Immune Disorders and Hypersensitivity Reactions

Overview of Immune Disorders

This chapter focuses on:

  • Two main categories of immune disorders:

    1. Hypersensitivity reactions

    2. Autoimmune diseases

Hypersensitivity Reactions

Hypersensitivity reactions are categorized as an overreaction of our immune system to typically non-threatening antigens.

Toxic Epidermal Necrolysis

  • Definition: A rare hypersensitivity reaction often triggered by drug metabolites, like those from antibiotics or corticosteroids.

  • Mechanism: Drug metabolites are incorrectly recognized as harmful and provoke an immune response, leading to the separation of the epidermis from the dermis, damaging the protective skin barrier.

  • Consequences: Patients may die from opportunistic infections due to skin barrier damage. Early misdiagnosis can occur, often leading to inappropriate treatment with antibiotics, which can exacerbate the condition.

General Concept of Hypersensitivity

The term "hypersensitivity" refers to an exaggerated immune response triggered by harmless antigens. Four types are classified based on their mechanisms:

  1. Type I: Anaphylactic hypersensitivity

  2. Type II: Cytotoxic hypersensitivity

  3. Type III: Immune complex-mediated hypersensitivity

  4. Type IV: Delayed-type hypersensitivity

Type I Hypersensitivity (Anaphylactic)

  • Definition: A common and swift immune response to allergens, often termed as "allergic reactions."

  • Mechanism: Within minutes of exposure to an allergen, symptoms manifest. B cells produce IgE antibodies, which bind to mast cells triggering degranulation and release of chemical mediators such as:

    • Histamine: Causes vasodilation and increased vascular permeability, leading to swelling.

    • Leukotrienes and Prostaglandins: Local hormones that further influence local tissue responses.

  • Symptoms: Can present as localized reactions (e.g., hives) or systemic reactions (e.g., anaphylaxis).

    • Localized reactions can be annoying but not life-threatening.

    • Systemic reactions (anaphylactic reactions) can lead to anaphylactic shock, characterized by a drastic drop in blood pressure and airway constriction. Treatment includes epinephrine injections (e.g., EpiPen).

  • Theory on Evolutionary Purpose: Proposed that these allergic reactions evolved as a protective mechanism against parasites.

    • The Hygiene Hypothesis postulates that reduced exposure to pathogens increases the prevalence of allergies in developed countries.

Steps in Type I Hypersensitivity

  1. Sensitization Phase: Upon first exposure, allergens trigger B cells to produce IgE, which then binds to mast cells. This phase may sometimes require multiple exposures.

  2. Subsequent Exposure: When re-exposed, allergens cross-link the bound IgE on mast cells, leading to degranulation and release of mediators, causing allergy symptoms.

Type II Hypersensitivity (Cytotoxic)

  • Characteristics: Also known as cytotoxic hypersensitivity, involves antibodies binding to antigens on the surface of cells, leading to cell destruction.

  • Examples:

    • Thrombocytopenic Purpura: Drug binds to the surface of platelets, leading to their destruction by IgG and complement activation, causing low platelet count and resultant bleeding.

    • Transfusion Reactions: Occur when a person receives blood incompatible with their own blood type, resulting in hemolysis of red blood cells.

    • Hemolytic Disease of the Newborn: Maternal antibodies cross the placenta and target fetal red blood cells, causing hemolysis.

Type III Hypersensitivity (Immune Complex-Mediated)

  • Definition: Involves the formation of immune complexes from soluble antigen-antibody complexes that deposit in tissues, triggering inflammation.

  • Examples:

    • Rheumatoid Arthritis: Immune complexes deposit in joints, causing inflammation and joint damage.

    • Lupus (Systemic Lupus Erythematosus): Autoantibodies target proteins normally hidden from the immune system, leading to widespread inflammation.

    • Serum Sickness and Arthrus Reaction: Mid to late responses to injected antigens or antibodies, leading to localized inflammation or systemic response.

Type IV Hypersensitivity (Delayed)

  • Characteristics: Dominated by T cells and takes days for symptoms to manifest. Examples include:

    • Contact Dermatitis: Reaction to materials like poison ivy where the antigen modifies host proteins, eliciting a delayed response.

    • Tuberculin Reaction: Used in TB testing to detect prior exposure to Mycobacterium tuberculosis through T cell-mediated responses.

Autoimmune Diseases

Autoimmune diseases involve the immune system erroneously attacking the body's own tissues, often linked to a loss of self-tolerance.

Mechanisms of Autoimmunity

  • Clonal Deletion: During T and B cell development, cells that react to self-antigens are eliminated.

  • Clonal Anergy: Mechanism to eliminate self-reactive cells that escape clonal deletion later in life.

  • Regulatory T cells: Help maintain tolerance by suppressing immune responses to self.

  • Circumstances Leading to Autoimmunity:

    • Access of the immune system to previously hidden antigens (e.g., injury, inflammation).

    • Molecular mimicry: Pathogens present antigens similar to host antigens, leading to cross-reactivity.

Examples of Autoimmune Diseases

  1. Graves' Disease: This condition results in overproduction of thyroid hormones due to autoantibodies stimulating thyroid receptor activation, leading to hyperthyroidism.

  2. Myasthenia Gravis: Autoantibodies against acetylcholine receptors cause muscle weakness and fatigue.

  3. Lupus: Autoantibodies target various self-antigens, leading to complex formation that deposit in multiple tissues causing a wide variety of symptoms.

  4. Rheumatoid Arthritis: Autoantibodies (e.g., rheumatoid factors) form immune complexes that deposit in joints and lead to inflammation and joint damage.

  5. Multiple Sclerosis: T cells attack myelin-producing cells, leading to neurological symptoms due to loss of myelin sheath and subsequent neuronal communication.

  6. Hashimoto's Thyroiditis: Autoimmune destruction of thyroid cells via T cell-mediated processes leading to hypothyroidism.

  7. Type 1 Diabetes Mellitus: T cell-mediated destruction of insulin-producing beta cells in the pancreas results in hyperglycemia.

Immune Reactions and HLA

Human Leukocyte Antigen (HLA) is crucial for understanding immune compatibility and susceptibility to certain autoimmune diseases.

  • Importance in Transplantation: Matching HLA between donor and recipient can increase transplantation success rates and minimize rejection risks.

Graft versus Host Disease (GVHD)

  • Definition: Occurs when immune cells from a transplanted tissue react against the recipient's body, often due to immunosuppression.

  • Symptoms can range from mild to severe, depending on the extent and areas affected. Treatment generally involves continued immunosuppression to minimize GVHD complications.