Microbiology - Chapter 19: Diseases of the Immune System

Overview of Hypersensitivity

• Hypersensitivity is defined as any immune response against a foreign antigen that is exaggerated beyond the norm.

• There are four distinct types of hypersensitivity reactions, classified by their mechanisms and timing:

  • Type I (Immediate): Involves Immunoglobulin E ($IgE$) antibody against soluble antigen, triggering mast cell degranulation.

  • Type II (Cytotoxic): Involves Immunoglobulin G ($IgG$) and Immunoglobulin M ($IgM$) antibodies directed against cellular antigens, leading to cell damage mediated by other immune system effectors (complement and antibodies).

  • Type III (Immune-complex mediated): Involves the interaction of $IgG$, $IgM$, and occasionally $IgA_1$ antibodies with antigen to form immune complexes. Accumulation of these complexes in tissue leads to damage mediated by other immune effectors.

  • Type IV (Delayed or cell-mediated): T-cell–mediated reactions involving tissue damage by activated macrophages and cytotoxic T cells.

Type I Hypersensitivity: Sensitization and Degranulation

• Mechanism of Sensitization:

  • On first exposure to an allergen in a susceptible individual, antigen-presenting cells ($APCs$) process and present allergen epitopes with major histocompatibility complex ($MHC$) II to T helper cells.

  • B cells also process and present the same allergen epitope to $T_{H2}$ cells.

  • $T_{H2}$ cells release cytokines $IL-4$ and $IL-13$ to stimulate B cell proliferation and differentiation into $IgE$-secreting plasma cells.

  • The $IgE$ molecules bind to mast cells via their $Fc$ region, sensitizing them for future activation.

• Mechanism of Degranulation:

  • Upon subsequent exposure, the allergen cross-links the $IgE$ molecules already bound to the mast cells.

  • This cross-linking activates the mast cells, causing the release of preformed chemical mediators from granules (degranulation) and the synthesis of newly formed chemical mediators.

• Chemical Mediators of Mast Cells:

  • Preformed Components (Table 19.1):

  • Heparin: Stimulates the generation of bradykinin, which causes increased vascular permeability, vasodilation, bronchiole constriction, and increased mucus secretion.

  • Histamine: Causes smooth-muscle contraction, increases vascular permeability, and increases mucus and tear formation.

  • Serotonin: Increases vascular permeability, causes vasodilation, and induces smooth-muscle contraction.

  • Newly Formed Chemical Mediators (Table 19.2):

  • Leukotriene: Causes smooth-muscle contraction and mucus secretion; increases vascular permeability.

  • Prostaglandin: Causes smooth-muscle contraction and vasodilation.

  • TNF-̑ (cytokine): Causes inflammation and stimulates cytokine production by other cell types.

Clinical Signs and Diagnosis of Type I Reactions

• Localized Reactions:

  • The site of the reaction depends on the portal of entry.

  • Inhaled Allergens: May trigger allergic rhinitis (hay fever). Symptoms include watery nasal discharge, sneezing, itchy throat and eyes, and excessive tear production. Common triggers include pollen, mold spores, flowering plants, certain trees, and dust mites.

  • Skin Reactions: Often present as rashes or hives.

  • Ingested Allergens: Peanuts and other foods can provoke severe reactions in sensitive individuals.

• Systemic Type I Reaction (Anaphylaxis):

  • Can be life-threatening and require immediate intervention with an epinephrine auto-injector ($e.g.$, EpiPen).

  • Epinephrine counteracts the severe drop in blood pressure associated with systemic shock.

  • Effects of Anaphylaxis on the Body:

  • Nervous System: Mental confusion, anxiety, and a subconscious feeling of "doom."

  • Circulatory System: Drastic drop in blood pressure (anaphylactic shock), weak and rapid pulse, and heart palpitations (fluttering sensations).

  • Respiratory System: Wheezing, squeezing sensation in lungs, bronchial swelling making breathing difficult, and fluid buildup in lungs causing chest tightness.

  • Head and Neck: Facial swelling (lips, tongue, throat), which can block the airway; trouble swallowing or choking sensations; hoarse voice or slurred speech; metallic taste in the mouth.

  • Digestive System: Nausea, vomiting, abdominal pain, cramps, and bloating.

  • Integumentary System: Pale or red skin, hives (raised, itchy, painful red bumps). Blue skin (cyanosis) indicates a critical loss of oxygen.

• Diagnostic Skin Test:

  • The skin-prick test is used to identify potential allergens. A positive result is characterized by a "wheal" (raised area) and a surrounding "flare" (redness).

Type II (Cytotoxic) Hypersensitivity

• Type II reactions involve the destruction of cells by the immune response, usually via complement activation and antibodies.

• Example 1: Hemolytic Transfusion Reaction (HTR):

  • Occurs when a patient receives incompatible blood ($e.g.$, Type A donor blood given to a Type B recipient).

  • The recipient's anti-A isohemagglutinin $IgM$ antibodies bind to and agglutinate the donor's red blood cells ($RBCs$).

  • Bound antibodies activate the classical complement cascade, leading to the destruction of donor $RBCs$ and hemolytic anemia.

• Example 2: Hemolytic Disease of the Newborn (HDN):

  • Occurs when an $Rh^-$ mother carries an $Rh^+$ fetus.

  • During birth, fetal $Rh^+$ erythrocytes enter the mother’s circulation, leading to the production of anti-Rh $IgG$ antibodies.

  • In a subsequent pregnancy with an $Rh^+$ fetus, these $IgG$ antibodies cross the placenta and attack fetal erythrocytes.

  • Prevention: Administering $Rho(D)$ immune globulin (RhoGAM) during and after pregnancy. This globulin binds fetal $Rh^+$ $RBCs$ in the mother's bloodstream before her primary immune response can be activated.

Type III (Immune-Complex Mediated) Hypersensitivity

• Caused by the formation of antigen-antibody complexes (immune complexes) that deposit in tissues.

• Mechanism: Complex deposition triggers complement activation, which recruits neutrophils. Enzymes released by neutrophils cause tissue damage.

• Localized Reactions:

  • Hypersensitivity pneumonitis

  • Glomerulonephritis: Damage to the kidneys; may require dialysis.

• Systemic Reactions:

  • Systemic Lupus Erythematosus (SLE)

  • Rheumatoid Arthritis (RA)

Type IV (Delayed or Cell-Mediated) Hypersensitivity

• Regulated by the interaction of antigens, $APCs$, and T cells. Inflammation typically occurs $12-24$ hours after exposure.

• The Tuberculin Response (Mantoux Test):

  • Used to screen for Tuberculosis ($TB$). A Tine test (using a scarification device) is less reliable than the Mantoux skin test.

  • Results: An induration of $15$ or more $mm$ is considered positive in individuals with no risk factors; smaller cut-offs apply to high-risk groups.

• Contact Dermatitis:

  • Examples include reactions to poison ivy.

  • Sensitization: First exposure does not cause a reaction but produces memory helper T cells.

  • Secondary Exposure: Memory T cells activate, producing cytokines that recruit macrophages and cytotoxic T cells to create inflammatory lesions. The lesion persists until the allergen is removed.

• Graft Rejection and Graft versus Host Disease (GVHD):

  • Graft Types:

  • Autograft: From the patient's own body.

  • Isograft: From an identical twin.

  • Allograft (Heterologous): From another person.

  • Xenograft (Heterograft): From another species ($e.g.$, pig).

  • GVHD: Occurs primarily in bone marrow transplants where the graft attacks the host.

  • Acute GVHD: Occurs within months; affects skin, liver, and GI tract.

  • Chronic GVHD: Late complication (sometimes years later); affects many organs and mimics autoimmune disorders.

Autoimmune Diseases

• General Characteristics:

  • The immune system produces antibodies and cytotoxic T cells that target normal body cells.

  • Most develop spontaneously. They are more common in older individuals and women.

• Etiology Hypotheses:

  • Combination of genetic and environmental factors (sunlight, infections, chemicals, medications).

  • Failure of regulatory T and B cells to maintain tolerance.

  • Antigen Mimicry: Pathogen antigens resemble self-antigens, causing cross-reactivity.

  • Hidden Self-Antigens: Trauma or disease exposes antigens previously sequestered from the immune system.

Specific Autoimmune Disorders

• Organ-Specific:

  • Graves’ Disease: Hypertrophy of the thyroid (goiter) and exophthalmia (Graves ophthalmopathy/bulging eyes).

  • Hashimoto Thyroiditis: Leads to goiter and thyroid destruction.

  • Celiac Disease: Reaction to gluten (wheat, barley, rye) resulting in damage to the small intestine.

  • Type I Diabetes: T-cell dependent destruction of pancreatic beta cells in the islets, leading to a lack of insulin, hyperglycemia, extreme thirst, and fatigue.

• Systemic Autoimmune Disorders (Table 19.6):

  • Multiple Sclerosis (MS): Cytotoxic T-cell destruction of myelin sheaths in the CNS. Symptoms: Visual disturbances, muscle weakness, numbness, impaired coordination.

  • Myasthenia Gravis: Autoantibodies block acetylcholine receptors ($AChr$) at the neuromuscular junction. Symptoms: Extreme muscle weakness, potentially fatal respiratory arrest.

  • Psoriasis: Cytokine activation of keratinocytes causes rapid epidermal turnover. Symptoms: Itchy, thick red skin with silvery scales.

  • Rheumatoid Arthritis (RA): Type III reaction involving immune complexes ($antibodies bound to antibodies$). Symptoms: Joint inflammation, pain, and disfigurement (especially hands and feet).

  • Systemic Lupus Erythematosus (SLE): Type III reaction where autoantibodies target DNA and proteins. Anti-nuclear antibodies ($ANAs$) are present in > 95% of patients. Symptoms: Butterfly rash, photosensitivity, kidney dysfunction, and systemic inflammation.

Immunodeficiency Diseases

• Primary Immunodeficiencies: Result from genetic or developmental defects; typically develop in infants.

  • Chronic Granulomatous Disease: Impaired bacterial killing within phagolysosomes.

  • Selective IgA Deficiency: Inability to produce secretory $IgA$, predisposes to lung/GI infections.

  • Severe Combined Immunodeficiency Disease (SCID): B and T cell defects ($e.g.$, David Vetter, "The Bubble Boy"). Most common is X-linked SCID.

  • X-linked Agammaglobulinemia: Flawed B-cell differentiation; absence of specific antibodies.

  • DiGeorge Syndrome (22q11.2 deletion): Underdeveloped thymus leading to T-cell deficiency.

• Secondary (Acquired) Immunodeficiencies: Develop later in life due to external causes.

  • Causes: Immunosuppressive therapies (chemotherapy/radiation), malnutrition, or viral infections.

  • HIV/AIDS: Impaired cell-mediated immunity due to $CD4$ T-cell lymphopenia, leading to opportunistic infections and rare cancers.

Summary of Hypersensitivity Types (Figure 19.11 / Table 19.7)