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IMMUNITY — Guyton & Hall

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1. TYPES OF IMMUNITY

A. Innate (Non-specific) Immunity

• Skin and mucosal barriers
• Phagocytosis by neutrophils and macrophages
• Acid secretions in the stomach
• Normal bacterial flora of the gut
• Chemical substances in blood (lysozyme, complement, natural killer cells)

B. Acquired (Adaptive) Immunity

C. Active vs. Passive Immunity

• Active immunity: The person's own immune system forms antibodies/T cells in response to an antigen (natural infection or vaccination)
• Passive immunity: Temporary protection from infused antibodies or activated T cells obtained from an immunized donor; antibodies last 2–3 weeks in recipient

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2. COMPONENTS OF THE IMMUNE SYSTEM

A. Mononuclear Phagocyte System (MPS) / Reticuloendothelial System

B. Lymphoid Component

• Lymph nodes — most extensive site; intercept antigens in peripheral tissues
• Spleen — intercepts blood-borne antigens
• Submucosal areas of GI tract — intercept antigens entering from the gut
• Tonsils and adenoids — intercept antigens via upper respiratory tract
• Thymus — T-cell maturation/preprocessing
• Bone marrow — B-cell maturation/preprocessing

• Formed in bone marrow → migrate to thymus → undergo rapid proliferation and differentiation
• Thymus removes T cells that react against the body's own antigens (self-tolerance)
• Types:
  • Helper T cells (CD4+) — secrete lymphokines (IL-2, IL-3, IL-4, IL-5, IFN-γ); activate B cells, cytotoxic T cells, macrophages
  • Cytotoxic T cells (CD8+) — directly kill virus-infected cells and cancer cells by releasing perforins and cytotoxic substances
  • Suppressor T cells — suppress activity of other T and B cells (prevent autoimmunity)
  • Memory T cells — long-lived; rapid response to re-exposure

• Preprocessed in the fetal liver and bone marrow
• On antigen stimulation → differentiate into plasma cells → secrete antibodies
• Also produce memory B cells

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3. ANTIGENS

• Definition: Chemical substances (usually proteins or large polysaccharides) that initiate acquired immunity — they are "antibody generators"
• Molecular weight requirement: Usually ≥ 8000 daltons
• Epitopes: Regularly recurring molecular groups on the antigen surface that determine antigenicity (stereochemical basis)
• Both types of acquired immunity (humoral and cell-mediated) are initiated by antigens

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4. ANTIBODIES (Immunoglobulins)

Classes of Immunoglobulins

Mechanism of Antibody Action

1. Agglutination — cross-links multiple antigens, causing clumping
2. Precipitation — forms insoluble antigen-antibody complexes
3. Neutralization — covers toxic sites of antigens
4. Lysis — direct rupture of bacterial or other cell membranes
5. Opsonization — coating antigen to enhance phagocytosis

Complement System

• A system of ~20 plasma proteins activated by antigen-antibody complexes
• Classical pathway: activated by IgG or IgM bound to antigen
• Alternative pathway: activated by polysaccharides or IgA
• End result: membrane attack complex (MAC) → cell lysis
• Other effects: chemotaxis (C5a), opsonization (C3b), vasodilation/increased permeability (C3a, C5a — anaphylatoxins)

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5. DEVELOPMENT OF HUMORAL IMMUNITY

1. Antigen exposure: Antigen enters lymphoid tissue and is processed by antigen-presenting cells (APCs), especially macrophages
2. B-cell activation: Antigen binds specific B-cell receptors; Helper T cells (CD4+) provide co-stimulation via lymphokines (especially IL-4, IL-5)
3. Clonal expansion: Activated B cells proliferate to form a clone
4. Plasma cell differentiation: Clone members become plasma cells → secrete large quantities of specific antibodies into lymph → blood
5. Memory B cells: Some clone members become long-lived memory cells
6. Primary vs. Secondary response:
   • Primary: Lag period of days; relatively small antibody production; mainly IgM initially
   • Secondary (anamnestic): Rapid (within hours), massive antibody response; mainly IgG; due to memory B cells

• Most antigens require helper T-cell co-stimulation for B-cell activation
• Lymphokines released by helper T cells (IL-2, IL-4, IL-5) promote B-cell proliferation and differentiation
• T-independent antigens (some polysaccharides) can stimulate B cells directly without T-cell help

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6. DEVELOPMENT OF CELL-MEDIATED IMMUNITY

1. Antigen presentation: APCs present antigen fragments on MHC class I (to CD8+ T cells) or MHC class II (to CD4+ helper T cells)
2. T-cell activation: Antigen binds T-cell receptor (TCR); helper T cells release IL-2 (key autocrine/paracrine growth factor)
3. Clonal expansion: Activated T cells proliferate
4. Effector functions:
   • Cytotoxic T cells — directly kill target cells by releasing perforins (punch holes in membrane) and granzymes; induce apoptosis
   • Helper T cells — release lymphokines: IL-2 (T-cell growth), IFN-γ (macrophage activation), IL-3, GM-CSF (enhance phagocyte production)
   • Activated macrophages — increased phagocytic and killing capacity
5. Memory T cells: Persist long-term; rapid recall response

• Interleukin-2 (IL-2): Causes proliferation of T cells (autocrine)
• Interleukin-3: Stimulates growth of all blood cells
• Interferon-γ (IFN-γ): Activates macrophages, enhances cytotoxicity
• Migration inhibitory factor: Keeps macrophages at site of infection
• Lymphotoxin (TNF-β): Directly kills cells

• T cells that would react against self-antigens are destroyed (clonal deletion) in the thymus
• B cells reactive to self-antigens are deleted in the bone marrow
• Failure → autoimmune disease

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7. HYPERSENSITIVITY REACTIONS

Type I — Anaphylactic / Atopic (IgE-mediated)

• Mechanism: Antigen → IgE production → IgE binds to mast cells and basophils → re-exposure causes degranulation → histamine, leukotrienes, prostaglandins, bradykinin release
• Clinical: Hay fever, asthma, urticaria, anaphylaxis
• Note: Certain people have atopic tendency — they produce excess IgE against ordinary substances (allergens)
• Anaphylaxis: Most severe form — systemic vasodilation, increased capillary permeability → circulatory shock; can be rapidly fatal
• Treatment: Epinephrine (antagonizes effects), antihistamines

Type II — Cytotoxic (Antibody-mediated)

• Mechanism: IgG or IgM antibodies against cell surface antigens → complement activation → cell lysis or phagocytosis
• Examples: Transfusion reactions, Rh hemolytic disease, autoimmune hemolytic anemia

Type III — Immune Complex (Serum Sickness type)

• Mechanism: Antigen-antibody complexes deposited in tissues → complement activation → inflammation
• Examples: Post-streptococcal glomerulonephritis, SLE vasculitis

Type IV — Delayed-Type Hypersensitivity (Cell-mediated)

• Mechanism: Activated T cells (not antibodies) — sensitized by prior exposure → on re-exposure, T cells infiltrate tissues within 24–72 hours → release cytokines → macrophage invasion → tissue damage
• Examples: Poison ivy contact dermatitis, tuberculin reaction, organ rejection
• Note: The toxin of poison ivy itself causes little harm; the danger is from the T-cell response it provokes

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8. TISSUE TRANSPLANTATION

Graft Types

• Autograft: Donor = Recipient (same individual) — no rejection
• Isograft: Identical twins — no rejection
• Allograft: Same species, different individual — rejection risk
• Xenograft: Different species — strong rejection

Basis of Rejection — HLA System

• The most important antigens causing rejection are Human Leukocyte Antigens (HLAs) — part of the Major Histocompatibility Complex (MHC)
• Each person has 6 HLA antigens on their tissue cell membranes
• There are about 150 different HLAs, creating >1 trillion possible combinations
• Rejection is mediated primarily by cytotoxic T cells (CD8+) recognizing foreign HLA
• Tissue typing: HLAs identified on lymphocytes using antisera + complement — dye uptake test for membrane damage

Prevention of Rejection

• Rampant bacterial and viral infections
• Cancer incidence increased several-fold (immune surveillance impaired)

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9. IMMUNODEFICIENCY DISORDERS

Primary (Congenital) Immunodeficiencies

• Complete lack of lymphocytes → newborn dies of overwhelming bacterial infection within days (unless treated)
• Demonstrate that lymphocytes are essential to survival

• DiGeorge syndrome — thymic aplasia → no T cells → impaired cell-mediated immunity
• Bruton's agammaglobulinemia — no B cells → no antibodies (IgM, IgG, IgA, IgE all absent)
• Severe Combined Immunodeficiency (SCID) — both T and B cells absent

Secondary (Acquired) Immunodeficiencies

• AIDS (HIV infection):
  • HIV specifically attacks and destroys helper T cells (CD4+ cells)
  • Without helper T cells: B cells cannot produce antibodies, cytotoxic T cells cannot be activated
  • Result: Susceptibility to opportunistic infections (Pneumocystis jirovecii pneumonia, CMV, toxoplasmosis) and cancers (Kaposi's sarcoma)
• Iatrogenic immunodeficiency: From immunosuppressive drugs (see transplantation above)
• Neonatal antibody deficiency: Gamma globulins fall to <½ of original level by end of first month (maternal antibodies being catabolized faster than infant produces its own); protection from inherited antibodies lasts ~6 months

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10. HEMOGLOBIN-OXYGEN DISSOCIATION CURVE

The Curve

• Shape: Sigmoid (S-shaped) — due to cooperative binding (each O₂ bound increases affinity for next)
• X-axis: PO₂ (mm Hg); Y-axis: % Hemoglobin saturation (left) and Volume% O₂ (right)

Key Reference Points

• 15 g Hb/100 mL blood × 1.34 mL O₂/g Hb = 20.1 mL O₂/100 mL blood (at 100% saturation = 20 vol%)
• Normal delivery: 19.4 mL (arterial) − 14.4 mL (venous) = ~5 mL O₂ per 100 mL blood per pass
• During exercise: up to 15 mL O₂/100 mL blood can be extracted

Shifts of the Dissociation Curve

• ↑ H⁺ (↓ pH) — Bohr effect
• ↑ CO₂ (PCO₂)
• ↑ Temperature
• ↑ 2,3-Bisphosphoglycerate (BPG/DPG)

• ↓ H⁺ (↑ pH)
• ↓ CO₂
• ↓ Temperature
• ↓ BPG
• Fetal Hb (HbF) — has higher O₂ affinity than adult HbA
• CO poisoning — CO shifts curve left AND reduces Hb available for O₂ binding

Bohr Effect

• When blood passes through tissues: CO₂ diffuses in → ↑ PCO₂ → ↑ H₂CO₃ → ↑ H⁺ → right shift → more O₂ released to tissues
• In the lungs: CO₂ diffuses out → ↓ PCO₂ → ↓ H⁺ → left shift → more O₂ loaded onto Hb from alveoli

BPG Effect

• Normal BPG always keeps curve slightly right-shifted
• In prolonged hypoxia → BPG increases markedly → curve shifts further right → O₂ released at up to 10 mm Hg higher tissue PO₂ than without BPG
• Important adaptation to hypoxia (altitude, poor tissue perfusion)

During Exercise

• ↑ CO₂ + ↑ H⁺ + ↑ temperature in exercising muscle → major right shift in muscle capillaries
• Allows O₂ release at PO₂ as high as 40 mm Hg even when 70% O₂ already removed
• In lungs: opposite shift → more O₂ loaded

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SUMMARY TABLE — Immunity at a Glance

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1. Types of Immunity — Innate vs. Acquired (Humoral + Cell-mediated), Active vs. Passive
2. Components of Immune System
   • MPS (Monocyte-Macrophage/Reticuloendothelial System) — Histiocytes, Kupffer cells, alveolar macrophages, splenic macrophages, lymph node macrophages
   • Lymphoid component — T cells (helper, cytotoxic, suppressor, memory) + B cells; locations: lymph nodes, spleen, thymus, bone marrow, gut, tonsils
3. Antigens — MW ≥8000, proteins/polysaccharides, epitopes
4. Antibodies — 5 classes (IgG/M/A/E/D), mechanisms of action, complement system
5. Humoral Immunity Development — B cell → plasma cell pathway, primary vs. secondary response, role of helper T cells
6. Cell-Mediated Immunity Development — MHC presentation, T-cell activation, perforins, lymphokines (IL-2, IFN-γ, etc.), self-tolerance
7. Hypersensitivity — Type I (IgE/anaphylaxis), II (cytotoxic), III (immune complex), IV (delayed/T-cell)
8. Tissue Transplantation — HLA system, graft rejection mechanism, immunosuppressants (cyclosporine, tacrolimus, azathioprine, glucocorticoids)
9. Immunodeficiency — AIDS (HIV kills helper T cells), congenital (SCID, DiGeorge, Bruton's), neonatal antibody gap
10. Hb-O₂ Dissociation Curve — Sigmoid shape, key values (95/40 mmHg → 97%/75% saturation), right vs. left shift factors (Bohr effect, BPG, temperature, CO₂), clinical applications