HYPERSENSITIVITY REACTIONS

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      // ══════════════════════════════════════════
      // DEFINITION
      // ══════════════════════════════════════════
      h1("DEFINITION"),
      boxPara("Hypersensitivity is defined as an exaggerated or augmented immune response to an antigen (allergen) that is harmful to the host. It requires a presensitized state — the harmful response occurs upon second or subsequent exposure to the same antigen."),
      spacer(80),
      boldPara("Classified by: ", "Gell and Coombs (1963) into 4 types: Type I, II, III (antibody-mediated) and Type IV (T-cell mediated)."),
      spacer(100),

      // ══════════════════════════════════════════
      // CLASSIFICATION TABLE
      // ══════════════════════════════════════════
      h1("1. CLASSIFICATION TABLE — Gell and Coombs"),
      spacer(80),

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            hdrCell("Feature", 1200),
            hdrCell("Type I\n(Immediate)", 1700),
            hdrCell("Type II\n(Cytotoxic)", 1700),
            hdrCell("Type III\n(Immune Complex)", 1950),
            hdrCell("Type IV\n(Delayed / DTH)", 1976)
          ]
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        // Data rows
        new TableRow({ children: [subHdrCell("Other Name", 1200), dataCell("Anaphylactic / Atopic", 1700, GRAY_LIGHT), dataCell("Antibody-Dependent Cytotoxic", 1700, GRAY_LIGHT), dataCell("Immune Complex-Mediated", 1950, GRAY_LIGHT), dataCell("Delayed-Type Hypersensitivity", 1976, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("Immunoglobulin", 1200), dataCell("IgE", 1700), dataCell("IgG, IgM", 1700), dataCell("IgG, IgM", 1950), dataCell("None (T-cell mediated)", 1976)] }),
        new TableRow({ children: [subHdrCell("Effector", 1200), dataCell("Mast cell degranulation", 1700, GRAY_LIGHT), dataCell("Complement + ADCC", 1700, GRAY_LIGHT), dataCell("Complement + Neutrophils", 1950, GRAY_LIGHT), dataCell("CD4+ Th1 + Macrophages", 1976, GRAY_LIGHT)] }),
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        new TableRow({ children: [subHdrCell("Key Mediators", 1200), dataCell("Histamine, Leukotrienes, PGD2", 1700), dataCell("C3b, MAC, Perforin", 1700), dataCell("C3a, C5a, Lysosomal enzymes", 1950), dataCell("IFN-γ, IL-2, TNF-β", 1976)] }),
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        new TableRow({ children: [subHdrCell("Skin Test", 1200), dataCell("Wheal & flare (immediate)", 1700), dataCell("—", 1700), dataCell("Arthus (6 hrs)", 1950), dataCell("Induration (48–72 hrs)", 1976)] })
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      // ══════════════════════════════════════════
      // MECHANISMS
      // ══════════════════════════════════════════
      h1("2. MECHANISM OF EACH TYPE"),
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      // TYPE I
      h2("Type I — Immediate (IgE-Mediated) Hypersensitivity"),
      h3("Phase 1: Sensitization (First Exposure)"),
      numberedItem("Allergen (pollen, penicillin, dust mite) enters the body for the first time"),
      numberedItem("APCs present antigen to Th2 cells → Th2 cells release IL-4 and IL-13"),
      numberedItem("B cells undergo class-switching → produce IgE antibodies"),
      numberedItem("IgE binds by its Fc portion to high-affinity FcεRI receptors on mast cells and basophils"),
      numberedItem("Patient is now SENSITIZED — no clinical symptoms yet"),
      h3("Phase 2: Elicitation (Re-exposure)"),
      numberedItem("Same allergen cross-links two or more IgE molecules on mast cell surface"),
      numberedItem("Cross-linking triggers MAST CELL DEGRANULATION"),
      numberedItem("Preformed mediators (histamine, tryptase, heparin) are released immediately"),
      numberedItem("Newly formed mediators (leukotrienes, prostaglandins, PAF) are synthesized from arachidonic acid"),
      numberedItem("Results in: vasodilation, bronchospasm, increased vascular permeability, pruritus"),
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      h4("Mediators of Type I Hypersensitivity"),
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        new TableRow({ children: [subHdrCell("Preformed (granule)", 2200), dataCell("Histamine", 3000, GRAY_LIGHT), dataCell("Vasodilation, increased permeability, bronchospasm, pruritus", 3826, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("Preformed (granule)", 2200), dataCell("Tryptase, Heparin, ECF-A", 3000), dataCell("Proteolysis, anticoagulation, eosinophil recruitment", 3826)] }),
        new TableRow({ children: [subHdrCell("Newly Formed", 2200), dataCell("Leukotrienes C4, D4, E4 (SRS-A)", 3000, GRAY_LIGHT), dataCell("Bronchoconstriction, increased mucus (100x stronger than histamine)", 3826, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("Newly Formed", 2200), dataCell("Prostaglandin D2 (PGD2)", 3000), dataCell("Bronchospasm, vasodilation", 3826)] }),
        new TableRow({ children: [subHdrCell("Newly Formed", 2200), dataCell("PAF (Platelet Activating Factor)", 3000, GRAY_LIGHT), dataCell("Platelet aggregation, bronchoconstriction", 3826, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("Cytokines", 2200), dataCell("TNF-α, IL-4, IL-5", 3000), dataCell("Inflammation, IgE production, eosinophil activation (late phase)", 3826)] })
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      spacer(140),

      // TYPE II
      h2("Type II — Cytotoxic (Antibody-Dependent) Hypersensitivity"),
      numberedItem("IgG or IgM antibodies are directed against cell-surface antigens or extracellular matrix"),
      numberedItem("Antibody binding activates complement via classical pathway → MAC (membrane attack complex) → cell lysis"),
      numberedItem("Cells coated with IgG are also destroyed by ADCC (NK cells and macrophages via FcγR)"),
      numberedItem("Opsonization: C3b-coated cells are phagocytosed by macrophages"),
      numberedItem("Drugs (e.g., penicillin) can haptenize RBCs → antibody formation against drug-RBC complex → hemolysis"),
      numberedItem("Special case (Type V): Antibodies to cell surface receptors stimulate/block function without lysis — e.g., Graves' disease (TSH-R antibody)"),
      spacer(80),

      // TYPE III
      h2("Type III — Immune Complex-Mediated Hypersensitivity"),
      numberedItem("Antigen-antibody (IgG/IgM) complexes form in excess in circulation"),
      numberedItem("When complexes persist and are not cleared, they deposit in tissues (glomeruli, joints, vessel walls)"),
      numberedItem("Deposited immune complexes activate complement → C3a and C5a (anaphylatoxins)"),
      numberedItem("C5a is a potent chemoattractant → recruits neutrophils to the site"),
      numberedItem("Neutrophils release lysosomal enzymes and ROS → tissue damage and inflammation (vasculitis, nephritis, arthritis)"),
      spacer(60),
      h4("Two Subtypes:"),
      bullet("Arthus Reaction (Local): IgG + injected antigen → local complement activation within 12 hours"),
      bullet("Serum Sickness (Systemic): Large antigen excess → systemic immune complex deposition at 6–21 days"),
      spacer(80),

      // TYPE IV
      h2("Type IV — Delayed-Type (Cell-Mediated) Hypersensitivity"),
      numberedItem("No antibody involved — purely T-cell mediated"),
      numberedItem("First exposure: Antigen processed by APCs (Langerhans cells) → presented to CD4+ Th1 cells via MHC Class II → memory T cells form"),
      numberedItem("Re-exposure (48–72 hrs later): Antigen re-presented to sensitized T cells"),
      numberedItem("Activated Th1 cells release cytokines: IFN-γ, IL-2, TNF-β"),
      numberedItem("IFN-γ activates macrophages → release TNF and lysosomal enzymes → granuloma formation, induration, necrosis"),
      spacer(60),
      h4("Subtypes of Type IV:"),
      bullet("Contact Hypersensitivity: Chemicals (nickel, urushiol from poison ivy) act as haptens → sensitize skin T cells"),
      bullet("Tuberculin-Type: Tuberculin skin test — positive = induration in 24–72 hrs (CD4+ Th1 response)"),
      bullet("Granulomatous: Chronic macrophage activation — e.g., tuberculosis, leprosy, sarcoidosis"),
      spacer(160),
      pageBreak(),

      // ══════════════════════════════════════════
      // EXAMPLES
      // ══════════════════════════════════════════
      h1("3. EXAMPLES — Disease Classification"),
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        new TableRow({ tableHeader: true, children: [hdrCell("Disease / Condition", 5000), hdrCell("Type of Hypersensitivity", 4026)] }),
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        new TableRow({ children: [dataCell("Bronchial Asthma", 5000), dataCell("Type I", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Hay Fever (Allergic Rhinitis)", 5000, GRAY_LIGHT), dataCell("Type I", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Atopic Dermatitis (Eczema)", 5000), dataCell("Type I", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Food Allergy (shellfish, peanuts)", 5000, GRAY_LIGHT), dataCell("Type I", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Hemolytic Transfusion Reaction (ABO mismatch)", 5000), dataCell("Type II", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Rh Hemolytic Disease of Newborn", 5000, GRAY_LIGHT), dataCell("Type II", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Autoimmune Hemolytic Anemia", 5000), dataCell("Type II", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Goodpasture Syndrome", 5000, GRAY_LIGHT), dataCell("Type II", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Graves' Disease (TSH-R antibody)", 5000), dataCell("Type II (V)", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Myasthenia Gravis (AChR antibody)", 5000, GRAY_LIGHT), dataCell("Type II (V)", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Systemic Lupus Erythematosus (SLE)", 5000), dataCell("Type III", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Post-Streptococcal Glomerulonephritis", 5000, GRAY_LIGHT), dataCell("Type III", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Serum Sickness", 5000), dataCell("Type III", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Arthus Reaction", 5000, GRAY_LIGHT), dataCell("Type III (local)", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Contact Dermatitis (poison ivy, nickel, formaldehyde)", 5000), dataCell("Type IV", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Tuberculin (Mantoux) Test", 5000, GRAY_LIGHT), dataCell("Type IV", 4026, GRAY_LIGHT, true)] }),
        new TableRow({ children: [dataCell("Organ Graft Rejection (allograft)", 5000), dataCell("Type IV", 4026, WHITE, true)] }),
        new TableRow({ children: [dataCell("Tuberculosis granuloma / Leprosy (tuberculoid)", 5000, GRAY_LIGHT), dataCell("Type IV", 4026, GRAY_LIGHT, true)] })
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      spacer(160),
      pageBreak(),

      // ══════════════════════════════════════════
      // PHARMACOLOGICAL MANAGEMENT
      // ══════════════════════════════════════════
      h1("4. PHARMACOLOGICAL MANAGEMENT"),
      spacer(80),

      // Type I management
      h2("Type I Hypersensitivity — Management"),
      spacer(60),
      tableNoBorder([
        new TableRow({ tableHeader: true, children: [hdrCell("Drug / Class", 2200), hdrCell("Example(s)", 1800), hdrCell("Mechanism of Action", 2600), hdrCell("Clinical Use", 2426)] }),
        new TableRow({ children: [subHdrCell("EPINEPHRINE (First-line)", 2200), dataCell("Adrenaline", 1800, GRAY_LIGHT), dataCell("α1 (vasoconstriction) + β2 (bronchodilation); reverses anaphylaxis", 2600, GRAY_LIGHT), dataCell("Severe anaphylaxis — IM injection", 2426, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("H1 Antihistamines", 2200), dataCell("Diphenhydramine, Cetirizine, Loratadine", 1800), dataCell("Competitive block of H1 receptors → reduce vasodilation, pruritus, urticaria", 2600), dataCell("Allergic rhinitis, urticaria, mild allergy", 2426)] }),
        new TableRow({ children: [subHdrCell("Corticosteroids", 2200), dataCell("Prednisolone, Dexamethasone, Hydrocortisone", 1800, GRAY_LIGHT), dataCell("Inhibit phospholipase A2 → block arachidonic acid → reduce LTs + PGs; suppress cytokines", 2600, GRAY_LIGHT), dataCell("Severe allergy, asthma, late-phase reaction", 2426, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("Leukotriene Antagonists (LTRA)", 2200), dataCell("Montelukast, Zafirlukast", 1800), dataCell("Block CysLT1 receptors → reduce bronchoconstriction and mucus secretion", 2600), dataCell("Bronchial asthma, allergic rhinitis", 2426)] }),
        new TableRow({ children: [subHdrCell("Mast Cell Stabilizers", 2200), dataCell("Sodium Cromoglycate, Nedocromil", 1800, GRAY_LIGHT), dataCell("Block Cl- channels → prevent mast cell degranulation → inhibit histamine + mediator release", 2600, GRAY_LIGHT), dataCell("Prophylaxis in asthma, allergic rhinitis", 2426, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("Beta-2 Agonists", 2200), dataCell("Salbutamol, Formoterol", 1800), dataCell("Activate β2 receptors on bronchial smooth muscle → bronchodilation", 2600), dataCell("Acute asthma attack", 2426)] }),
        new TableRow({ children: [subHdrCell("Xanthines", 2200), dataCell("Theophylline", 1800, GRAY_LIGHT), dataCell("Inhibit phosphodiesterase → increase cAMP → bronchodilation + mast cell stabilization", 2600, GRAY_LIGHT), dataCell("Chronic asthma", 2426, GRAY_LIGHT)] }),
        new TableRow({ children: [subHdrCell("Anti-IgE Monoclonal Ab", 2200), dataCell("Omalizumab", 1800), dataCell("Binds free IgE → prevents IgE binding to FcεRI on mast cells → no degranulation", 2600), dataCell("Severe allergic asthma, chronic urticaria", 2426)] }),
        new TableRow({ children: [subHdrCell("Allergen Immunotherapy", 2200), dataCell("Desensitization shots", 1800, GRAY_LIGHT), dataCell("Repeated low-dose allergen shifts Th2→Th1, increases IgG4 (blocking Ab), reduces IgE", 2600, GRAY_LIGHT), dataCell("Long-term allergy management", 2426, GRAY_LIGHT)] })
      ]),
      spacer(140),

      // Type II management
      h2("Type II Hypersensitivity — Management"),
      spacer(60),
      tableNoBorder([
        new TableRow({ tableHeader: true, children: [hdrCell("Drug / Approach", 3000), hdrCell("Mechanism", 3000), hdrCell("Use", 3026)] }),
        new TableRow({ children: [dataCell("Corticosteroids (Prednisolone)", 3000, GRAY_LIGHT), dataCell("Suppress antibody production and complement activation", 3000, GRAY_LIGHT), dataCell("Autoimmune hemolytic anemia, Goodpasture syndrome", 3026, GRAY_LIGHT)] }),
        new TableRow({ children: [dataCell("Plasmapheresis", 3000), dataCell("Removes circulating autoantibodies and immune complexes", 3000), dataCell("Goodpasture syndrome, myasthenia gravis", 3026)] }),
        new TableRow({ children: [dataCell("IVIG", 3000, GRAY_LIGHT), dataCell("Saturates FcRn receptors → faster degradation of pathogenic IgG", 3000, GRAY_LIGHT), dataCell("Autoimmune conditions, ITP", 3026, GRAY_LIGHT)] }),
        new TableRow({ children: [dataCell("Rituximab (anti-CD20 mAb)", 3000), dataCell("Depletes B cells → reduces autoantibody production", 3000), dataCell("Autoimmune hemolytic anemia, vasculitis", 3026)] })
      ]),
      spacer(140),

      // Type III management
      h2("Type III Hypersensitivity — Management"),
      spacer(60),
      tableNoBorder([
        new TableRow({ tableHeader: true, children: [hdrCell("Drug / Approach", 3000), hdrCell("Mechanism", 3000), hdrCell("Use", 3026)] }),
        new TableRow({ children: [dataCell("Corticosteroids", 3000, GRAY_LIGHT), dataCell("Suppress complement activation, neutrophil function, cytokine production", 3000, GRAY_LIGHT), dataCell("SLE, vasculitis, serum sickness", 3026, GRAY_LIGHT)] }),
        new TableRow({ children: [dataCell("NSAIDs", 3000), dataCell("COX inhibition → reduce prostaglandin-mediated inflammation", 3000), dataCell("Joint pain in SLE, serum sickness", 3026)] }),
        new TableRow({ children: [dataCell("Hydroxychloroquine", 3000, GRAY_LIGHT), dataCell("Inhibit TLR signaling → reduce immune complex deposition and flares", 3000, GRAY_LIGHT), dataCell("SLE (first-line adjunct)", 3026, GRAY_LIGHT)] }),
        new TableRow({ children: [dataCell("Immunosuppressants (Azathioprine, MMF, Cyclophosphamide)", 3000), dataCell("Reduce B and T cell activity → less immune complex formation", 3000), dataCell("Lupus nephritis (Type III), vasculitis", 3026)] }),
        new TableRow({ children: [dataCell("Plasmapheresis", 3000, GRAY_LIGHT), dataCell("Physically removes circulating immune complexes", 3000, GRAY_LIGHT), dataCell("Severe SLE, cryoglobulinemia", 3026, GRAY_LIGHT)] })
      ]),
      spacer(140),

      // Type IV management
      h2("Type IV Hypersensitivity — Management"),
      spacer(60),
      tableNoBorder([
        new TableRow({ tableHeader: true, children: [hdrCell("Drug / Approach", 3000), hdrCell("Mechanism", 3000), hdrCell("Use", 3026)] }),
        new TableRow({ children: [dataCell("Topical/Systemic Corticosteroids", 3000, GRAY_LIGHT), dataCell("Suppress T-cell activation; reduce cytokine release and macrophage activation", 3000, GRAY_LIGHT), dataCell("Contact dermatitis (first-line)", 3026, GRAY_LIGHT)] }),
        new TableRow({ children: [dataCell("Calcineurin Inhibitors (Tacrolimus, Cyclosporine)", 3000), dataCell("Block calcineurin → inhibit IL-2 transcription → suppress T-cell proliferation", 3000), dataCell("Contact dermatitis, organ transplant rejection", 3026)] }),
        new TableRow({ children: [dataCell("Anti-TNF Biologics (Infliximab, Adalimumab)", 3000, GRAY_LIGHT), dataCell("Block TNF-α → reduce macrophage activation and granuloma formation", 3000, GRAY_LIGHT), dataCell("TB granuloma complications, Crohn's disease", 3026, GRAY_LIGHT)] }),
        new TableRow({ children: [dataCell("Antituberculosis Drugs (HRZE)", 3000), dataCell("Treat the causative organism driving Type IV granuloma in TB", 3000), dataCell("Tuberculosis", 3026)] }),
        new TableRow({ children: [dataCell("Antigen Avoidance", 3000, GRAY_LIGHT), dataCell("Fundamental — remove sensitizing antigen entirely", 3000, GRAY_LIGHT), dataCell("Contact dermatitis (nickel, latex)", 3026, GRAY_LIGHT)] })
      ]),
      spacer(160),
      pageBreak(),

      // ══════════════════════════════════════════
      // FLOWCHART
      // ══════════════════════════════════════════
      h1("5. TYPE I HYPERSENSITIVITY — MECHANISM FLOWCHART"),
      spacer(80),

      // The flowchart is represented as a series of visually styled boxes using shaded paragraphs
      new Paragraph({
        children: [new TextRun({ text: "FIRST EXPOSURE TO ALLERGEN", font: "Arial", size: 22, bold: true, color: WHITE })],
        shading: { type: ShadingType.SOLID, color: BLUE_MID, fill: BLUE_MID },
        alignment: AlignmentType.CENTER,
        spacing: { before: 0, after: 0 },
        border: { top: { style: BorderStyle.THICK, size: 6, color: TEAL }, bottom: { style: BorderStyle.THICK, size: 6, color: TEAL }, left: { style: BorderStyle.THICK, size: 6, color: TEAL }, right: { style: BorderStyle.THICK, size: 6, color: TEAL } }
      }),
      new Paragraph({ children: [new TextRun({ text: "(Pollen, dust mite, penicillin, food antigen)", font: "Arial", size: 18, italics: true, color: "555555" })], alignment: AlignmentType.CENTER, spacing: { before: 40, after: 80 } }),
      new Paragraph({ children: [new TextRun({ text: "▼", font: "Arial", size: 28, bold: true, color: TEAL })], alignment: AlignmentType.CENTER, spacing: { after: 40 } }),

      new Paragraph({
        children: [new TextRun({ text: "Allergen → APCs present to Th2 cells → IL-4 and IL-13 released", font: "Arial", size: 20, color: BLUE_DARK })],
        shading: { type: ShadingType.SOLID, color: BLUE_LIGHT, fill: BLUE_LIGHT },
        alignment: AlignmentType.CENTER, spacing: { before: 0, after: 0 },
        border: { top: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, bottom: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, left: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, right: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID } }
      }),
      new Paragraph({ children: [new TextRun({ text: "▼", font: "Arial", size: 28, bold: true, color: TEAL })], alignment: AlignmentType.CENTER, spacing: { before: 40, after: 40 } }),

      new Paragraph({
        children: [new TextRun({ text: "B cells undergo class-switching → Produce IgE antibodies", font: "Arial", size: 20, color: BLUE_DARK })],
        shading: { type: ShadingType.SOLID, color: BLUE_LIGHT, fill: BLUE_LIGHT },
        alignment: AlignmentType.CENTER, spacing: { before: 0, after: 0 },
        border: { top: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, bottom: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, left: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, right: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID } }
      }),
      new Paragraph({ children: [new TextRun({ text: "▼", font: "Arial", size: 28, bold: true, color: TEAL })], alignment: AlignmentType.CENTER, spacing: { before: 40, after: 40 } }),

      new Paragraph({
        children: [new TextRun({ text: "IgE binds to FcεRI receptors on MAST CELLS and BASOPHILS  →  Patient is SENSITIZED", font: "Arial", size: 20, bold: true, color: BLUE_DARK })],
        shading: { type: ShadingType.SOLID, color: BLUE_LIGHT, fill: BLUE_LIGHT },
        alignment: AlignmentType.CENTER, spacing: { before: 0, after: 0 },
        border: { top: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, bottom: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, left: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, right: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID } }
      }),
      spacer(80),

      new Paragraph({
        children: [new TextRun({ text: "SECOND EXPOSURE TO SAME ALLERGEN", font: "Arial", size: 22, bold: true, color: WHITE })],
        shading: { type: ShadingType.SOLID, color: "C0392B", fill: "C0392B" },
        alignment: AlignmentType.CENTER,
        spacing: { before: 40, after: 0 },
        border: { top: { style: BorderStyle.THICK, size: 6, color: "922B21" }, bottom: { style: BorderStyle.THICK, size: 6, color: "922B21" }, left: { style: BorderStyle.THICK, size: 6, color: "922B21" }, right: { style: BorderStyle.THICK, size: 6, color: "922B21" } }
      }),
      new Paragraph({ children: [new TextRun({ text: "▼", font: "Arial", size: 28, bold: true, color: TEAL })], alignment: AlignmentType.CENTER, spacing: { before: 40, after: 40 } }),

      new Paragraph({
        children: [new TextRun({ text: "Allergen cross-links two IgE molecules on mast cell surface", font: "Arial", size: 20, color: BLACK })],
        shading: { type: ShadingType.SOLID, color: "FDECEA", fill: "FDECEA" },
        alignment: AlignmentType.CENTER, spacing: { before: 0, after: 0 },
        border: { top: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, bottom: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, left: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, right: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" } }
      }),
      new Paragraph({ children: [new TextRun({ text: "▼", font: "Arial", size: 28, bold: true, color: TEAL })], alignment: AlignmentType.CENTER, spacing: { before: 40, after: 40 } }),

      new Paragraph({
        children: [new TextRun({ text: "MAST CELL DEGRANULATION", font: "Arial", size: 24, bold: true, color: WHITE })],
        shading: { type: ShadingType.SOLID, color: "922B21", fill: "922B21" },
        alignment: AlignmentType.CENTER,
        spacing: { before: 0, after: 0 },
        border: { top: { style: BorderStyle.THICK, size: 8, color: "641E16" }, bottom: { style: BorderStyle.THICK, size: 8, color: "641E16" }, left: { style: BorderStyle.THICK, size: 8, color: "641E16" }, right: { style: BorderStyle.THICK, size: 8, color: "641E16" } }
      }),
      spacer(80),

      // Two-column mediators
      tableNoBorder([
        new TableRow({
          children: [
            new TableCell({
              width: { size: 4513, type: WidthType.DXA },
              shading: { type: ShadingType.SOLID, color: "D6EAF8", fill: "D6EAF8" },
              borders: { top: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, bottom: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, left: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID }, right: { style: BorderStyle.SINGLE, size: 4, color: BLUE_MID } },
              children: [
                new Paragraph({ children: [new TextRun({ text: "PREFORMED MEDIATORS", font: "Arial", size: 20, bold: true, color: BLUE_DARK })], alignment: AlignmentType.CENTER }),
                new Paragraph({ children: [new TextRun({ text: "(Released immediately)", font: "Arial", size: 17, italics: true, color: "555555" })], alignment: AlignmentType.CENTER, spacing: { after: 60 } }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Histamine", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Tryptase", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Heparin", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "ECF-A (Eosinophil Chemotactic Factor)", font: "Arial", size: 19 })] })
              ]
            }),
            new TableCell({
              width: { size: 4513, type: WidthType.DXA },
              shading: { type: ShadingType.SOLID, color: "FDEDEC", fill: "FDEDEC" },
              borders: { top: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, bottom: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, left: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, right: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" } },
              children: [
                new Paragraph({ children: [new TextRun({ text: "NEWLY FORMED MEDIATORS", font: "Arial", size: 20, bold: true, color: "922B21" })], alignment: AlignmentType.CENTER }),
                new Paragraph({ children: [new TextRun({ text: "(From arachidonic acid)", font: "Arial", size: 17, italics: true, color: "555555" })], alignment: AlignmentType.CENTER, spacing: { after: 60 } }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Leukotrienes C4, D4, E4", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Prostaglandin D2 (PGD2)", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "PAF (Platelet Activating Factor)", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "TNF-α, IL-4, IL-5", font: "Arial", size: 19 })] })
              ]
            })
          ]
        })
      ]),
      spacer(80),
      new Paragraph({ children: [new TextRun({ text: "▼", font: "Arial", size: 28, bold: true, color: TEAL })], alignment: AlignmentType.CENTER, spacing: { before: 20, after: 20 } }),

      tableNoBorder([
        new TableRow({
          children: [
            new TableCell({
              width: { size: 4513, type: WidthType.DXA },
              shading: { type: ShadingType.SOLID, color: "E8F8F5", fill: "E8F8F5" },
              borders: { top: { style: BorderStyle.SINGLE, size: 4, color: TEAL }, bottom: { style: BorderStyle.SINGLE, size: 4, color: TEAL }, left: { style: BorderStyle.SINGLE, size: 4, color: TEAL }, right: { style: BorderStyle.SINGLE, size: 4, color: TEAL } },
              children: [
                new Paragraph({ children: [new TextRun({ text: "LOCAL REACTION (Atopy)", font: "Arial", size: 20, bold: true, color: TEAL })], alignment: AlignmentType.CENTER }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Hay Fever", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Asthma", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Urticaria / Eczema", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Food allergy", font: "Arial", size: 19 })] })
              ]
            }),
            new TableCell({
              width: { size: 4513, type: WidthType.DXA },
              shading: { type: ShadingType.SOLID, color: "FDEDEC", fill: "FDEDEC" },
              borders: { top: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, bottom: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, left: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" }, right: { style: BorderStyle.SINGLE, size: 4, color: "C0392B" } },
              children: [
                new Paragraph({ children: [new TextRun({ text: "SYSTEMIC REACTION (Anaphylaxis)", font: "Arial", size: 20, bold: true, color: "922B21" })], alignment: AlignmentType.CENTER }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Hypotension / Shock", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Laryngeal edema", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Bronchospasm", font: "Arial", size: 19 })] }),
                new Paragraph({ numbering: { reference: "bullets", level: 0 }, children: [new TextRun({ text: "Cardiovascular collapse — FATAL", font: "Arial", size: 19, bold: true })] })
              ]
            })
          ]
        })
      ]),
      spacer(160),

      // ══════════════════════════════════════════
      // CONCLUSION
      // ══════════════════════════════════════════
      h1("CONCLUSION"),
      spacer(80),
      boxPara("Hypersensitivity reactions represent a spectrum of immune-mediated tissue damage with distinct mechanisms, mediators, and clinical presentations — their understanding is clinically indispensable for the rational selection of pharmacological agents, from epinephrine in anaphylaxis to calcineurin inhibitors in delayed-type hypersensitivity, and forms the immunological basis for treating allergic, autoimmune, and inflammatory diseases in clinical practice.", "E8F8F5"),
      spacer(120),

      // References
      h2("References"),
      bullet("Jawetz, Melnick & Adelberg's Medical Microbiology, 28th Edition — Chapter: Hypersensitivity (pp. 150-153)"),
      bullet("Roitt's Essential Immunology, 13th Edition — Chapter 14: Allergy and Other Hypersensitivities"),
      bullet("Janeway's Immunobiology, 10th Edition — Chapter 14: Allergic Diseases and Hypersensitivity Reactions"),
      bullet("Goodman & Gilman's The Pharmacological Basis of Therapeutics, 14th Edition"),
      bullet("Katzung's Basic and Clinical Pharmacology, 16th Edition"),
      spacer(80)
    ]
  }]
});

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