Immune System – Innate and Adaptive Defences Summary

Overview of Immune Defences

• The body treats any non-self entity as hostile: “if you’re not with us, you’re against us.”
• Immunity = resistance to disease. Two inter-related tiers:
– Innate (nonspecific) system – always “on,” responds within minutes.
– Adaptive (specific) system – slower to mobilise, but highly targeted and has memory.
• Diagrammatic organisation (Fig 21.1):
• Innate ➜ Surface barriers (skin, mucous membranes) + Internal defences (phagocytes, NK cells, inflammation, antimicrobial proteins, fever).
• Adaptive ➜ Humoral (B-cell–driven) + Cellular (T-cell–driven) responses; systems overlap continuously.

Innate (Nonspecific) Defences

Surface Barriers – First Line

• Intact epidermis: heavily keratinised, resistant to weak acids/bases, bacterial enzymes, toxins.
• Mucous membranes line all body cavities open to exterior (digestive, respiratory, urinary, reproductive).
• Table 21.1 highlights mechanical & chemical features:
– Acid mantle of skin & vagina (pH < $6$ ) inhibits bacteria/fungi.
– Keratin provides physical resistance.
– Mucus traps microbes; nasal hairs filter; cilia sweep debris.
– Gastric juice (HCl + proteases); lacrimal fluid & saliva contain lysozyme; urine’s acidity flushes UT.
• Protective chemicals: acids, lysozyme, mucin → mucus, defensins (antimicrobial peptides), sebum lipids & dermcidin in sweat.
• Breach of barrier (nicks, shaving, tooth-brushing) calls 2nd line into action.

Internal Cellular & Chemical Defences – Second Line

Pattern-Recognition Receptors (PRRs)

• Cells carry Toll-like receptors (TLRs; 11 types) recognising specific microbial shapes → trigger innate responses.

Phagocytes

• Neutrophils (most abundant WBC) become phagocytic on encounter.
• Macrophages (“big eaters”) arise from monocytes:
– Free macrophages wander; fixed (e.g., liver stellate) stay put.
• Steps of phagocytosis (Fig 21.2b): adhesion → pseudopod engulfment → phagosome→ phagolysosome → digestion → exocytosis.
• Respiratory burst (helper-T-cell induced) generates $\text{O}<em>2^{-}$ , $\text{H}</em>2\text{O}_2$ , bleach; increases pH/osmolarity; defensins perforate membranes.
• Opsonisation: coating with opsonins (complement protein C3b or antibodies) provides “handles” for phagocytes.

Natural Killer (NK) Cells

• Large granular lymphocytes patrol blood & lymph; kill virus-infected or cancer cells lacking normal MHC I.
• Non-phagocytic: bind target ➜ release perforins & granzymes ➜ apoptosis; also enhance inflammation.

Inflammation – Tissue Response to Injury

• Triggers: trauma, heat, chemicals, infection.
• Benefits: confines damage, disposes debris, alerts adaptive arm, sets stage for repair.
• Cardinal signs: redness, heat, swelling, pain (± impaired function).
• Chemical “alarm” (Table 21.2): histamine (mast cells), kinins, prostaglandins, complement, cytokines.
• Events (Fig 21.4):

Vasodilation ➜ hyperaemia (redness, heat).
↑ capillary permeability ➜ exudate, fibrin mesh walls-off area, edema presses nerves (pain).
Phagocyte mobilisation (Fig 21.3): leukocytosis → margination → diapedesis → chemotaxis. Neutrophils arrive first; macrophages later dominate.
• Pus = dead neutrophils + tissue debris + microbes; may form abscess needing drainage.
• Granulomas form when pathogens (e.g., TB) resist killing – bacteria walled-off long-term.

Antimicrobial Proteins

• Interferons (IFNs) – virus-infected cells secrete IFN-α/β ➜ nearby cells produce antiviral proteins; IFN-γ activates macrophages & NK; used clinically for hepatitis C, warts, MS.
• Complement – >20 plasma proteins (C1–C9, etc.).
– Activation pathways (Fig 21.6): Classical (antibody-dependent), Lectin, Alternative → converge at C3.
– C3b ➜ opsonisation & initiates MAC (C5b + C6-C9) causing lysis; C3a/C5a amplify inflammation, chemotaxis.

Fever

• Pyrogens (IL-1, etc.) from leukocytes/macrophages reset hypothalamic thermostat > $37\,^\circ\text{C}$ .
• Benefits: sequesters iron/zinc in liver & spleen; ↑ metabolic rate → faster repair.

Adaptive (Specific) Defences – Third Line

Core Features

• Involves B & T lymphocytes (not in innate).
• Specific, systemic, has memory.
• Two arms:
– Humoral (antibody-mediated) – extracellular targets (bacteria, free viruses, toxins).
– Cellular (cell-mediated) – intracellular targets (infected cells, cancer, grafts).

Antigens

• Anything provoking adaptive response.
• Complete antigens – immunogenicity + reactivity.
• Haptens – reactive but not immunogenic until bound to body protein (e.g., penicillin, poison ivy).
• Antigenic determinants – specific sites recognised; most proteins have many (Fig 21.7).
• Self-antigens/MHC: coded by genes of major histocompatibility complex; unique except identical twins; present self or foreign peptides.

Cells of Adaptive Immunity

Lymphocyte Development (Fig 21.8)

Origin: hematopoietic stem cells in red marrow.
Maturation:
– B cells in bone marrow, T cells in thymus.
– Immunocompetence (unique antigen receptor) + self-tolerance (non-reactive to self).
– T-cell education (Fig 21.9): Positive selection (recognise self-MHC) ➜ Negative selection (don’t bind self-antigen) – only $\sim2\%$ survive.
Seeding secondary organs & circulation.
Antigen encounter ➜ clonal selection (specific lymphocyte activated).
Proliferation → effector & memory cells.

Antigen-Presenting Cells (APCs)

• Dendritic cells – at frontiers; migrate to nodes; best at activating naive T.
• Macrophages – phagocytic; present to maintain T-cell activation; become “angry” killers when stimulated.
• B lymphocytes – present to helper T to get “help.”

Humoral Immunity

B-Cell Activation (Fig 21.11)

• Antigen binds B-cell receptor (membrane Ig) → endocytosis → clonal selection.
• Usually requires TH cytokine co-stimulation (T-dependent).
• Effector cells = plasma cells (live $4–5$ days, secrete $\sim2000$ Ab/s).
• Memory B cells for future.

Primary vs Secondary Response (Fig 21.12)

• Primary lag $3–6\,$ days; Ab peaks ~ $10\,$ days then falls.
• Secondary: within $\le2–3\,$ days, higher titer, affinity maturation, lasts weeks-months – basis for vaccination.

Active vs Passive Immunity (Fig 21.13)

• Active = own B cells produce Ab (infection or vaccine).
• Passive = given Ab (maternal IgG/IgA, antiserum, antivenom); provides immediate, short-term (< $3\,$ wk) protection, no memory.

Antibody (Ig) Structure (Fig 21.14)

• Y-shaped monomer: 2 heavy (H) + 2 light (L) chains, each with Variable (V) & Constant (C) regions.
• Antigen-binding sites formed by $V<em>H + V</em>L$ .
• Stem (Fc) dictates class & effector function (complement binding, placental transfer, secretion, etc.).

Five Classes (MADGE; Table 21.5)

• $\text{IgM}$ – pentamer; first made; potent agglutinator; activates complement.
• $\text{IgA}$ – dimer in secretions (saliva, milk, mucus); guards entrances.
• $\text{IgD}$ – B-cell receptor.
• $\text{IgG}$ – most abundant (≈ $75\%$ plasma Ig); crosses placenta; complement activator.
• $\text{IgE}$ – binds mast/basophils; triggers histamine in allergies & parasitic worms.

Mechanisms of Antibody Action (PLAN)

• Precipitation (solubles), Lysis via complement (MAC), Agglutination (cells), Neutralisation (blocks toxins/virus).
• Opsonisation via C3b/Ab enhances phagocytosis.

Cellular Immunity

T-Cell Subsets (Fig 21.16)

• CD4 ➜ Helper T (TH) or Regulatory T (Treg).
• CD8 ➜ Cytotoxic T (Tc).
• All can form memory clones.

Antigen Presentation & MHC Restriction (Table 21.6)

• Class I MHC: on all nucleated cells; display endogenous peptides (self or viral/cancer).
– Recognised by CD8/Tc ➜ kill if non-self peptide.
• Class II MHC: on APCs; display exogenous peptides; recognised by CD4/TH ➜ coordinate response.
• Dendritic cells can “cross-present” exogenous Ag on MHC I to activate CD8.

T-Cell Activation (Fig 21.17)

Antigen binding – TCR + CD4/8 bind MHC-peptide.
Co-stimulation – costim molecules (e.g., B7 ↔ CD28). Absence ➜ anergy.
• Proliferation driven by cytokines (IL-2 autocrine). Memory cells form; effector activity peaks ~ $1\,$ week, then apoptosis.

Cytokines (Table 21.7)

• Interleukins (IL-1 triggers IL-2 production; IL-2 = key growth factor).
• IFNs, TNF, TGF-β, IL-10 (suppressor), IL-17 (links innate & autoimmunity).

Effector Functions

• Helper T – “generals” of immunity: activate B, CD8, macrophages; release IL-2, IFN-γ; subsets: TH1 (cellular), TH2 (humoral/parasites), TH17 (inflammation).
• Cytotoxic T – patrol & kill by:
– Perforin + granzymes (Fig 21.19) ➜ apoptosis.
– Fas-FasL receptor interaction ➜ apoptosis.
• Regulatory T – dampen response, prevent autoimmunity, important for graft tolerance.

Clinical Correlates & Homeostatic Imbalances

• Complement/MAC crucial vs bacteria; parasitic worms handled by IgE-coated eosinophils.
• Monoclonal antibodies – diagnostics (pregnancy, STIs), therapies (lymphoma, autoimmune).
• Transplants – allografts common; match ABO + MHC; immunosuppression risk of infection; 10-yr survival ~ $50\%$ .
• Immunodeficiencies: SCID (congenital lack of B/T); Hodgkin’s lymphoma; AIDS (HIV targets CD4 via reverse transcriptase; high mutation).
• Autoimmune diseases (loss of self-tolerance): RA, MS, Graves, Type 1 DM, SLE, MG, glomerulonephritis.
– Mechanisms: antigen mimicry, new self-antigens, faulty clonal deletion; therapies block cytokines, costim, induce Treg.
• Hypersensitivities:
– Type I (immediate/IgE) – allergies, anaphylaxis (treated with epinephrine).
– Type II (cytotoxic/IgG,M) – transfusion reaction.
– Type III (immune complex) – SLE, glomerulonephritis.
– Type IV (delayed/T-cell) – contact dermatitis, TB skin test.

Development & Aging

• Stem cells in liver/spleen (weeks 1-9), then red marrow.
• Newborn relies on maternal Ig & TH2; exposure educates TH1.
• Psychoneuro-immunology: stress, grief, sleep loss inhibit immunity.
• Vitamin D required for CD8→Tc; deficiency linked to autoimmunity.
• Thymic atrophy post-puberty; naïve T/B production wanes; chronic low-grade inflammation in elderly promotes atherosclerosis, Alzheimer’s.

High-Yield Numbers, Terms & Equations

• Lag of primary humoral response: $3–6\text{ days}$ ; Ab peak $\approx10\text{ days}$ .
• Plasma cell Ab secretion rate $\approx2\times10^3\text{/s}$ for $4–5\text{ days}$ .
• Only $\sim2\%$ of T cells survive thymic selection.
• Normal body temp $= 37\,^\circ\text{C}$ ; fever > $38\,^\circ\text{C}$ typically.