JR

Lymphatic & Immune System – Core Vocabulary

Introduction & Chapter Objectives

  • Civilian case reports (1981, Los Angeles & New York) of rare Pneumocystis pneumonia and Kaposi’s sarcoma in 29–36-year-old men → clue that a major component of immunity was absent.
  • Discovery of HIV → description as causative agent of Acquired Immune Deficiency Syndrome (AIDS); once nearly 100\% fatal, now a chronic disease due to antiretrovirals.
  • Chapter-level competencies:
    • Identify lymphatic structures & cells.
    • Distinguish innate vs. adaptive immunity.
    • Explain immunodeficiency & hypersensitivity.
    • Relate immune mechanisms to transplantation, cancer, ageing, stress & other body systems.

Anatomy of the Lymphatic & Immune Systems

Basic Definitions

  • Immune system = cells + organs that neutralise/destroy pathogens.
  • Lymphatic system = vessel network returning excess interstitial fluid, transporting lipids & hosting immune cells.

Functions of the Lymphatic System

  • Drains plasma filtrate from capillaries: 20\,\text{L day}^{-1} exit, 17\,\text{L} re-enter directly, 3\,\text{L} return as lymph.
  • Transports dietary lipids/fat-soluble vitamins (lacteals → chyle).
  • Acts as highway & staging area (lymph nodes) for leukocytes.
  • Blockage/destruction ⇒ lymphedema (protein-rich swelling).

Structural Components

  • Capillaries: blind-ended, one-cell-thick endothelium, anchored by collagen filaments; open when interstitial pressure rises.
  • Lacteals (small intestine): absorb triglyceride-rich chyle.
  • Larger vessels: possess frequent semilunar valves → beaded appearance; movement via skeletal muscle & breathing (no heart pump).
  • Trunks & ducts:
    • Right lymphatic duct drains right head/thorax/arm → right subclavian v.
    • Thoracic duct (origin: cisterna chyli) drains remainder → left subclavian v.; asymmetrical system.

Primary vs. Secondary Lymphoid Organs

  • Primary: red bone marrow (B-cell maturation; hematopoiesis), thymus (T-cell maturation; cortex = dense thymocytes, medulla = lighter).
  • Ageing: thymic involution ≈ 3\% tissue loss yr⁻¹ until ~45 y then 1\% yr⁻¹ → concept of immunosenescence; linked to foxn1 gene & sex hormones.
  • Secondary: lymph nodes, spleen, mucosal lymphoid tissues (tonsils, Peyer’s patches, BALT, MALT) — sites of naïve lymphocyte activation.
    • Common architectural themes: lymphoid follicles, reticular fiber mesh, germinal centres, high endothelial venules.

Lymph Node Micro-anatomy

  • Encapsulated; afferent vs. efferent vessels; compartments via trabeculae.
  • Cortex: follicles (B-cell GC centre, T-cell mantle).
  • Medulla: cords (B & plasma cells) + sinuses (collecting lymph).

Spleen

  • ~12\,\text{cm}, fragile; attached by gastrosplenic ligament.
  • Red pulp (RBC filtration, fixed & free macrophages).
  • White pulp (lymphoid follicles around central arteriole) → adaptive responses to blood-borne antigens.

Lymphoid Nodules & Mucosal Sites

  • Non-encapsulated clusters; tonsils (palatine, pharyngeal/adenoid), Peyer’s patches (M-cells sample lumen), BALT.
  • Function: front-line IgA-mediated immunity; teach paediatric immune systems.

Organisation of Immune Function

Temporal Phases

  1. Barrier defenses (skin, mucosa, secretions) – instantaneous.
  2. Innate immune response – rapid, non-specific (phagocytes, NK, complement, cytokines).
  3. Adaptive immune response – slower but specific (lymphocytes, antibodies, memory).

Hematopoiesis & Cell Classes

  • All blood cells from hematopoietic stem cells (life-long supply):
    • Phagocytes (macrophages, neutrophils, dendritic cells).
    • Lymphocytes (B, T, plasma, NK).
    • Granulocytes (basophils, eosinophils, mast cells).
  • Body contains 10^{12} lymphocytes.

T, B, Plasma, NK Overview

  • B cells: produce antibodies; mature in marrow → plasma cells (antibody factories).
  • T cells: helper (CD4⁺), cytotoxic (CD8⁺) etc.; mature in thymus.
  • Plasma cells: eccentric nucleus, abundant rER.
  • NK cells (innate): perforin/granzyme or Fas-L apoptosis of virus-infected or transformed cells.

Barrier Defenses (Innate)

  • Skin: keratinised, acidic sweat/sebum, desquamation.
  • Mucus & cilia: trap + move debris to stomach.
  • Saliva: lysozyme.
  • Stomach acid: pH ≈ 1.5 – 3.5.
  • Normal flora: occupy niches.

Cells & Mechanisms of Innate Response

Phagocytes

  • Macrophages: roaming/fixed (Kupffer, alveolar, histiocytes); first responders; antigen presentation.
  • Neutrophils: granulocytes; chemotaxis via IL-8, leukotrienes; form pus post-mortem.
  • Monocytes: blood precursors.

Pattern Recognition

  • PRRs (e.g., Toll-like receptors) detect PAMPs; limited repertoire but constitutive.

Soluble Mediators

  • Cytokines (local) & chemokines (chemotaxis).
  • Early-induced proteins: interferons (antiviral), mannose-binding lectin, C-reactive protein (opsonins).
  • Complement cascade: alternate vs. classical; C3 cleavage central; outcomes: opsonisation (C3b), chemotaxis (C3a, C5a), membrane attack complex (C5-C9).

Inflammation (4 + 1 signs: heat, redness, pain, swelling, ± loss of function)

  1. Injury → mast cells release histamine, prostaglandins, leukotrienes.
  2. Vasodilation ↑ blood flow (heat/redness).
  3. ↑ vascular permeability → edema.
  4. Phagocyte recruitment (neutrophils then macrophages).
  • Acute vs. chronic; aids debris removal, clotting, antigen transport.

Adaptive Immunity – T Lymphocytes

Advantages

  • Specificity (~10^{11} unique receptors), memory (primary vs. secondary), self-tolerance.

TCR & Antigens

  • αβ-TCR: two chains (variable + constant domains); each T cell expresses one specificity.
  • Epitope ≈ ≤6 aa or 1–2 sugars.

Antigen Processing & Presentation

  • MHC I: all nucleated cells; presents endogenous peptides → activates CD8⁺ cytotoxic T cells.
  • MHC II: professional APCs (macrophage, dendritic, B cell); presents exogenous peptides → activates CD4⁺ helper T cells.
  • Proteasome/TAP route (MHC I) vs. endocytic/Golgi fusion route (MHC II).

T-Cell Development (Thymus)

  • Double negative → positive selection (bind self-MHC) → double positive → negative selection (avoid self-antigen) → single positive (CD4 or CD8).
  • Only ~2\% survive.

Activation & Clonal Expansion

  • Antigen + self-MHC + co-stimulation → proliferation of selected clone → effector & memory cells.

Functional Subsets

  • CD4⁺ Helper T (Th):
    • Th1: activate macrophages; secrete IFN-γ, TGF-β.
    • Th2: assist B cells; secrete IL-4/5/6/10.
    • Treg (CD4⁺CD25⁺): suppress; IL-10, TGF-β.
  • CD8⁺ Cytotoxic T (Tc): perforin, granzyme, Fas-L apoptosis of infected/abnormal cells.

Adaptive Immunity – B Lymphocytes & Antibodies

Development & Tolerance

  • Marrow generates ~10^{14} BCR specificities via gene rearrangement.
  • Central deletion/anergy for self-reactive clones + peripheral dependence on Th2 help.

Activation

  • T-dependent antigens (proteins): BCR binds → internalise → present via MHC II → Th2 cytokines (2-signal rule).
  • T-independent antigens (repeating carbs): extensive BCR cross-linking suffices.

Plasma vs. Memory Cells

  • Plasma: terminal, relocate to marrow, secrete antibodies then die.
  • Memory: long-lived, rapid secondary response.

Antibody Structure & Classes

  • 2 heavy + 2 light chains; Fc (effector) vs. Fab (antigen-binding).
  • IgM: pentamer (10 sites); first made; strong complement activator.
  • IgD: membrane BCR only.
  • IgG: monomer; major blood Ab; crosses placenta; main secondary Ab; complement.
  • IgA: monomer (blood) / dimer (secretions, colostrum); mucosal defense.
  • IgE: binds mast cells/eosinophils; allergy & antiparasite.
  • Class switching retains specificity but changes heavy chain isotype (IgM → IgG/IgA/IgE).

Primary vs. Secondary Antibody Responses

  • Primary: lag of ~4–5 d; low titer IgM then IgG.
  • Secondary: immediate, high-titer predominantly IgG/IgA; basis of immunological memory.

Active vs. Passive Immunity

  • Active: self-generated (infection or vaccination).
  • Passive: transferred Ab (placenta IgG, milk IgA, antiserum injections); quick but no memory.

Immune Responses to Pathogens

  • Bacteria: opsonisation, complement, Th1-activated macrophage nitric-oxide killing; some strains (M. tuberculosis) resist digestion.
  • Fungi: targeted as bacteria; opportunistic when immunity low.
  • Parasites (helminths): IgE-mediated mast-cell degranulation & eosinophil attack; mucosal flushing.
  • Viruses: IFNs, NK cells (MHC I-low), cytotoxic T cells; antibodies neutralise extracellular phase; seroconversion (↑Ab, ↓virus).
  • Immune evasion: antigenic variation (influenza), multiple strains (S. aureus), immunosuppressive molecules, hiding in cells.

Dysfunctions of Immunity

Immunodeficiencies

  • Inherited: complement defects, SCID (both B & T absent) → bone marrow or gene therapy.
  • Acquired: HIV uses CD4 + CCR5/CXCR4; progressive CD4⁺ decline → opportunistic infections.

Hypersensitivities

  1. Type I Immediate IgE-mediated (allergy, anaphylaxis); treated w/ antihistamines, epinephrine; skin wheel-and-flare test.
  2. Type II IgG/IgM + complement → cell lysis (mismatched transfusion, erythroblastosis fetalis).
  3. Type III Immune complex deposition (SLE) → complement activation.
  4. Type IV Delayed, T-cell mediated (TB skin test, poison ivy).

Autoimmunity

  • Breakdown of tolerance → diseases (RA, SLE, rheumatic fever via molecular mimicry). Influenced by genes (MHC alleles) & environment; hygiene hypothesis.

Transplantation & Cancer Immunology

Blood & Rh Factor

  • A/B/O & Rh antigens critical; Rh-negative mothers + Rh-positive fetus → hemolytic disease; prophylaxis = anti-Rh IgG.

Tissue Typing & Rejection

  • Key polymorphic loci: HLA-A, B, C (class I) & DP, DQ, DR (class II).
  • Need ≥3/6 match + immunosuppressants (e.g., cyclosporin A).
  • Graft-versus-host disease: donor marrow lymphocytes attack recipient.

Cancer Immune Surveillance

  • 3 phases: elimination → equilibrium → escape (mutation).
  • Viral-linked cancers: Kaposi’s (HHV-8), hepatocellular (HBV), cervical (HPV); vaccines prevent some.
  • Experimental cancer vaccines (melanoma, renal cell) boost anti-tumour T-cell answers.

Psychoneuroimmunology & Stress

  • Immune organs innervated by sympathetic nerves; leukocytes bear neurotransmitter receptors.
  • Short-term stress: boosts innate but diverts from adaptive; minimal harm in healthy adults.
  • Chronic stress: suppresses both arms → ↑infection & disease; mediated partly by cortisol.

Ethical, Practical & Future Considerations

  • Ageing population (≥25\% over 60 by 2050 in US) → focus on reversing thymic involution & immunosenescence (gene therapy, thymic grafts).
  • Hygiene vs. allergy: over-sanitisation may tilt immunity toward IgE responses.
  • Ongoing challenges: HIV vaccine due to rapid mutation, antimicrobial resistance (MRSA), limited organ donors.
  • Interdisciplinary research (immunology, genetics, endocrinology, psychology) essential for future therapies.