Chapter 22 (Part 2) – Adaptive Immune System & Body Defenses

Adaptive Immunity: Core Principles

  • Adaptive (specific) immunity = third line of defense; mounted after innate barriers are breached.
    • Requires specific lymphocyte–antigen interaction → clonal proliferation.
    • Lag of several days → explains longer response time vs. innate arm.
  • Two cooperating branches:
    • Cell-mediated immunity → T-lymphocytes (helper, cytotoxic, regulatory, memory).
    • Antibody-mediated (humoral) immunity → B-lymphocytes → plasma cells → antibodies.

Antigens, Immunogens & Self-Tolerance

  • Antigen = substance binding a TCR/BCR or antibody.
    • Foreign antigens differ from host molecules → normally stimulate response.
    • Self-antigens (endogenous) normally ignored; failure → autoimmunity.
    • Antigenic determinant (epitope) = unique site recognized; shape-specific.
  • Immunogen = antigen able to induce a response.
    • Immunogenicity ↑ with foreignness, size, complexity, quantity.
    • Haptens: small molecules (< full antigen); immunogenic only when attached to carrier; classic example = urushiol in poison ivy.
  • Autoimmune disorders (clinical view): loss of tolerance through cross-reactivity, altered self, or privilege escape.
    • Examples: rheumatic heart disease, type 11 diabetes, multiple sclerosis, celiac disease.

Lymphocyte Receptors & Subsets

  • Both T & B cells bear ≈ 100 000100\,000 identical receptor complexes each, specific for one epitope.
  • T-Cells
    • TCR (αβ heterodimer) plus CD molecules.
    • CD4 on helper T (Th).
    • CD8 on cytotoxic T (Tc).
    • Subsets: helper Th (CD4$^+$), cytotoxic Tc (CD8$^+$), memory, regulatory (Treg).
  • B-Cells
    • BCR (membrane IgM/IgD) — no CD molecules; recognizes intact soluble or particulate antigen without APC.

Antigen Presentation & MHC

  • Purpose: display peptide → allow T-cell surveillance.
  • Presenting cell categories:
    • All nucleated cells (body-wide).
    • Professional APCs: dendritic cells, macrophages, B-cells.
  • MHC (= HLA) gene products
    • Class I (MHCI): on all nucleated cells.
    • Peptides derived via endogenous pathway inside RER.
      • Normal self-peptide → tolerated.
      • Viral/tumor peptide → “foreign” → signals CD8$^+$ Tc to kill.
    • Class II (MHCII): expressed only on APCs (plus their MHCI).
    • Peptides from exogenous pathway (phagocytosed) loaded in phagolysosome → presented to CD4$^+$ Th.

Clinical Correlate – Transplantation

  • MHC molecules are genetically unique; perfect match rare.
  • Pre-donation testing: HLA typing + ABO.
  • Host innate/adaptive arms attempt rejection ⇒ need lifelong immunosuppression (except corneal graft owing to immune privilege).

Life Cycle of Lymphocytes

  1. Formation/Selection (primary organs)
    • T-cells: red marrow → thymus.
      • Random TCR generation; transiently express both CD4 & CD8.
      • Positive selection (cortex): must bind self-MHC.
      • Negative selection (medulla): must not bind self-peptide (central tolerance).
      • ≈98%\approx 98\% fail → apoptosis.
      • Survivors → lose one co-receptor:
      • Keep CD4 → helper.
      • Keep CD8 → cytotoxic.
      • Tregs: self-reactive CD4$^+$ cells diverted to peripheral tolerance.
    • B-cells: mature in red marrow; selection ensures functional but non-auto-reactive BCR.
  2. Activation (antigen challenge) in secondary organs (lymph node, spleen, tonsil, MALT).
    • Leads to clonal expansion of effector + memory progeny (clonal selection).
  3. Effector response at infection site.
    • Th migrate & secrete cytokines (e.g., IL-2, IL-4) coordinating all arms.
    • Tc induce apoptosis (perforin + granzymes).
    • Plasma cells remain in node, secrete large quantities of antibody into blood/lymph.
  • Recirculation: lymphocytes continuously exit, patrol blood/lymph to maximize encounter probability.

Detailed Activation Signals

Helper T (CD4$^+$)
  1. Signal 1: TCR + peptide-MHCII on APC; CD4 stabilization.
  2. Signal 2: Costimulation & IL-2 autocrine loop.
    • Outcome: proliferation → activated Th + memory Th.
    • Absence of signal 2 → anergy/Treg induction.
Cytotoxic T (CD8$^+$)
  1. Signal 1: TCR + peptide-MHCI on APC; CD8 stabilization.
  2. Signal 2: IL-2 from activated Th.
    • Outcome: activated Tc + memory Tc.
B-Lymphocyte
  1. Signal 1: Antigen cross-links BCRs; B-cell internalizes & displays on MHCII.
  2. Signal 2: Cognate Th binds MHCII–peptide and secretes IL-4 (and other cytokines).
    • Outcome: proliferation → plasma cells (majority) + memory B-cells (long-lived).
    • T-independent activation possible but no memory or class switching.

T-Cell Effector Mechanisms

  • Helper T-Cells
    • Secrete cytokines (e.g., IL-2,IL-4,IFN-γ\text{IL-2}, \text{IL-4}, \text{IFN-}\gamma):
    • Activate Tc, B-cells, macrophages, NK, neutrophils.
  • Cytotoxic T-Cells
    • Recognize specific MHCI-antigen on target → release perforin (creates pores) + granzymes (enter → apoptosis).
    • Useful vs. virus-infected, tumor, transplanted cells.

Antibody (Immunoglobulin) Structure

  • Y-shaped monomer: 22 heavy + 22 light chains linked by disulfide bonds.
    • Variable (Fab) regions at tips → antigen-binding sites (usually 22 per Ab).
    • Constant (Fc) region → defines class & effector functions.
    • Hinge confers flexibility.

Functional Actions of Antibodies (Fab-Mediated)

  • Neutralization: cover active/toxic sites → pathogen/toxin rendered non-infective.
  • Agglutination: cross-link entire cells → clumping (esp. bacteria).
  • Precipitation: cross-link soluble antigens → insoluble complexes cleared by phagocytes.

Fc-Region Effector Functions

  • Complement activation (classical pathway) — mainly IgG & IgM.
  • Opsonization — Fc binding to phagocyte receptors enhances engulfment.
  • ADCC (NK activation) — IgG Fc binds NK, triggers perforin/granzyme release.

Five Immunoglobulin Classes

  • IgG (≈ 75!–!85%75!–!85\% of serum Abs)
    • Versatile; crosses placenta → hemolytic disease of newborn.
  • IgM (pentamer; intravascular)
    • First produced; excellent agglutination & complement fixer; indicates current infection.
  • IgA (dimer in secretions)
    • Mucosal defense (saliva, tears, mucus, colostrum); prevents epithelial adherence.
  • IgD
    • Membrane receptor on naïve B-cells; signals readiness for activation.
  • IgE
    • Low levels; rises with parasites & allergies; binds mast cells/basophils → histamine etc.
  • Class switching: plasma cell changes constant region under Th cytokine direction; allows same specificity, new Fc function.

Immunologic Memory & Antibody Titers

  • Primary response (1st exposure or vaccine)
    • Lag 3–63\text{–}6 days; IgM peaks then IgG after 1–21\text{–}2 weeks.
  • Secondary response (re-exposure)
    • Lag <1 day; rapid, greater, longer-lasting IgG (and class-switched Abs) due to memory cells.

Vaccination & Herd Immunity

  • Vaccines = attenuated/killed organisms or subunits; induce memory without disease.
    • Some require boosters for sustained titer.
  • Herd immunity: if ≥83%\ge 83\%–94%94\% population immune, disease spread suppressed.

Active vs. Passive Immunity

  • Active (infection or vaccine): host produces Ab + memory.
  • Passive (maternal IgG/IgA, antiserum, monoclonal Abs): immediate Ab supply, no memory.

Hypersensitivities (Clinical View)

  • Humoral-mediated
    • Acute (Type I) allergy: seconds; IgE-mast cell → histamine → asthma, hives, anaphylaxis.
    • Sub-acute (Types II & III): 11–33 h.
  • Cell-mediated
    • Delayed (Type IV): 11–33 days; e.g., contact dermatitis, TB test.

HIV/AIDS (Clinical View)

  • HIV targets CD4$^+$ Th cells → immunodeficiency.
  • Transmission via bodily fluids (sex, needles, breastmilk).
  • AIDS diagnosis: Th count <200\;\text{cells}\,/\,\text{mm}^3.
  • Death usually from opportunistic infection/cancer; prevention = safe practices, antiviral therapy.