Innate & Adaptive Immunity, Disease Emergence, Vaccination & Immunotherapy – Detailed Study Notes

8.1 Barriers as Preventative Mechanisms

  • Overview

    • Infectious diseases result from pathogens transferred between hosts.

    • Survival depends on multilayered defence; the inherited, non-specific layer is the innate immune system.

    • Innate traits are present from birth, respond identically to all non-self substances and generate no memory cells.

  • Entry points for pathogens

    • Animals ⇒ eye, nose, mouth, bladder, reproductive tract, broken skin.

    • Plants ⇒ stomata (gas-exchange pores).

    • Both kingdoms evolved barriers to prevent entry.

  • Barrier categories

    • Physical, Chemical, Biological (microbiota). These form the first line of defence.

  • Physical barriers

    • Plants

    • Waxy cuticle ⇒ inhibits attachment of pathogens.

    • Rigid cellulose cell wall ⇒ structural blockade to fungi & bacteria.

    • Animals

    • Exoskeleton (e.g. ants) ⇒ external armor.

    • Skin ⇒ tightly-packed, keratinised cells; superficial dead layer shed with adhering microbes; remains effective only while intact.

  • Chemical barriers

    • Plants

    • Toxins / secondary metabolites (e.g. Solanum lycopersicum molecules disrupting insect digestion).

    • Chemical messengers from infected cells trigger neighbouring cells to up-regulate toxins or initiate apoptosis, walling-off the pathogen.

    • Animals

    • Enzymes ⇒ lysozyme in tears, saliva, breast milk breaks bacterial walls.

    • Acids ⇒ skin fatty acids, gastric juice pH≈2\text{pH}\approx2, slightly acidic vaginal secretions & urine; alkaline seminal fluid containing defensins.

  • Microbiota (biological) barriers

    • Resident flora on skin, gut, reproductive tract compete for nutrients/space and modulate pH/O2_2.

    • Analogy ⇒ thick grass crowding out other seeds.

8.2 Inflammation

  • Purpose ⇒ rapid, non-specific reaction when barriers breached.

  • Sequence (skin splinter example)

    1. Tissue damage ⇒ damaged cells release cytokines.

    2. Platelets aggregate, release fibrin → clot.

    3. Mast cells degranulate histamine + cytokines.

    4. Histamine actions:

    • Binds vascular endothelium ⇒ cells contract, ↑ permeability (swelling).

    • Induces smooth-muscle relaxation ⇒ vasodilation (heat, redness).

    • Excessive release ↓ blood pressure ⇒ anaphylaxis.

    1. Cytokines create chemoattractant gradient.

  • Key innate cells & functions

    • Mast cells ⇒ sentinel; histamine + cytokines.

    • Macrophages ⇒ “big eaters”; >100 bacteria each; clear apoptotic blebs; antigen-presenting.

    • Neutrophils ⇒ first responders from blood; short-lived; pus constituent.

    • Dendritic cells ⇒ peripheral tissues; phagocytose then migrate to lymph node to present antigen.

    • Eosinophils ⇒ 1−3%1{-}3\% WBCs; amplify cytokines; anti-helminth; contribute to allergy tissue damage.

    • Natural Killer (NK) cells ⇒ patrol, recognise missing MHCI\text{MHCI}, release perforin + granzymes → apoptosis/lysis of virally-infected or cancer cells.

  • Molecular mediators

    • Complement proteins (>3030) ⇒ opsonisation, chemoattractant trail, membrane attack complexes.

    • Interferons (>$20$ types) ⇒ secreted by virally-infected cells; induce neighbouring cells’ PKR enzyme & up-regulate MHCI\text{MHCI}; activate NK & macrophages.

    • Pyrogenic cytokines (IL-11, IL-66, TNF) ⇒ act on hypothalamus, raise set-point →39∘C\to39^{\circ}\text{C} (fever) which inhibits microbial enzymes yet tolerable for human enzymes.

  • Clinical application

    • Debate on treating low-grade fever; at 40∘C40^{\circ}\text{C} plus ⇒ active cooling, antipyretics.

8.3 Initiation of the Immune System (Antigens)

  • Antigen (Ag) ⇒ “antibody generator”; any molecule triggering immune response.

  • Self vs non-self

    • Self-antigens ⇒ tolerated by owner, provoke response in others.

    • Non-self antigens ⇒ foreign; initiate response.

    • MHCI\text{MHCI} glycoproteins (all nucleated cells except RBC) mark self; MHC diversity critical for transplant matching.

  • Pathogen evasion examples

    • Bacterial biofilm shields; secretion of immune-suppressive molecules.

    • Viruses & protozoa (e.g. Plasmodium) hide intracellularly displaying host MHCI\text{MHCI}.

  • Antigen presentation pathway
    APC\text{APC} phagocytoses antigen → lysosomal digestion → peptide + MHCII\text{MHCII} complex presented → recognition by B/T cells in lymph node → adaptive immunity.

8.4 Pathogens & Allergens

  • Cellular pathogens

    • Bacteria (binary fission every ≈20\approx20 min) ⇒ e.g. B. anthracis, S. pyogenes.

    • Fungi (eukaryotic; hyphae; opportunists e.g. Candida albicans).

    • Protozoa (single-celled eukaryotes; motile; e.g. Plasmodium malaria).

    • Multicellular parasites ⇒ worms, ticks, lice.

  • Non-cellular pathogens

    • Viruses (RNA/DNA + capsid ± envelope; obligate intracellular).
      • Entry varies – endocytosis (influenza), membrane fusion (HIV), pore formation (polio).

    • Prions ⇒ misfolded proteins convert α\alpha-helix → β\beta-sheet; cause spongiform encephalopathies (CJD, BSE).

  • Transmission & vectors

    • Zoonosis, mosquito vectors (e.g. M. ulcerans hypothesised via mosquitoes), phage therapy concept.

  • Allergens & hypersensitivity

    • Innocuous molecules provoke IgE production upon repeated exposure; IgE binds mast cells → exaggerated histamine release → hay fever, anaphylaxis.

9.1 The Lymphatic System

  • Functions

    • Drain interstitial fluid (lymph) & return to blood.

    • Transport immune cells & antigens.

  • Components

    • Lymph vessels (open, with valves; flow via skeletal-muscle pump).

    • Primary lymphoid tissues ⇒ bone marrow (all WBC genesis; B-cell maturation), thymus (T-cell maturation; self-reactive clones deleted; peaks at puberty).

    • Secondary tissues ⇒ lymph nodes, spleen, tonsils, appendix.

  • Lymph nodes

    • Afferent lymph brings antigen-laden fluid.

    • Houses naïve & memory B/T cells; site of antigen presentation & clonal selection.

    • Removal/damage ➔ lymphoedema (fluid build-up; infection risk).

9.2 The Adaptive Immune Response

  • Properties ⇒ specific, learns, memory, slower on first exposure (~2121 days), faster on re-exposure.

  • Cell origin ⇒ haematopoietic stem cells in bone marrow.

  • B-lymphocytes

    • Naïve B-cell activation requires:
      11. Antigen binding to membrane Ig.
      22. IL cytokines from activated helper T-cell.

    • Upon activation → clonal proliferation → differentiate into:
      • Plasma cells ⇒ mass-produce identical antibodies (humoral response).
      • Memory B cells ⇒ long-lived; rapid secondary response (see graph: secondary IgG spike surpasses primary IgM).

  • Antibody structure/function

    • 22 heavy + 22 light chains; hinge for agglutination; constant Fc triggers complement/ phagocytosis.

    • Classes: IgM (first), IgG (long-term, crosses placenta), IgA (secretions, breast milk), IgE (allergy, parasites), IgD (B-cell receptor).

  • Threat types

    • Extracellular (bacteria, parasites) vs Intracellular (viruses, some bacteria e.g. Mycobacterium).

9.3 Helper & Cytotoxic T-Cells

  • T-lymphocyte maturation ⇒ bone marrow → thymus (positive/negative selection).

  • Helper T-cells (CD4+4^{+})

    • Require antigen-specific MHCII\text{MHCII} presentation + co-stimulatory cytokine.

    • Undergo clonal proliferation; secrete interleukins to activate B-cells & cytotoxic T-cells.

  • Cytotoxic T-cells (CD8+8^{+})

    • Recognise antigen on MHCI\text{MHCI} or stressed self without MHCI.

    • Release perforin (pore) + granzymes (caspase activation) OR trigger Fas-FasL death receptor ⇒ apoptosis.

    • Cell-mediated immunity crucial for virus, tumour surveillance, transplant rejection.

9.4 Natural vs Artificial Immunity

  • Active immunity (organism makes memory)

    • Natural: post-infection recovery.

    • Artificial: vaccination (antigens + adjuvant; may be attenuated or subunit); boosters renew memory.

  • Passive immunity (no memory made)

    • Natural: maternal IgG via placenta, IgA via milk.

    • Artificial: antiserum/ antivenom (pre-formed antibodies); temporary (weeks).

  • Vaccination logistics

    • Adjuvants (e.g. aluminium salts) enhance inflammation → stronger adaptive response.

    • Variolation (historical smallpox scab inoculation) vs modern safe vaccines.

10.1 Emergence & Re-emergence of Pathogens

  • Disease classification

    • Non-infectious (nutritional, genetic, environmental, cancer).

    • Infectious → contagious vs non-contagious.

  • Epidemiology terms

    • Endemic (<11–stable).

    • Epidemic (surge in region).

    • Pandemic (multi-continent).

  • Drivers of emergence

    • Zoonosis, increased travel, urban density, antimicrobial resistance, declining vaccination, bioterrorism.

  • Historical impact in Australia

    • Post-17881788 European pathogens (smallpox, TB, influenza, syphilis) decimated Aboriginal & Torres Strait Islander populations (~90%90\% decline within 1010 yrs).

    • Traditional medicines (e.g. Eremophila spp.) effective for native ailments but lacked efficacy against novel microbes.

10.2 Control & Prevention of Pathogens

  • Transmission routes

    • Direct contact, fomite, droplets, airborne (aerosol ≤5\leq5 µm), faecal-oral, vectors.

  • Prevention measures

    • Personal hygiene (soap reduces surface tension; wash ≥20\geq20 s).

    • Safe food storage (\leq4∘C4^{\circ}\text{C} or \geq65∘C65^{\circ}\text{C}).

    • Clean water infrastructure; sewage treatment.

    • Vaccination programs (+ herd immunity).

    • Biosecurity: customs restrictions, aircraft disinfection, sentinel animals.

  • Outbreak response

    • Identify pathogen (morphology, Gram stain, susceptibility, PCR sequencing).

    • Isolate/quarantine based on incubation period; contact tracing; social distancing.

    • Vector control (repellents, bed nets, draining standing water, larvicidal bacteria).

  • Ebola 2014−162014{-}16 example ⇒ late detection, weak healthcare, funeral practices → epidemic (≈50%\approx50\% CFR).

10.3 Vaccination Programs & Herd Immunity

  • National Immunisation Program (Australia) ⇒ free scheduled vaccines + boosters.

  • Virulence vs spread

    • Avirulent → host mobile → higher R0_0. Highly virulent → host bedridden → lower spread.

  • Basic Reproduction Number (R0_0)

    • R0<1 disease wanes; R</em>0=1R</em>0=1 stable; R_0>1 epidemic.

    • Examples: measles 12−1812{-}18 (herd threshold ≈94%\approx94\%), COVID-19 early estimate ≈3.5\approx3.5.

  • Herd immunity

    • Protects vulnerable (newborn, elderly, immunocompromised).

    • Threshold H=1−1R0H = 1-\dfrac1{R_0} (e.g. measles H≈0.94H\approx0.94).

    • Social distancing lowers effective reproduction number RtR_t.

10.4 Immunotherapy (Cancer & Autoimmunity)

  • Allergen desensitisation

    • Monthly escalating allergen doses ↑ regulatory T-cells; symptom relief 5−85{-}8 yrs; oral drops alternative.

  • Cancer biology recap

    • Mutations disrupt cell cycle ⇒ benign vs malignant tumours; metastasis via blood/lymph.

    • Cancer evades immunity by down-regulating MHCI\text{MHCI}, secreting immunosuppressive cytokines.

  • Conventional treatments ⇒ surgery, chemotherapy (targets dividing cells), radiotherapy (DNA damage).

  • Immunotherapy types

    • Checkpoint inhibitors (anti-PD-1, anti-CTLA-4) block “off” signals on cytotoxic T-cells.

    • CAR T-cell therapy: patient T-cells + viral vector → express chimeric receptor vs tumour antigen → expanded, reinfused.

    • Cancer vaccines: preventive (HPV, HBV) or therapeutic (melanoma).

    • Monoclonal antibodies: lab-cloned B-cell produces antibody vs tumour antigen; produced via hybridoma (B-cell × myeloma fusion).

  • Autoimmune immunotherapy

    • Autoimmune diseases (type 11 diabetes, RA, MS) involve autoantibodies & self-reactive T-cells.

    • Treatments: TNF-α inhibitors, anti-IL-66, monoclonal antibodies blocking B-cell activation, experimental CAR-T suppressor cells.