hypersensitivity

Overview of Hypersensitivity

• Definition:

  • A normal immune response that is inappropriately triggered, excessive, and produces undesirable effects on the body.

  • An immune response directed toward a harmless molecule encountered in the environment.

  • Upon subsequent exposure to the antigen, an inflammatory reaction occurs.

• Immune System Component Review:

  • Antigens:

  • Substances recognized by the immune system as foreign.

  • Composed of proteins or carbohydrates.

  • Function to trigger an immune response.

  • Lymphocytes:

  • B-Lymphocytes:

    • Produce antibodies or immunoglobulins specific to a particular antigen.

    • Bind to specific antigens to neutralize or destroy them.

  • T-Lymphocytes:

    • Express T-cell receptors that recognize specific antigens.

    • Cytotoxic T-cells ($CD8$): Directly toxic to specific target cells.

    • Helper T-cells ($CD4$): Assist other immune cells, including B-cells, in mounting an immune response.

• Basic Triggers of Hypersensitivity:

  • Triggered when an antigen reacts with either antibodies or T-cells.

  • Involves either an antigen-antibody reaction or an antigen-lymphocyte reaction.

• Four Primary Classifications:

  • Type I Hypersensitivity: Antibody-mediated hypersensitivity.

  • Type II Hypersensitivity: Antibody-mediated hypersensitivity.

  • Type III Hypersensitivity: Antibody-mediated hypersensitivity.

  • Type IV Hypersensitivity: T-cell mediated hypersensitivity.

Type I Hypersensitivity: IgE-Mediated Reaction

• Characteristics and Timing:

  • Immediate reaction occurring within $15 - 20\,\text{minutes}$ of exposure.

  • Requires initial sensitization to the antigen through previous exposure.

• Common Antigens (Allergens):

  • Environmental: Animal dander, bee venom.

  • Foods: Nuts, seafood, eggs.

  • Medications: Penicillin, contrast dye.

• Etiology and Genetic Link:

  • Children with $1$ allergic parent have a $2 - 3 \times$ higher risk.

  • Children with $2$ allergic parents have a $5 - 10 \times$ higher risk.

  • Identical twins display a $50\%$ concordance rate.

• Key Cellular Components:

  • B-lymphocytes.

  • Plasma cells.

  • IgE antibodies (immunoglobulins).

  • Mast cells.

• Step-by-Step Pathogenesis:

  • Initial exposure to an allergen/antigen occurs.

  • The antigen is recognized and presented to immune cells.

  • Helper T-cells ($CD4$) stimulate B-cells.

  • B-cells become activated and mature into antibody-secreting plasma cells.

  • Plasma cells produce antigen-specific IgE antibodies.

  • IgE antibodies attach to mast cells via their Fc receptors.

  • Upon subsequent exposure to the same antigen, the antigen binds to and cross-links the IgE antibodies attached to mast cells.

  • IgE-antigen cross-linking triggers mast cell degranulation.

  • Mast cells dump intracellular chemical mediators, primarily histamine, into surrounding tissues.

• Anatomical Effects of Histamine:

  • Intravascular: Anaphylactic shock.

  • Skin: Urticaria (hives), angioedema, atopic dermatitis, wheal-flare reaction.

  • Respiratory System: Rhinitis, asthma.

  • Gastrointestinal System: Nausea, vomiting, cramping pain, diarrhea.

• Mediator Activities and Associated Clinical Manifestations:

  • Potent Vasodilation:

  • Stuffy nose.

  • Lower blood pressure.

  • Wheals on skin.

  • Increased Vascular Permeability:

  • Edema.

  • Runny nose.

  • Bronchial Smooth Muscle Constriction:

  • Breathing difficulties.

  • Wheezing.

  • Stimulation of Irritant Receptors:

  • Itching (pruritus).

• Localized vs. Systemic Type I Reactions:

  • Localized (Atopic Reactions):

  • Conditions: Allergic rhinitis, asthma, urticaria (hives).

  • Common triggers: Pollen, dust, mold, animal dander.

  • Systemic Reactions:

  • Mediated by systemic release of chemical mediators.

  • Clinical features: Bronchial constriction, airway obstruction, vascular collapse (shock).

  • Common triggers: Medications, bee venom, food.

Type II Hypersensitivity: Cytotoxic and Antibody-Mediated Reactions

• General Mechanism:

  • Cell surface markers (antigens) stimulate the production of specific antibodies.

  • IgG or IgM antibodies recognize and attach to cell surface antigens.

  • Direct destruction of the target cell occurs via cell lysis, phagocytosis, or antibody-dependent cellular cytotoxicity (ADCC) involving cytotoxic T cells, natural killer (NK) cells, macrophages, and neutrophils.

• Common Antigens and Associated Clinical Conditions:

  • Antigens: Blood cells or the body's own tissue cells.

  • Conditions: Red blood cell destruction following mismatched blood transfusion, hemolytic anemia, Myasthenia Gravis, Erythroblastosis Fetalis (hemolytic disease of the newborn).

• Erythroblastosis Fetalis Pathogenesis:

  • An Rh-negative woman and an Rh-positive man conceive an Rh-positive child.

  • Cells from the Rh-positive fetus enter the Rh-negative woman's bloodstream ($0$).

  • The Rh-negative woman becomes sensitized, producing Rh-positive maternal antibodies against Rh-positive red blood cells.

  • In a subsequent pregnancy with an Rh-positive fetus, maternal Rh-positive antibodies cross the placenta and attack fetal red blood cells.

• Transfusion Reactions and Blood Group Rules:

  • Key Involved Components: IgG and IgM antibodies, complement system, white blood cells (WBCs).

  • Blood Transfusion Compatibility Rules:

  • Type A+: Can receive A+, A-, O+, O-.

  • Type A-: Can receive A-, O-.

  • Type B+: Can receive B+, B-, O+, O-.

  • Type B-: Can receive B-, O-.

  • Type AB+: Universal recipient (can receive all blood types).

  • Type AB-: Can receive all negative blood types (A-, B-, AB-, O-).

  • Type O+: Can donate to all positive blood groups.

  • Type O-: Universal donor (can donate to all blood groups; used in emergency situations).

  • Rh Factor Specifications:

  • Rh+: Expresses the D antigen.

  • Rh-: Lacks the D antigen.

  • Transfusion Hemolysis Steps:

  • Step 1: Donated Type A blood expressing Type A antigens enters the bloodstream of a Type B recipient.

  • Step 2: Anti-A antibodies in the plasma of the Type B recipient bind to the donated Type A red blood cells.

  • Step 3: Bound anti-A antibodies activate the complement cascade, causing intravascular hemolysis and release of hemoglobin.

  • Clinical Rules: Always cross-match blood before transfusion; wrong transfusions cause severe hemolysis.

• Complement Cascade Mechanism in Type II Reactions:

  • Activation occurs via Classical or Alternative pathways.

  • Formation of C1 complex leading to C2a and C4b fragments.

  • Generation of C3 convertase, leading to C3 hydrolysis into C3a and C3b fragments.

  • C3b cleaves C5 into C5a and C5b.

  • Assembly of C5b, C6, C7, C8, and C9 together to form the cylindrical Membrane Attack Complex (MAC) embedded in the cell membrane.

  • Water enters through the MAC into the intracellular space, causing the cell to swell and burst.

• Clinical Manifestations of Type II Reactions:

  • Skin Reactions: Hives (urticaria), itching (pruritus), edema.

  • Respiratory Reactions: Wheezing, shortness of breath, chest tightness.

  • Gastrointestinal Symptoms: Nausea, vomiting, diarrhea.

Type III Hypersensitivity: Immune Complex-Mediated Reactions

• Pathophysiology and Mechanism:

  • Formation of soluble antigen-antibody (IgG and IgM) complexes that circulate and deposit into vessel walls and tissue basement membranes.

  • Presence of deposited immune complexes activates the complement cascade.

  • Complement activation produces inflammatory mediators and recruits inflammatory cells, specifically neutrophils, mast cells, and WBCs.

  • Enzymes released from activated neutrophils cause structural damage to endothelial cells and tissue basement membranes.

• Common Antigens:

  • Foreign Antigens: Bacteria, viruses, drugs, antivenoms, vaccines.

  • Self-Antigens (Autoantigens): DNA, cell receptors.

• Exemplary Clinical Conditions:

  • Post-streptococcal glomerulonephritis.

  • Rheumatoid arthritis.

  • Systemic lupus erythematosus (SLE).

• Clinical Manifestations:

  • Symptoms depend directly on the specific anatomical site where immune complexes deposit and the location of resulting tissue inflammation and damage.

Type IV Hypersensitivity: Delayed and T-Cell-Mediated Reactions

• Key Features:

  • NO ANTIBODIES are involved in Type IV reactions.

  • Mediated strictly by cellular immunity involving T-cells ($CD8$ cytotoxic T-cells $T_c$, $CD4$ helper T-cells $TH1$, and memory T-cells).

  • Exhibits a delayed clinical onset.

• Common Antigens:

  • Plant oils (e.g., poison ivy, poison oak, poison sumac).

  • Cosmetics.

  • Clothing.

  • Dyes.

  • Adhesives.

  • Nickel alloy.

  • Tuberculin antigen.

  • Gluten.

  • Transplanted organs or tissues.

• Etiology and Step-by-Step Pathogenesis:

  • Small, incomplete antigens known as haptens penetrate the skin.

  • Haptens bind to endogenous protein carriers to form a complete, immunogenic antigen.

  • Antigen Presenting Cells (APCs) recognize, capture, and present the antigen to T-cells.

  • $TH1$ helper T-cells secrete cytokines that recruit and activate macrophages and cytotoxic T-cells ($CD8$).

  • Activated macrophages and cytotoxic T-cells release tissue-damaging enzymes and mediators.

• Clinical Manifestations:

  • Contact Dermatitis: Manifests as skin rash and severe itching.

  • Tuberculin Skin Test Reaction: Localized induration and redness.

  • Systemic Inflammatory Response: Fever and generalized body aches.

  • Neurological Deficits: Occurs if T-cells attack the myelin sheath (e.g., Multiple Sclerosis).

• Exemplary Clinical Conditions:

  • Contact dermatitis.

  • Type 1 Diabetes Mellitus (T1DM).

  • Multiple Sclerosis.

Hypersensitivity Summary Comparison

• Type I:

  • Primary Immune Reactant: IgE.

  • Antigen Form: Soluble antigen.

  • Mechanism of Activation: Allergen-specific IgE antibodies bind to mast cells via their Fc receptors. Specific allergen binding cross-links IgE and induces mast cell degranulation.

  • Examples: Local and systemic anaphylaxis, seasonal hay fever, food allergies, drug allergies.

• Type II:

  • Primary Immune Reactants: IgG or IgM.

  • Antigen Form: Cell-bound antigen.

  • Mechanism of Activation: IgG or IgM antibody binds to cellular antigen, triggering complement activation and cell lysis. IgG also mediates ADCC with cytotoxic T cells, NK cells, macrophages, and neutrophils.

  • Examples: Red blood cell destruction after transfusion with mismatched blood types, hemolytic disease of the newborn.

• Type III:

  • Primary Immune Reactants: IgG and IgM.

  • Antigen Form: Soluble antigen.

  • Mechanism of Activation: Antigen-antibody complexes deposit in tissues. Complement activation provides inflammatory mediators and recruits neutrophils. Neutrophil enzyme release causes tissue damage.

  • Examples: Post-streptococcal glomerulonephritis, rheumatoid arthritis, systemic lupus erythematosus.

• Type IV:

  • Primary Immune Reactant: T cells.

  • Antigen Form: Soluble or cell-bound antigen.

  • Mechanism of Activation: $TH1$ cells secrete cytokines, which activate macrophages and cytotoxic T cells.

  • Examples: Contact dermatitis, Type 1 Diabetes Mellitus, multiple sclerosis.

Pharmacological Treatments for Hypersensitivity

• Immunosuppressants:

  • Act to suppress cell-mediated immune responses.

• Anti-Inflammatory Medications:

  • Decrease overall inflammatory responses.

  • Examples include corticosteroids (e.g., Topical Hydrocortisone Cream $1\%$).

• Antihistamines:

  • Inhibitors of Histamine Release / Mast Cell Stabilizers:

  • Stabilize mast cell membranes and inhibit degranulation.

  • Useful in asthma and COPD management.

  • Drugs: Cromolyn sodium, leukotriene modifiers.

  • Histamine Receptor Antagonists:

  • Block histamine action directly at target receptor sites.

  • $H_1$ Receptor Antagonists:

    • Target $H_1$ receptors involved in itching, edema, inflammation, rash, runny nose, red/watery eyes, and sneezing.

    • First Generation: Diphenhydramine (Routes: PO, IM, IV; causes higher levels of sedation; treats motion sickness).

    • Second Generation: Cetirizine, Loratadine, Fexofenadine (Route: PO).

  • $H_2$ Receptor Antagonists:

    • Target $H_2$ receptors involved in gastric acid secretion.

    • Drug: Famotidine.

• Epinephrine Pharmacology:

  • Classification: Adrenergic agonist, sympathomimetic agent with dual alpha ($\alpha$) and beta ($\beta$) receptor activity.

  • Indications: Severe allergic reactions (anaphylaxis ONLY), cardiac arrest, severe asthma attacks.

  • Mechanisms of Action:

  • Halts the release of chemical mediators from mast cells.

  • $\alpha$-Adrenergic Activation: Causes $\alpha$-mediated vasoconstriction to raise blood pressure and reverse vasodilation.

  • $\beta$-Adrenergic Activation: Causes $\beta$-mediated bronchodilation to relieve airway obstruction.

  • Major Adverse Effects: Tachycardia, hypertension, dysrhythmias, restlessness, tremor.

  • Dosing and Concentrations:

  • Anaphylaxis IM Injection Standard Concentration: $1:1000$.

  • Adult Dosage: $0.2 - 1\,\text{mg}$ (Maximum adult single dose is $0.5\,\text{mg}$).

  • Pediatric Dosage: $0.01\,\text{mg/kg}$.

  • Available Formulations: $1\,\text{mg}$ in $1\,\text{mL}$ vial ($1:1000$ concentration), $30\,\text{mL}$ vial ($1:1000$ concentration), $1\,\text{mg}$ in $10\,\text{mL}$ vial ($1:10,000$ concentration).

  • Routes of Administration:

  • Intramuscular (IM): Preferred route in anaphylaxis.

  • Intravenous (IV): Preferred route in cardiac arrest.

  • Subcutaneous (SQ).

  • Inhalation: Nasal spray, nebulized.

  • Endotracheal (ET) tube.

  • Nursing Considerations & Patient Education:

  • MONITOR CLOSELY: Frequently evaluate vital signs and monitor for either reversal or return of symptoms.

  • Dosage Verification: Verify dosage carefully; OVERDOSE CAN BE FATAL.

  • Patient Education: Instruct patient to take exactly as directed, contact provider immediately following administration of a dose, and undergo mandatory follow-up evaluation because allergen exposure duration can outlast epinephrine activity duration.

• Step-by-Step EpiPen Auto-Injector Administration:

  • Formulation: EpiPen Auto-Injectors deliver a fixed dose of $0.3\,\text{mg}$ epinephrine (e.g., EpiPen 2-Pak containing two $0.3\,\text{mg}$ auto-injectors and one trainer unit).

  • Step 1: Hold the EpiPen in a firm fist with the blue cover pointing upward ("BLUE TO THE SKY").

  • Step 2: Pull the blue cap straight upward to remove it.

  • Step 3: Place the orange tip against the outer thigh at a $90^{\circ}$ angle ("ORANGE TO THE THIGH"). Do NOT press down on skin yet. (Note: Injection can be administered through clothing if necessary).

  • Step 4: Swing the EpiPen away and then push firmly into the outer thigh until a distinct click is heard ("CLICK!").

  • Step 5: Hold firmly in place against the thigh while counting slowly to three ($1...2...3...$).

  • Step 6: Remove the EpiPen from the thigh. Gently massage the injection area for $10\,\text{seconds}$. Call $911$ immediately.

Autoimmunity Mechanisms and Management

• Definition:

  • An abnormal and destructive immune response directed against host "self" cells and tissues.

• Immunological Tolerance Mechanisms:

  • Central Tolerance:

  • T-lymphocytes and B-lymphocytes recognize self-proteins and do NOT initiate an immune response.

  • If developing lymphocytes recognize self-antigens, they are selectively eliminated within central lymphoid tissues and organs.

  • Peripheral Tolerance (Anergy):

  • If self-reactive lymphocytes escape central tolerance deletion, they become functionally inactivated (anergic) in peripheral tissues.

  • Disease Etiology:

  • Autoimmune diseases occur when both central and peripheral immunological tolerance mechanisms fail, leading to self-tissue and organ destruction.

• Target Structures in Autoimmune Disease:

  • Cellular Targets: Destruction of $\beta$-cells in the pancreas in Type 1 Diabetes Mellitus (T1DM).

  • Receptor Targets: Destruction or blockade of acetylcholine receptors in Myasthenia Gravis by anti-acetylcholine receptor (anti-AChR) antibodies.

• Etiology and Risk Factors:

  • Multifactorial Etiology: Combination of genetic background and environmental factors; may involve an overly aggressive immune system.

  • Antigenic Mimicry:

  • Specific bacterial and viral antigens structurally resemble host self-antigens.

  • Immune cells fail to distinguish foreign pathogens from self-antigens.

  • Autoimmunity typically manifests following an antecedent infection.

  • Identified Risk Factors:

  • Female sex.

  • Advanced age / Immunosenescence (gradual decline in immune system function).

  • Ethnicity.

  • Viral or bacterial infections.

  • Obesity.

• Pharmacological Treatment Options for Autoimmunity:

  • Goal: Stop or slow down the self-directed immune response.

  • Key Drug Classes: Immunosuppressants, corticosteroids, chemotherapy agents.

  • Clinical Balance: Must carefully balance the risk of acquiring opportunistic infections against the therapeutic goal of immune suppression.