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Immunity — Guyton & Hall Textbook of Medical Physiology (Chapter 35)

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1. Innate (Non-specific) Resistance

• Neutrophils and macrophages are the primary phagocytic cells
• Macrophages are fixed in the reticular meshwork of lymph nodes, spleen, and bone marrow — "filter" blood and lymph
• During inflammation, blood monocytes migrate into tissues and enlarge into macrophages

1. Vasodilation → ↑ local blood flow
2. ↑ capillary permeability → fluid leaks into interstitial spaces
3. Clotting of interstitial fluid (fibrinogen leakage)
4. Migration of neutrophils and monocytes into tissues
5. Tissue swelling

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2. Acquired (Adaptive) Immunity

Two Types

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3. Lymphocytes

Origin & Distribution

• Both T and B lymphocytes originate from pluripotent hematopoietic stem cells in bone marrow
• Lymph nodes, spleen, submucosal areas of GI/respiratory tracts, bone marrow, and thymus all contain lymphocytes
• About 1 trillion lymphocytes are in the body

Maturation

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4. Lymphocyte Clones & Antigen Specificity

• Before birth, millions of different lymphocyte clones develop, each capable of responding to ONE specific antigen
• Each clone has unique surface receptor proteins that match only one antigen
• Total B-lymphocyte clones: up to 10 million different types
• Clonal selection: when an antigen enters, it activates only the clone(s) that recognize it

Mechanism of Activation

• Antigen binds to specific receptor on the lymphocyte surface
• This activates the lymphocyte → proliferation and differentiation
• Helper T cells (CD4+) are often required to assist B-cell and cytotoxic T-cell activation
• Macrophages present antigens to T cells using MHC (HLA) molecules

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5. Humoral Immunity & Antibodies

B-Cell Activation → Plasma Cells

1. Antigen binds specific B-lymphocyte clone
2. B lymphocytes enlarge → lymphoblasts → plasmoblasts → plasma cells
3. Each plasma cell produces ~2,000 antibody molecules/second
4. Process takes ~4 days, producing ~500 cells per original plasmablast

Memory Cells

• Some activated B lymphocytes become memory cells (instead of plasma cells)
• Memory cells populate lymphoid tissue and remain dormant
• On second exposure: faster (within hours), stronger, longer-lasting response → secondary immune response

Primary vs. Secondary Response

Lifelong Immunity by Long-lived Plasma Cells

• Long-lived plasma cells reside in bone marrow and gut-associated lymphoid tissue
• Can produce antibodies for decades (e.g., smallpox antibodies detectable 70 years post-vaccination; 1918 H1N1 antibodies still functional 90 years later)

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6. Nature of Antibodies (Immunoglobulins)

• Antibodies are gamma globulins called immunoglobulins (Igs)
• Molecular weight: 160,000–970,000
• Constitute ~20% of all plasma proteins
• Composed of light + heavy polypeptide chains with disulfide bonds

Five Classes of Immunoglobulins

Structure

• Each antibody has two antigen-binding sites (Fab regions) and one Fc region
• The Fc region binds complement and macrophage receptors

Mechanisms of Action

1. Agglutination — cross-links antigens into clumps
2. Precipitation — renders soluble antigens insoluble
3. Neutralization — covers toxic sites on antigens
4. Lysis — directly ruptures cell membranes (via complement)
5. Opsonization — coats bacteria to enhance phagocytosis

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7. The Complement System

• The complement system consists of ~20 proteins in plasma (normally inactive)
• Antibody binding to antigen activates the complement cascade

Key Actions of Complement

1. Opsonization — C3b coats bacteria, promoting phagocytosis
2. Chemotaxis — C5a attracts neutrophils and macrophages
3. Agglutination of bacteria
4. Lysis of bacteria via membrane attack complex (MAC) (C5b-C9)
5. Activation of mast cells/basophils → histamine release → inflammation
6. Neutralization of viruses

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8. Cell-Mediated Immunity — T Lymphocytes

Types of T Lymphocytes

How Cytotoxic T Cells Kill

1. Attach to target cell membrane
2. Release perforins → create holes in cell membrane
3. Release granzymes (cytotoxic substances) → induce apoptosis
4. One CTL can kill multiple targets sequentially

Lymphokines Released by Helper T Cells

• Interleukin-2 (IL-2) — proliferation signal for T and B cells
• Interleukin-3, -4, -5 — B-cell growth/differentiation
• Interferon-gamma (IFN-γ) — activates macrophages
• Granulocyte-macrophage colony-stimulating factor (GM-CSF) — stimulates bone marrow

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9. Tolerance — Why the Body Doesn't Attack Itself

• During preprocessing in thymus (T cells) and bone marrow (B cells), lymphocytes that react with self-antigens are destroyed → negative selection
• The thymus also generates Tregs to suppress any autoreactive cells that escape
• This process renders the immune system tolerant of self

Autoimmune Diseases (Failure of Tolerance)

• Rheumatic fever — antibodies to heart valves (molecular mimicry with strep)
• Glomerulonephritis — antibodies to glomerular basement membrane
• Myasthenia gravis — antibodies to acetylcholine receptors
• Multiple sclerosis — immune attack on myelin sheaths
• SLE (lupus) — antibodies to multiple self-antigens

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10. Immunization

Active Immunization

Passive Immunity

• Transfer of ready-made antibodies (not self-generated)
• Sources: human serum, animal serum, monoclonal antibodies
• Examples: anti-tetanus, anti-rabies, anti-snake venom immune sera
• Advantage: immediate protection
• Disadvantage: temporary only (weeks to months); foreign antibodies may be eliminated quickly

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11. Allergies and Hypersensitivity

Atopic Allergies (Type I / IgE-Mediated)

• Some people produce IgE instead of IgG/IgM in response to allergens
• IgE binds to mast cells and basophils in skin, lungs, gut
• On re-exposure, antigen cross-links IgE → mast cell degranulation
• Releases: histamine, leukotrienes, bradykinin, heparin
• Clinical: asthma, urticaria, rhinitis, anaphylaxis

• Vasodilation → shock
• Bronchospasm → airway obstruction
• Can be fatal within minutes without epinephrine

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12. Sex Differences in Immunity

• Females generally mount stronger innate and adaptive immune responses than males
• This leads to better vaccine responses but also higher susceptibility to autoimmune diseases in females
• Sex hormones (estrogen, testosterone) and X-linked immune genes contribute

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Blood Groups & Immune Reactions (Related)

• ABO blood group antigens are genetically determined glycoproteins on red blood cells
• Natural antibodies (anti-A, anti-B) form without prior antigen exposure
• Mismatched transfusion → agglutination + complement-mediated hemolysis → can be fatal
• Rh system: Rh-negative mothers can be sensitized by Rh-positive fetal RBCs → erythroblastosis fetalis in subsequent pregnancies

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