Blood Transfusion: In transfusion reactions, immediate cessation of the transfusion and supportive care, including blood volume replacement and oxygen therapy, may be required.

Type III: Immune Complex-mediated Hypersensitivity

Type III hypersensitivity reactions involve the formation of immune complexes, which are aggregates of antigens and antibodies. These immune complexes can deposit in tissues, leading to inflammation and tissue damage.

Pathophysiology of Type III Hypersensitivity

In Type III hypersensitivity, immune complexes are formed when antibodies (typically IgG or IgM) bind to soluble antigens. These complexes can circulate in the blood and deposit in various tissues, such as the kidneys, skin, joints, and blood vessels. The deposited immune complexes activate the complement system, resulting in tissue inflammation and damage.

Complement Activation: The immune complexes activate the classical complement pathway, leading to the recruitment of inflammatory cells such as neutrophils, macrophages, and eosinophils.
Inflammation and Tissue Damage: The recruited cells release inflammatory mediators, which cause vasculitis, tissue necrosis, and fibrosis.

Clinical Manifestations of Type III Hypersensitivity

Type III hypersensitivity can lead to a variety of diseases, including:

Systemic Lupus Erythematosus (SLE): In SLE, immune complexes deposit in multiple organs, causing widespread inflammation and damage. Common symptoms include a butterfly-shaped rash, joint pain, kidney dysfunction, and hematologic abnormalities.
Rheumatoid Arthritis (RA): In RA, immune complexes deposit in the joints, leading to chronic inflammation, pain, and eventual destruction.
Serum Sickness: This is an acute reaction that occurs after the administration of foreign serum or antiserum. It is characterized by fever, rash, arthralgia, and lymphadenopathy.
Arthus Reaction: This is a localized form of Type III hypersensitivity, often seen after repeated exposure to an antigen (e.g., vaccine). It causes tissue necrosis and inflammation at the site of antigen exposure.

Diagnosis of Type III Hypersensitivity

Diagnosis involves detecting circulating immune complexes or specific antibodies associated with autoimmune diseases. Tests may include:

Anti-nuclear Antibody (ANA) Test: Commonly used to diagnose SLE.
Complement Levels: Low complement levels can indicate immune complex formation and deposition.
Biopsy: In some cases, tissue biopsy can reveal immune complex deposition and inflammation.

Treatment of Type III Hypersensitivity

Treatment strategies include:

Immunosuppressive Drugs: Medications like corticosteroids, cyclophosphamide, and hydroxychloroquine can reduce inflammation and immune complex formation.
Plasmapheresis: In severe cases, plasmapheresis may remove circulating immune complexes.

Type IV: Delayed-type Hypersensitivity (Cell-mediated)

Type IV hypersensitivity, also known as delayed-type hypersensitivity (DTH), is mediated by T lymphocytes (T cells) rather than antibodies. This reaction typically develops 24–72 hours after exposure to the antigen. Type IV hypersensitivity involves a delayed inflammatory response driven by helper T cells and cytotoxic T cells, which recruit and activate other immune cells like macrophages and neutrophils.

Pathophysiology of Type IV Hypersensitivity

In Type IV hypersensitivity, the immune response is driven by the activation of T cells, particularly CD4+ helper T cells and CD8+ cytotoxic T cells.
When an individual is exposed to an allergen, the antigen is processed by antigen-presenting cells (APCs) like dendritic cells, which then present the antigen to naïve T cells in the lymph nodes.
This triggers the activation and proliferation of memory T cells.
On subsequent exposure to the same antigen, memory T cells release cytokines (such as interferon-gamma), which activate macrophages and other inflammatory cells.
This leads to local tissue inflammation, tissue damage, and the hallmark of Type IV hypersensitivity reactions: delayed inflammation and granuloma formation in chronic cases.

The delayed nature of Type IV hypersensitivity can be distinguished from the immediate responses seen in Types I-III, and the reaction peaks at 48-72 hours.

Clinical Manifestations of Type IV Hypersensitivity

Type IV hypersensitivity can manifest in a variety of conditions, which can involve skin, organs, or other tissues:

Contact Dermatitis: This is a common Type IV hypersensitivity, often triggered by allergens such as poison ivy, nickel, fragrances, and latex. It results in red, itchy rashes, blisters, and inflammation at the contact site with the allergen.
Tuberculin Skin Test (TST) Reaction: The tuberculin skin test (also known as the Mantoux test) is used to assess for exposure to Mycobacterium tuberculosis. A positive result, marked by induration (raised, firm area) at the injection site 48–72 hours after testing, indicates previous exposure to the bacteria and is an example of a Type IV hypersensitivity reaction.
Chronic Graft Rejection: In organ transplant patients, Type IV hypersensitivity contributes to chronic rejection of the transplanted organ, where T cells attack the transplanted tissue, leading to fibrosis and dysfunction of the organ.
Granulomatous Inflammation: In diseases such as sarcoidosis, tuberculosis, and Crohn’s disease, Type IV hypersensitivity forms granulomas—clusters of immune cells (macrophages, T cells) that wall off the antigen. Granulomas can cause tissue damage and organ dysfunction.

Diagnosis of Type IV Hypersensitivity

The diagnosis of Type IV hypersensitivity reactions typically involves the following:

Patch Testing: This is commonly used for diagnosing allergic contact dermatitis. Small amounts of potential allergens are applied under patches, and the skin is observed for reactions after 48–72 hours.
Tuberculin Skin Test (TST): As mentioned earlier, this test is used to diagnose tuberculosis exposure and assess the immune response to Mycobacterium tuberculosis.
Histopathology: In cases of granulomatous inflammation, a biopsy of the affected tissue may reveal granulomas and evidence of T cell-mediated tissue damage.

Treatment of Type IV Hypersensitivity

Treatment for Type IV hypersensitivity primarily focuses on managing inflammation and reducing the immune response. Common treatment options include:

Topical Corticosteroids: These are frequently used to reduce inflammation and relieve symptoms in conditions like contact dermatitis.
Oral Corticosteroids: In more severe or widespread reactions, oral corticosteroids may be prescribed to reduce systemic inflammation.
Antihistamines: Although Type IV hypersensitivity is not mediated by histamine, antihistamines may alleviate symptoms of itching and discomfort in cases like contact dermatitis.
Immunosuppressive Drugs: For chronic or severe reactions (e.g., granulomatous diseases, chronic graft rejection), immunosuppressive drugs such as methotrexate, azathioprine, or biologics may be required to dampen the immune response.
Avoidance of Antigen Exposure: In the case of contact dermatitis or other antigen-triggered responses, avoiding exposure to the causative allergen is crucial in preventing further reactions.

Other Considerations in Hypersensitivity Reactions

General Mechanisms of Hypersensitivity Reactions

Hypersensitivity reactions can often overlap, and some individuals may experience more than one type of hypersensitivity at a time. These reactions are generally triggered by environmental, genetic, and immunological factors, leading to various clinical conditions. A common feature across all hypersensitivity reactions is an inappropriate immune response against harmless substances, which leads to tissue damage and clinical symptoms.

Genetics: Genetic factors can predispose individuals to hypersensitivity reactions. Certain gene variants in cytokine production, immune receptor expression, or immune regulation pathways may increase the likelihood of developing allergic or autoimmune diseases.
Environmental Factors: Exposure to environmental factors such as allergens (e.g., pollen, dust mites, pet dander) and pathogens can increase the likelihood of hypersensitivity reactions. The hygiene hypothesis suggests that a lack of early childhood exposure to infectious agents may increase the risk of allergic conditions.
Immunologic Mechanisms: The immune system’s role in hypersensitivity is multifaceted, involving not only antibodies (in Type I, II, and III reactions) but also T cell-mediated immunity (in Type IV reactions). Dysregulation of immune tolerance can contribute to hypersensitivity.

Treatment and Management of Hypersensitivity Reactions

The treatment of hypersensitivity reactions depends on the type and severity of the reaction. Below are general management strategies:

Prevention: The best way to manage hypersensitivity reactions is to avoid triggering allergens or antigens when possible. For instance, people with food allergies must avoid the offending foods, while individuals with pollen allergies can use air filters or stay indoors during peak pollen seasons.
Medications: The treatment of hypersensitivity reactions typically involves drugs that manage symptoms or prevent excessive immune responses:
- Antihistamines: Used primarily in Type I hypersensitivity to block histamine receptors and alleviate symptoms of itching, sneezing, and swelling.
- Corticosteroids: Used to reduce inflammation in a variety of hypersensitivity reactions, including in asthma, autoimmune diseases, and skin reactions.
- Immunosuppressive Agents: In severe or chronic hypersensitivity reactions, medications like methotrexate, cyclophosphamide, or biologic agents can suppress immune function to reduce inflammation and tissue damage.
- Epinephrine: The treatment of anaphylaxis, a severe Type I hypersensitivity reaction, requires the rapid administration of epinephrine to reverse airway constriction, reduce vascular permeability, and prevent cardiovascular collapse.
Desensitization: In allergic rhinitis, asthma, or insect sting allergies, allergen-specific immunotherapy (allergy shots) may be used. This involves gradually increasing doses of the allergen to help the immune system become desensitized to it.
Supportive Care: In severe reactions, such as anaphylaxis, immediate supportive care is necessary. This may include oxygen administration, intravenous fluids, and in extreme cases, intubation or ventilation.
Education: Educating patients on recognizing the symptoms of hypersensitivity reactions and using appropriate treatments (such as carrying an epinephrine auto-injector for anaphylaxis) is crucial for long-term management