DG

Adaptive Immune System

Adaptive Immunity – Big Picture

  • SPECIFICITY & MEMORY
    • Learns antigens; improves with each exposure (response gets faster & stronger)
    • First exposure: latency \approx 3{-}5\text{ days} (mix-and-match search for correct receptor)
    • Subsequent exposures: may activate within hours (memory cells already circulating)
  • LIMITATION: slow first-time ramp-up ⇨ innate defences must ‘hold the line’ initially

Humoral vs. Cellular Arms

  • Humoral (fluid) immunity
    • Mediated by B cells & antibodies
    • Patrols blood, lymph, mucosal secretions
  • Cellular immunity
    • Mediated by T cells
    • CD8⁺ cytotoxic T lymphocytes (CTL) monitor & kill infected/self-altered cells
    • CD4⁺ helper T cells coordinate every other immune component

Antigens, Determinants & Why “Better & Better” Happens

  • Antigen = any molecule the immune system can recognise (NOT necessarily immunogenic)
    • Body is coated with self-antigens that are tolerated
  • Pathogen facts
    • Multiple antigens / pathogen (e.g. capsid proteins, flagellin, toxins)
    • Multiple epitopes (determinants) / antigen
    • Example: HPV capsomere with 14 epitopes × 3 antigens on bacterium ⇒ 42 potential adaptive responses
    • Each exposure may recruit additional B or T clones ⇨ layer upon layer of responses

Antigen-Presenting Cells (APCs) & MHC Landscape

  • Professional APCs: dendritic cells, macrophages, monocyte-derived cells
  • B cells can bind free antigen directly (independent APC) but require help for memory/class switch
  • Major Histocompatibility Complex (HLA in humans)
    • MHC-I
    • On every nucleated cell
    • Presents endogenous (self or viral) peptides
    • Recognised by CD8⁺ T cells
    • Foreign peptide on MHC-I ⇒ CTL-induced apoptosis
    • MHC-II
    • Only on APCs & activated B cells
    • Always displays foreign peptide
    • Recognised by CD4⁺ T cells ⇒ activation & coordination
    • Transplantation: closer HLA match ↓ rejection, ↓ lifelong immunosuppression

Lymphocyte Development, Somatic Recombination & Selection

  • Bone marrow progenitors create \approx 3\times10^{11} unique receptors (hypervariability / V(D)J recombination)
  • T cell maturation (thymus) / B cell maturation (bone marrow) pass two checkpoints:
    • Positive selection – can receptor bind either MHC class? (yes = survive)
    • Negative selection – does receptor ignore self-antigen? (fails ⇨ apoptosis)
  • \approx 98\% of new lymphocytes die during selection
  • Surviving T cells commit to CD4 or CD8 lineage

Clonal Selection, Effector vs Memory Pools

  • Naïve lymphocyte binds cognate antigen ⇒ clonal expansion
  • Majority ⇒ effector cells (fight now)
  • Minority ⇒ memory cells
    • Do NOT sit dormant; slowly self-replicate in lymphoid tissue and seed blood
    • Provide near-innate-speed activation on re-exposure

T-Cell Activation: “Double Hand-Shake” Safeguard

  • APC presents peptide-MHC-II ⇨ engages CD4⁺ helper T (Signal 1 + co-stimulation)
  • Helper T delivers cytokines (e.g. IL-2) ⇨ licenses APC to activate CD8⁺ CTL (Signal 2)
  • Regulatory T cells induced simultaneously to restrain CTL and prevent "close-enough" autoimmunity
  • Loss of CD4 (HIV) cripples: CTL activation, B-cell memory, innate enhancement → immunodeficiency

B-Cell Response & Antibody (Immunoglobulin) Classes

  • Surface B-cell receptor (BCR) = membrane-bound IgD (or IgM in immature stage)
  • Activation pathways
    1. T-cell–dependent (needs CD4 help) ⇒ class switch + memory
    2. T-cell–independent ⇒ huge burst of IgM only, no memory (useful in immediate threats e.g. venoms)
  • Class switching logic
    • Early response: IgM pentamer (highest avidity; short-lived)
    • Switch after \approx 3{-}5 days depending on location:
      • Blood ⇨ IgG (most abundant serum Ab; crosses placenta)
      • Mucosa/exocrine ⇨ IgA dimer (≥75\% of total Ab; secretions, breast milk; only Ab acting prophylactically)
    • IgE – commits early if receptor fits allergens/parasites; binds mast cells & basophils

Antibody Structure & Bio-Engineering

  • Y-shaped: Variable (Fab) arms bind antigen; Constant (Fc) stem interacts with host (Fc receptors on phagocytes, complement)
  • Monoclonal Abs in therapy
    • Anti-SARS-CoV-2 neutralising Fab fragments (Regeneron) – variable domains only
    • Bispecific Ab: one arm for CTL (CD8), one for tumour antigen ⇒ recruit killer T cell to cancer

Effector Mechanisms – “MATCH”

  • M – Membrane attack / lysis (complement, NK, CTL)
  • A – Agglutination (clump motile bacteria; also transfusion reactions)
  • T – Precipitation (pull soluble toxins/venoms out of solution)
  • C – Complement activation (opsonisation & lysis)
  • H – Neutralisation (block viral/ toxin binding sites; favoured for viruses)

IgA & Mucosal Immune System (MALT)

  • Gastro-intestinal tract has surface area > skin + lungs combined; hosts \approx 75\% of all lymphocytes producing IgA
  • M cells in gut epithelium express many receptors, intentionally sample luminal microbes, deliver to dendritic cells below
  • Result: IgA secreted into lumen coats mucosa; pathogens bound before attachment ⇒ infection prevented
  • Breast-milk IgA grants temporary mucosal immunity to infant

Hypersensitivity (Exaggerated / Inappropriate Responses)

  • Type I – IgE-mediated (allergy, anaphylaxis). Rx: antihistamines, desensitisation (e.g. peanut micro-dosing)
  • Type II – Cytotoxic IgG/complement (some drug reactions, haemolytic disease)
  • Type III – Immune-complex deposition (rare; e.g. serum sickness)
  • Type IV – Delayed T-cell–mediated (transplant rejection, contact dermatitis). Rx: steroids, immunosuppressants

Autoimmunity

  • Self antigen mistakenly treated as foreign; usually CD8⁺ driven
    • Examples: Type-1 diabetes (β-cells), Multiple sclerosis (myelin Schwann cells), Psoriatic arthritis (joint CT), SLE targets connective tissue
  • Common features: highly specific tissue targeting, genetic predisposition
  • Therapies:
    1. Immunosuppression (e.g. steroids for SLE)
    2. Radiation/chemotherapy (e.g. severe psoriatic arthritis)
    3. Symptomatic replacement (e.g. insulin in T1D)

Immunodeficiency vs Immunocompromise

  • Immunodeficiency = systemic weakness of immune system (e.g. ageing, neonates, AIDS, chemo/radiation patients)
  • Immunocompromised = any temporary breach/opening (wounds, smoking, malnutrition) allowing pathogens in
  • Chemo/radiation deliberately wipe immune cells ⇨ patients become immunodeficient & infection-prone

Key Numbers, Equations & Facts

  • Primary adaptive response latency = 3{-}5\,\text{days}
  • Diversity generated \sim 3\times10^{11} receptors
  • Thymic/B-cell selection attrition \sim 98\% apoptosis
  • IgG is only Ab crossing placenta; IgA predominant overall (secretions)
  • Gut hosts >75\% of lymphocytes; largest immunological surface

Ethical & Clinical Connections

  • Transplants: HLA matching lowers rejection & reduces chronic immunosuppression load
  • Monoclonal & bispecific Ab therapeutics promise tumour-targeted immunity; still years from Phase III
  • Breast-feeding advocacy: only way to deliver maternal IgA to newborn ⇨ fewer childhood infections
  • Desensitisation therapy reshaping paediatric allergy prevalence (peanuts, eggs, etc.)
  • HIV devastation tied to single receptor loss (CD4) ⇒ demonstrates centrality of helper T cells