Innate Immunity: Barriers, PRRs (TLR/NLR/RLR), inflammasome (NLRP3), complement, phagocytes, NK cells, type I IFNs, acute-phase response.
Adaptive Immunity: Antigen presentation (MHC I/II, cross-presentation), T-cell activation & differentiation (Th1/Th2/Th17/Tfh/Treg), B-cell activation, affinity maturation, memory.
Immunoglobulins: Structure, isotypes (IgM/G/A/E/D), class switch recombination (AID), neutralisation, opsonisation, ADCC, complement activation.
Cytokines & Chemokines: Signalling families, master cytokines, JAK/STAT, homing receptors & addressins.
Complement System: Classical/lectin/alternative activation, C3/C5 convertases, MAC, regulation (DAF/CD55, CD59), deficiency patterns.
Tolerance & Autoimmunity: Central (AIRE, negative selection), peripheral (anergy, Treg, CTLA-4/PD-1), molecular mimicry, epitope spreading.
Hypersensitivity: Types I–IV mechanisms and clinical examples.
Immunodeficiency: Primary (B/T/phagocyte/complement defects) & secondary (HIV, drugs, malnutrition), pattern recognition.
Transplantation & HLA: HLA genetics, rejection types, GVHD prevention.
Tumour Immunology & Immunotherapy: Immune surveillance, checkpoints (CTLA-4, PD-1/PD-L1), CAR-T, cytokine storm & irAEs.
Vaccines: Live/inactivated/subunit/toxoid/conjugate, mRNA/viral-vector, adjuvants, herd effects.
Laboratory Immunology: Flow cytometry, ELISA/CLIA, immunofixation, autoantibodies, complement assays (CH50/AH50), interferon-gamma release (TB), HLA typing.

🧱 Innate toolkit – fast, focused, finite

PRRs: TLR4→LPS; TLR3→dsRNA; TLR9→CpG DNA; RIG-I/MDA5→viral RNA; NLRP3→DAMPs (K\(^+\) efflux, crystals) → IL-1β/IL-18 via caspase-1.
Phagocyte killing: NADPH oxidase (CGD if defective) → superoxide; MPO → hypochlorite; iNOS → NO. Opsonins (IgG, C3b) accelerate uptake.
NK cells: “Missing-self” recognition (↓MHC I); ADCC via FcγRIII (CD16) binding IgG-coated targets. Balanced by activating vs inhibitory receptors.
Type I IFNs (α/β): Antiviral state (PKR, RNase L), ↑MHC I, activate NK cells; key in viral prodrome.

🎛️ Antigen presentation & T-cell priming

MHC I: All nucleated cells; endogenous peptides (proteasome → TAP → ER); CD8 T cells; HLA-A/B/C.
MHC II: APCs; exogenous peptides (endosome) protected by invariant chain/CLIP; CD4 T cells; HLA-DP/DQ/DR.
Signal 1: TCR + peptide–MHC; Signal 2: Co-stimulation CD28↔CD80/86; Signal 3: Cytokine milieu → fate (e.g., IL-12→Th1, IL-4→Th2, IL-6/TGF-β→Th17, IL-6/IL-21→Tfh, TGF-β/IL-2→Treg).
Cross-presentation: Dendritic cells load exogenous antigen onto MHC I to prime CD8 responses against viruses/tumours.

🧬 B cells – from signal to high-affinity antibody

Activation: Signal 1: BCR antigen binding; Signal 2: CD40 (B)–CD40L (Tfh) + cytokines → class switch (AID), germinal centre formation.
Germinal centres: Dark zone (proliferation + somatic hypermutation), light zone (selection on follicular dendritic cell antigen). Winners → plasma cells (long-lived, bone marrow) + memory.
T-independent antigens: Repetitive polysaccharides (capsules) activate marginal zone B cells → mainly IgM, weak memory; conjugate vaccines add protein carrier to recruit T help.

🧪 Cytokines – minimal list that explains most findings

IL-1, TNF-α, IL-6: Fever, acute-phase proteins, neutrophilia.
IL-2: T-cell growth (also Treg survival); used in IL-2 therapy historically.
IL-4/IL-13: Th2 skew, class switch to IgE, mucus, alternative macrophages.
IL-5: Eosinophils & IgA; helminths, allergy.
IL-12, IFN-γ: Th1 skew, macrophage activation, intracellular killing.
IL-17/IL-23: Neutrophilic mucosal defence; dysregulation → spondyloarthropathies/psoriasis.
IL-10, TGF-β: Immunoregulation, tolerance, scar matrix.
Type I IFNs: Antiviral state; ↑MHC I, flu-like symptoms.

🧷 Tolerance & autoimmunity – why self is usually spared

Central tolerance: Thymic negative selection (AIRE drives peripheral tissue antigen expression); B-cell receptor editing.
Peripheral: Anergy without co-stim; Treg suppression (FOXP3); checkpoints (CTLA-4 outcompetes CD28; PD-1 dampens TCR signalling).
Breakdown: Molecular mimicry (e.g., post-streptococcal rheumatic fever), epitope spreading (SLE), bystander activation (inflammation lowers thresholds).

📏 Core Tables & Equations

Isotype	Key Features	Where / Why
IgM	Pentamer (J-chain), strong complement activator	Primary response; intravascular
IgG	Opsonisation (FcγR), ADCC, crosses placenta	Main serum Ab; memory; longest \(t_{1/2}\) (~21 d)
IgA	Dimer (J-chain), secretory component via pIgR	Mucosa (GI/resp), breast milk
IgE	Binds FcεRI on mast cells/basophils	Allergy (Type I), anti-helminth
IgD	Naïve B-cell receptor	Co-expressed with IgM

🧭 T-helper subsets – who does what?

Subset	Master TF	Polarising cytokines	Effector cytokines	Function
Th1	T-bet	IL-12, IFN-γ	IFN-γ	Macrophage activation, intracellular bugs
Th2	GATA-3	IL-4	IL-4, IL-5, IL-13	Helminths, allergy, IgE switch
Th17	RORγt	TGF-β + IL-6/IL-23	IL-17, IL-22	Neutrophils, mucosal defence
Tfh	Bcl-6	IL-6, IL-21	IL-21	Germinal centre help, class switch
Treg	FOXP3	IL-2, TGF-β	IL-10, TGF-β	Suppression/tolerance

🧨 Hypersensitivity types – mechanism & examples

Type	Mechanism	Examples
I (Immediate)	IgE + mast cell degranulation	Anaphylaxis, hay fever, asthma
II (Antibody-mediated)	IgG/IgM against cell/ECM → opsonisation/ADCC/complement	Autoimmune haemolysis, Goodpasture, Graves/MG (receptor)
III (Immune complex)	Ag–Ab complexes deposit → complement/neutrophils	SLE, serum sickness, post-strep GN
IV (Delayed, T-cell)	CD4/8 effectors, macrophage activation	Contact dermatitis, TB skin test, Type 1 DM, MS

🧬 Complement – pathways, effectors, deficiency clues

Pathway	Trigger	Key steps	Clinical notes
Classical	IgM/IgG–Ag complexes	C1qrs → C4b2a (C3 convertase)	C1 esterase inhibitor ↓ → hereditary angio-oedema (bradykinin)
Lectin	MBL to mannose	MASP → C4b2a	Similar to classical without antibodies
Alternative	Spontaneous C3 “tickover”	C3bBb (C3 convertase)	Factor H/I defects → atypical HUS; properdin stabilises
Terminal	All converge	C5b-9 (MAC)	C5–9 deficiency → Neisseria infections

C3b: Opsonin; C5a: Potent chemoattractant; Regulation: DAF/CD55 & CD59 protect self (loss in PNH → haemolysis).

🧪 Primary immunodeficiencies – pattern recognition

Defect	Pathway	Clues
X-linked agammaglobulinaemia (BTK)	B-cell maturation	↓ all Ig, absent tonsils/lymph nodes, encapsulated bacteria
CVID	Ab production	Recurrent sinopulmonary infections, autoimmunity, lymphoma risk
SCID (IL2RG/JAK3/ADA)	T ± B ± NK	Severe infections, failure to thrive; no thymic shadow; urgent HSCT
DiGeorge (22q11)	Thymic hypoplasia	Cardiac outflow defects, hypocalcaemia, ↓T cells
Wiskott–Aldrich (WASP)	Cytoskeleton	Eczema, infections, thrombocytopenia (small platelets)
CGD (NADPH oxidase)	Respiratory burst	Catalase+ organisms, granulomas; abnormal DHR test
LAD-I (CD18)	Leukocyte adhesion	Delayed cord separation, no pus, leukocytosis
Complement (C2/C3/late)	Humoral innate	Encapsulated infections; late → Neisseria

📐 Test interpretation – Bayes in one line

PPV \(=\frac{\text{sens}\times \text{prevalence}}{\text{sens}\times \text{prev}+(1-\text{spec})\times(1-\text{prev})}\), NPV \(=\frac{\text{spec}\times(1-\text{prev})}{(1-\text{sens})\times\text{prev}+\text{spec}\times(1-\text{prev})}\). Implication: In low-prevalence screening (e.g., autoantibodies), false positives dominate unless specificity is very high.

📝 Quick self-quiz (hover to reveal answers)

Which cytokine drives eosinophil maturation? Ans: IL-5.
Which HLA types associate with coeliac disease? Ans: HLA-DQ2/DQ8.
Low CH50 with normal AH50 suggests deficiency in which pathway? Ans: Classical (C1/C2/C4).
Why do conjugate vaccines help infants? Ans: Provide T-dependent protein to enable class switch & memory against polysaccharides.
Which checkpoint targeted by nivolumab? Ans: PD-1.

🧭 Pathways & Checklists – from pattern to plan

Scenario	Dominant arm	Key players	What to measure	Therapeutic levers
Intracellular bacteria/viruses	Th1/CD8	IFN-γ, IL-12, MHC I	IFN-γ release (e.g., TB), lymphocyte subsets	IFN-α/β, optimise cellular immunity; avoid steroids unless indicated
Helminths/allergy	Th2/Eosinophils/IgE	IL-4/5/13, IgE, mast cells	Eos count, total/specific IgE	Anthelmintics; anti-IL-5/IL-4R biologics; antihistamines
Extracellular bacteria	Antibodies/complement	IgG/IgM, C3b, neutrophils	Immunoglobulins, CH50/AH50	Vaccination (conjugates), IVIG in agammaglobulinaemia
Granulomatous disease	Th1/macrophages	IFN-γ, TNF-α	Histology, IFN-γ assays	Anti-TNF can destabilise granulomas → screen for TB first
Autoantibody disease	Loss of tolerance	Autoantibodies, complement	ANA/dsDNA, ENA, RF/anti-CCP, C3/C4	Steroids, DMARDs, B-cell depletion (anti-CD20)

🧪 Flow cytometry – minimal, useful panel

T cells: CD3; helper CD4; cytotoxic CD8.
B cells: CD19/20; maturation CD27; light chain κ/λ restriction (clonality).
NK: CD16/56 (CD3-negative).
Activation/exhaustion: HLA-DR, CD38; PD-1, CTLA-4.

🧫 Autoantibodies – interpretation guardrails

High-titre ANA plus anti-dsDNA/Sm → SLE; low-titre ANA alone is non-specific.
Anti-CCP is specific for RA; anti-TSHR for Graves; anti-TPO in autoimmune thyroiditis.
ANCA: PR3-ANCA (c-ANCA) in GPA; MPO-ANCA (p-ANCA) in MPA/EGPA.

🧬 Transplant rejection – timing & histology

Hyperacute (mins–hrs): Pre-formed Abs → complement → thrombosis/necrosis.
Acute (days–weeks): Cellular (T-cells) ± humoral; interstitial lymphocytes, tubulitis/vasculitis.
Chronic (months–years): Intimal hyperplasia, fibrosis → progressive ischaemia.
GVHD (allogeneic HSCT): Donor T cells attack host (skin, liver, gut); prevent with calcineurin inhibitor + MTX/MMF.

🩺 Clinical Scenarios & Patterns

Recurrent sinopulmonary infections with encapsulated bacteria (Strep pneumo, H. influenzae): Think B-cell/Ig or complement (C3) defects; check quantitative Ig, vaccine responses, CH50.
Deep-seated abscesses with catalase-positive organisms (Staph aureus, Serratia): Think CGD; do DHR (oxidative burst) flow cytometry.
Severe viral/opportunistic infections (CMV, PCP): T-cell defects or immunosuppression; lymphocyte subsets, HIV test.
Anaphylaxis after penicillin or peanut: Type I HS; give IM adrenaline, airway support; later do specific IgE or supervised challenge.
C3-4 low with oedema/HTN post-infection: Type III HS (immune complex GN); complement/urinalysis/biopsy guide therapy.
Neisseria meningitidis recurrent: Late complement (C5–9) deficiency; vaccinate against meningococcal serogroups; consider prophylaxis.
Immune-related adverse events on checkpoint inhibitor: Colitis, hepatitis, thyroiditis, hypophysitis, pneumonitis-treat grade-wise with steroids; do not miss infection.

🧯 Cytokine release syndrome (CRS) & neurotoxicity (ICANS)

CRS: Fever, hypotension, hypoxia post CAR-T/biTE; IL-6 central → tocilizumab ± steroids (avoid if isolated neurotoxicity without systemic signs).
ICANS: Encephalopathy, aphasia, seizures; manage with steroids, seizure prophylaxis; rule out infection/bleed.

🛡️ Vaccines – quick strategy notes

Live attenuated (e.g., MMR, VZV): Strong cellular/humoral; avoid in severe immunosuppression/pregnancy.
Conjugate (e.g., MenACWY, Hib, PCV): Infant-effective via T-dependent responses; reduce carriage → herd effects.
mRNA/viral vector: Transient antigen expression; strong Tfh and antibody responses; reactogenic but non-integrating.

🧠 Study & Exam Tips

Tell the “three signals” story: For any T-cell question, state signal 1/2/3 and the resulting fate; for B-cells, add CD40–CD40L and AID.
Reduce cytokines to functions: IL-1/6/TNF (fever), IL-2 (T growth), IL-4/5/13 (Th2/allergy), IL-12/IFN-γ (Th1), IL-17/23 (mucosa), IL-10/TGF-β (regulate).
Use deficiency → bug patterns: Phagocyte = catalase+, late complement = Neisseria, B-cell/Ig = encapsulated, T-cell = viral/fungal.
Bayes check on tests: In low prevalence, a “positive” autoantibody may be noise-anchor to clinical pre-test probability.
Draw one schema/day: MHC processing, germinal centre, complement cascade, and hypersensitivity vignettes.

🚀 Rapid drill (answers hidden)

What co-stimulatory pair is blocked by abatacept? Ans: CD28–CD80/86 via CTLA-4-Ig fusion.
Why is IgM best at complement activation? Ans: Pentameric-single molecule efficiently binds C1q.
Which checkpoint blockade most linked to colitis? Ans: CTLA-4 inhibitors (e.g., ipilimumab).
Which cytokines define Th17? Ans: IL-17, IL-22 (driven by IL-6/TGF-β/IL-23).
Mechanism of Graves’ vs MG? Ans: Type II HS-stimulating Ab at TSHR (Graves), blocking Ab at AChR (MG).

Final thought: For any vignette: name the arm (innate/adaptive), the effector (cell/cytokine/Ab/complement), and the control (tolerance/checkpoint). The diagnosis and treatment usually follow. 💪

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Premedical Immunology 🧠

🔢 Key Areas of Study

📏 Core Tables & Equations

🧭 Pathways & Checklists – from pattern to plan

🩺 Clinical Scenarios & Patterns

🧠 Study & Exam Tips

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