Adaptive Immune System

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 (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

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

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

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

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

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

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

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

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

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

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 = 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

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