Immune System Overview
The immune system is a complex network of cells, tissues, and organs that defends the body against pathogens through innate (nonspecific) and adaptive (specific) immune responses.
The immune system is the body's integrated network of cells, molecules, and organs that collectively defend against infectious microbes, surveil for malignant cells, and maintain self-tolerance. Understanding its architecture is foundational because virtually every clinical discipline—from infectious disease to rheumatology, oncology, transplant medicine, and allergy—rests on immunological principles.
The immune system is a "double-edged sword" — it provides defence against microbes and defence against cancers, but can also cause allergic reactions, aberrant responses to infections, autoimmune disease, and malignancy [1].
Why This Matters Clinically
A safe clinician must recognise that immune dysfunction underlies an enormous breadth of pathology: immunodeficiency → recurrent/opportunistic infections; immune dysregulation → autoimmunity, allergy, transplant rejection; immune surveillance failure → malignancy. Every time you prescribe steroids, biologics, or chemotherapy, you are modifying this system.
Before memorising detail, internalise these concepts:
- Two arms of immunity — innate (rapid, non-specific, no memory) and adaptive (slower, specific, memory). They cooperate; innate immunity stimulates adaptive immunity.
- Self vs non-self discrimination — the central job of the immune system, mediated largely by MHC/HLA molecules. Failure → autoimmunity; over-reactivity → allergy.
- Clonal selection and immunological memory — the basis of vaccination and secondary immune responses.
- Th1/Th2/Th17 paradigm — cytokine milieu determines the type of adaptive response mounted.
- Complement system — bridges innate and adaptive immunity; deficiency → susceptibility to encapsulated organisms + autoimmunity (SLE).
- Hypersensitivity classification (Gell & Coombs) — Types I–IV; clinically differentiated by timing and lesion type.
- Immunodeficiency spectrum — primary (genetic/inborn errors) vs secondary (acquired: HIV, drugs, disease). Know the pattern of infections for each arm affected.
- Immune privilege and tolerance — mechanisms preventing the immune system from attacking self-tissues; breakdown → autoimmune disease.
- HLA system and transplant immunology — HLA matching determines transplant success; anti-HLA antibodies mediate rejection.
- Therapeutic immunomodulation — steroids, biologics (anti-TNF, anti-IL-6, anti-CD20), checkpoint inhibitors, IVIG — all manipulate specific immune pathways.
Innate Immune System
Innate immunity is immediate, in place even before infection; non-specific; limited diversity; no memory; stimulates adaptive immune response [1].
| Component | Key Details |
|---|---|
| Epithelial barriers | Skin, gastrointestinal, genitourinary, respiratory tract [1] |
| Antimicrobial peptides | e.g. cathelicidins, defensins — disrupt microbial membranes [1] |
| Pattern recognition | PAMPs (pathogen-associated molecular patterns) on microbes recognised by pattern recognition receptors (PRRs) on host cells: Toll-like receptors (TLR), NOD-like receptors (NLR), RIG-I-like receptors (RLR) [1] |
| Phagocytic cells | Neutrophils, macrophages — engulf and kill pathogens via oxidative burst (NADPH oxidase) and lysosomal enzymes [1] |
| Natural killer (NK) cells | Kill virus-infected and tumour cells without prior sensitisation; recognise cells lacking MHC class I ("missing self") |
| Complement system | Cascade of plasma proteins → opsonisation, membrane attack complex (MAC), chemotaxis; bridges innate and adaptive immunity [1] |
| Cytokines | Communication molecules between immune cells (e.g. TNF-α, IL-1, IL-6, IFN-α/β/γ) [1] |
| Platelets | Contribute to innate defence via antimicrobial peptides, complement activation, and clot formation [1] |
High Yield – Phagocyte Defects
If phagocytic killing is defective (e.g. Chronic Granulomatous Disease — NADPH oxidase subunit mutations: CYBB, CYBA, NCF1, NCF2, NCF4 [3]), patients are susceptible to catalase-positive organisms (S. aureus, Aspergillus, Serratia, Burkholderia, Nocardia) because catalase-negative organisms generate their own H₂O₂ which the defective neutrophils can still use.
- Macrophages and dendritic cells (antigen-presenting cells, APCs) engulf pathogens → process antigens → present on MHC class II to CD4+ T cells.
- Cytokine milieu produced by innate cells determines the direction of adaptive response (Th1, Th2, Th17).
- Complement activation products (C3b, C3d) enhance B-cell activation by co-ligating the B-cell receptor with the complement receptor CR2.
Adaptive Immune System
Adaptive immunity needs time — stimulated by exposure to antigens, activation of lymphocytes, elimination of antigen. It is specific, very diverse, and has memory. Consists of B and T lymphocytes and antibodies [1].
Cell-Mediated Immunity (T Cells)
| T-cell Type | Surface Marker | MHC Restriction | Function |
|---|---|---|---|
| Helper T cells | CD4+ | MHC class II | Orchestrate immune response via cytokines |
| Cytotoxic T cells | CD8+ | MHC class I | Kill virus-infected cells, tumour cells directly |
| Regulatory T cells (Treg) | CD4+ CD25+ FoxP3+ | — | Suppress excessive immune responses; maintain self-tolerance |
Naive CD4+ T cells (Th0) activated by interaction with antigen presented by MHC-II. Further differentiation based on predominant cytokine profile [4][5]:
| Subset | Differentiating Cytokines | Key Effector Cytokines | Function | Clinical Relevance |
|---|---|---|---|---|
| Th1 | IFN-γ, IL-12 | IFN-γ, TNF-α, IL-2 | Cell-mediated immunity → ↑macrophage, neutrophil, CD8+ T-cell activity → elimination of intracellular bacteria and viruses [4][5] | Granulomatous diseases, TB control |
| Th2 | IL-4, IL-5 | IL-4, IL-5, IL-13 | Humoral immunity → ↑IgE production, mast cell and eosinophil recruitment → elimination of extracellular pathogens (e.g. parasites) [4][5] | Allergy, atopic asthma, helminth defence |
| Th17 | IL-23, IL-1β | IL-17A, IL-17F, IL-22 | Neutrophil recruitment, mucosal defence | Psoriasis, autoimmune disease [6] |
| Treg | TGF-β, IL-2 | IL-10, TGF-β | Immune suppression, self-tolerance | Deficiency → autoimmunity; excess → tumour immune evasion |
Reciprocal inhibition → immune system directed towards a certain response to suit invading pathogen [4][5]. Th1 cytokines suppress Th2 and vice versa.
| Immunoglobulin | Features |
|---|---|
| IgG | Most abundant; crosses placenta (passive neonatal immunity); opsonisation, complement activation. 4 subclasses (IgG1–4) |
| IgA | Mucosal defence (secretory IgA in gut, respiratory tract, breast milk) |
| IgM | First antibody in primary response; pentamer → very efficient agglutination and complement activation |
| IgE | Binds mast cells/basophils → degranulation → Type I hypersensitivity; parasite defence |
| IgD | Surface marker on naive B cells; function largely unknown |
Antibodies are among the defences that the body uses to repel foreign invaders. Vaccines cause the immune system to make antibodies which protect us from infectious diseases. Antibodies prevent us from getting most diseases a second time. However, sometimes antibodies can be bad [8] — e.g. autoantibodies in SLE, anti-HLA antibodies in transplant rejection.
Atopy vs Allergy
Atopy = tendency to create more IgE → but this does not mean the IgE does anything → so high levels of IgE does not equal allergy [9]. There is correlation, but the clinical diagnosis of allergy requires both sensitisation (IgE) AND clinical symptoms on exposure. Don't over-interpret a high total IgE!
MHC / HLA System
HLA antigens (flags) are the way that the immune system finds out if something is self or foreign [8].
MHC class I is involved in regulation of anti-viral immune responses. MHC class II is involved in regulation of the cells of the immune system. Anucleated erythrocytes cannot support virus replication — hence no MHC class I [10].
| Feature | MHC Class I | MHC Class II |
|---|---|---|
| Genes | HLA-A, -B, -C | HLA-DP, -DQ, -DR |
| Expression | Nearly all nucleated cells | APCs (dendritic cells, macrophages, B cells), thymic epithelium |
| Presents peptides from | Intracellular antigens (viruses, tumour proteins) | Extracellular antigens (bacteria, parasites) |
| Recognised by | CD8+ cytotoxic T cells | CD4+ helper T cells |
| Clinical relevance | Viral immunity; NK cell regulation ("missing self"); transplant matching | Autoimmune disease associations (HLA-DR2/DR3 → SLE [11]); transplant matching |
The immune system looks for differences in HLA to see if there is a need to react. The amount of difference between a donor's flags and the recipient's flags can really make a difference in whether or not a transplanted organ survives. Antibodies to a donor's flags can do considerable damage to a transplanted organ [8].
| Disease | HLA Association |
|---|---|
| Ankylosing spondylitis | HLA-B27 |
| Type 1 diabetes | HLA-DR3, DR4, DQ2, DQ8 |
| SLE | HLA-DR2, DR3 [11] |
| Coeliac disease | HLA-DQ2, DQ8 |
| Rheumatoid arthritis | HLA-DR4 (shared epitope) |
Three activation pathways converge on C3:
| Pathway | Trigger | Components |
|---|---|---|
| Classical | Antigen-antibody complexes (IgG, IgM) | C1q → C1r → C1s → C4 → C2 → C3 |
| Lectin (MBL) | Mannose on microbial surfaces | MBL → MASP → C4 → C2 → C3 |
| Alternative | Spontaneous C3 hydrolysis on microbial surface; amplification loop | C3 → Factor B → Factor D → C3 |
Terminal pathway: C5b → C6 → C7 → C8 → C9 = Membrane Attack Complex (MAC) → cell lysis.
Functions: Opsonisation (C3b), chemotaxis (C3a, C5a), anaphylatoxins (C3a, C4a, C5a → mast cell degranulation), MAC-mediated lysis, immune complex clearance.
Complement Deficiency Patterns
- Early classical (C1q, C2, C4) → Autoimmune disease (SLE) — because immune complexes are not cleared [3][12]
- C3 → Severe pyogenic infections (encapsulated bacteria)
- Terminal (C5–C9) → Neisseria infections (meningococcal disease) — MAC needed to kill Neisseria
- C1-inhibitor deficiency → Hereditary angioedema (not urticaria) [13]
Type 1 and Type 4 most commonly examined [9].
| Type | Name | Mechanism | Timing | Clinical Examples |
|---|---|---|---|---|
| I | IgE-mediated (immediate) | Allergen cross-links IgE on mast cells → degranulation → histamine release | Within 1 hour (mostly seconds to minutes) [9] | Anaphylaxis, allergic rhinitis, atopic asthma, urticaria (acute) |
| II | Antibody-dependent | IgG/IgM against cell-surface antigens → complement/ADCC → cell destruction | Hours to days | Haemolytic transfusion reaction, autoimmune haemolytic anaemia, Goodpasture's, haemolytic disease of newborn |
| III | Immune complex | Ag-Ab complexes deposit in tissues → complement activation → tissue damage | Hours to days (Arthus: 4-8h; serum sickness: 7-14d) | SLE, post-strep GN, serum sickness, Arthus reaction |
| IV | Delayed-type (T-cell mediated) | Sensitised T cells encounter antigen → cytokine release → tissue damage | Beyond 1 hour; typically 24-72 hours [9] | Contact dermatitis, TB skin test, drug reactions (SJS/TEN, DRESS), transplant rejection (chronic) |
To differentiate clinically during history: ask about Timing (< 1 hour = immediate; > 1 hour = delayed) and Type/Nature of the lesion (delayed reactions are more serious) [9].
Everything in Type I is mast cell, histamine-related. This is why after COVID vaccine you sit there for a while before leaving [9].
Management of Hypersensitivity (Key Points)
Anaphylaxis (severe Type I): IM adrenaline 0.5 mg Q5min, IV chlorpheniramine, IV hydrocortisone, mast cell tryptase (0h, 2h, 24h), observe ≥ 24h for biphasic reaction [14].
Drug hypersensitivity: Stop offending drug immediately. For SCAR (SJS/TEN, DRESS, AGEP), manage in burns unit / ICU as needed [14].
Immunodeficiency — Overview
Systemic diseases/conditions that affect immune functions [1]:
- Breaks in physical barriers (e.g. skin, mucosa)
- Diabetes mellitus
- Cirrhosis
- Autoimmune disease (e.g. SLE)
- Malignancy
- Transplantation
- Iron overload
- Splenectomy
- Drugs (e.g. steroids)
- Malnutrition
- Pregnancy
- Extremes of age
AIDS (acquired immunodeficiency syndrome) — caused by HIV — main problem is reduced CD4+ T cells; also affects other parts of the immune system [1].
From Felix PY Lai Pediatrics [12] and Jerry's immunodeficiencies [3]:
| Immune Component Affected | Typical Infections / Manifestations | Classic Examples | Key Investigations |
|---|---|---|---|
| Phagocytic defect | Catalase +ve bacteria and fungi; lymphadenitis, hepatosplenomegaly, impaired wound healing, soft tissue abscesses, gingivitis [12] | CGD (NADPH oxidase mutations) | DHR flow cytometry (oxidative burst), NBT test |
| B-cell defect (antibody) | Recurrent bacterial sinopulmonary infections (S. pneumoniae, H. influenzae); chronic diarrhoea (Giardia, Enterovirus); bronchiectasis; encapsulated bacteria [12] | X-linked agammaglobulinaemia (BTK mutation), CVID | Serum Ig levels, KREC on newborn screening [3] |
| T-cell defect | Recurrent viral infections (VZV, CMV, HSV); PCP; chronic diarrhoea; FTT; GVHD [12] | SCID, DiGeorge syndrome | Lymphocyte subsets, TREC on newborn screening [3] |
| Combined (T + B) | All of the above; severe, early-onset | SCID | Low ALC (< 2500/mL), low/zero T-cell count [3] |
| Complement defect | Angioedema; autoimmune disease (SLE); encapsulated bacteria [12] | C2 deficiency (commonest), terminal complement deficiency | CH50, AH50, individual complement levels |
High Yield PID Examples from Lectures
| PID | Gene / Inheritance | Key Features | Treatment |
|---|---|---|---|
| SCID | IL2RG (X-linked) | All infections; fatal without treatment | HSCT [3] |
| Wiskott-Aldrich Syndrome | WAS (X-linked) | Tetrad: Eczema, micro-thrombocytopenia, immunodeficiency, bloody diarrhoea [3] | HSCT |
| Hyper-IgE Syndrome | STAT3 (AD, LOF) | Massive cold Staph abscesses, pneumatoceles, high IgE/eosinophils | Septrin + IVIG + secukinumab [3] |
| X-linked agammaglobulinaemia | BTK (X-linked) | Recurrent bacteria after maternal IgG wanes (~6 months) | IVIG / SCIG [3] |
Autoimmunity arises from loss of self-tolerance:
- Central tolerance — deletion of self-reactive T/B cells in thymus/bone marrow.
- Peripheral tolerance — anergy, regulatory T cells, clonal deletion of autoreactive cells that escape central tolerance.
Breakdown causes the immune system to attack self-tissues:
SLE is primarily a disease with abnormalities in immune regulation and is thought to be secondary to a loss of self-tolerance. Mediators of SLE are autoantibodies. Phagocytosis and clearing of immune complexes are defective in SLE. B cells or plasma cells that make autoantibodies are more persistently activated and driven to maturation by B cell activating factor and by persistently activated T helper cells making B-supporting cytokines such as IL-6 and IL-10 [11].
Genetic predisposition at the MHC locus (HLA-DR2, HLA-DR3); hormonal factors (estrogen); environmental triggers [11].
Autoimmunity in Pregnancy
Pregnancy is associated with changes in immune system → some autoimmune diseases may worsen, some may improve. Autoantibodies can cross the placenta and affect the baby (e.g. congenital heart block from maternal anti-Ro/La; neonatal lupus) [15].
The immune system looks for differences in HLA to see if there is a need to react. The amount of difference between a donor's flags and the recipient's flags can really make a difference in whether or not a transplanted organ survives [8].
| Rejection Type | Timing | Mechanism |
|---|---|---|
| Hyperacute | Minutes to hours | Pre-formed anti-donor antibodies (anti-HLA or ABO incompatibility) → complement activation → vascular thrombosis |
| Acute | Days to weeks | T-cell mediated (cellular) or antibody-mediated (humoral) against donor HLA |
| Chronic | Months to years | Ongoing immune injury → fibrosis, transplant vasculopathy |
Crossmatch: Pre-transplant test mixing recipient serum with donor lymphocytes. If antibodies present → positive crossmatch → transplant contraindicated (risk of hyperacute rejection).
| Population | Key Immune Consideration |
|---|---|
| Neonates | Immature adaptive immunity; rely on maternal IgG (transplacental) and IgA (breast milk); high susceptibility to encapsulated organisms |
| Elderly | Immunosenescence: ↓T-cell diversity, ↓vaccine response, ↑autoimmunity risk |
| Pregnant | Shift towards Th2 dominance to prevent fetal rejection; ↑susceptibility to intracellular pathogens (Listeria, TB); some autoimmune diseases improve (RA), some worsen (SLE) [15] |
| Splenectomy | Loss of splenic macrophages → ↑risk of encapsulated organisms (S. pneumoniae, H. influenzae, N. meningitidis) → need vaccination pre-splenectomy [1] |
| HIV/AIDS | Reduced CD4+ T cells → opportunistic infections (PCP, CMV, Toxoplasma, MAC, Cryptococcus, Kaposi sarcoma) [1] |
| Post-transplant / immunosuppressed | Drug-induced immunodeficiency; susceptibility depends on agent (steroids → broad; anti-TNF → TB reactivation [6]; rituximab → hypogammaglobulinaemia) |
Healthy immune system should be able to contain TB → only 10% of patients with latent TB become active in lifetime. Anything reducing immune capabilities will increase risk of TB activation [16].
HIV and TB have a bi-directional relationship: HIV immunosuppression increases chance of obtaining TB; TB induces host TNF-α response which increases HIV viraemia. Co-infection has higher mortality [16].
Diagnostic challenges in immunocompromised: many tests rely on an intact host response (e.g. TST). Recommendation → early bronchoscopy for respiratory specimen for AFB [16].
S. aureus releases antigen/protein that causes the immune system to become even more abnormal (superantigen phenomenon). Getting rid of S. aureus will help patients → bleach bath or antiseptic [7].
Superantigens bypass normal antigen processing: they cross-link MHC class II on APCs directly with the Vβ region of the TCR → massive non-specific T-cell activation → cytokine storm. Examples: Staphylococcal TSST-1 (toxic shock syndrome), Streptococcal pyrogenic exotoxins.
Exam Approach
- "Compare and contrast innate vs adaptive immunity" → Use a table; emphasise specificity, memory, speed, diversity.
- "Describe the Th1/Th2 paradigm and the hygiene hypothesis" → Draw the differentiation pathway, explain reciprocal inhibition, link to atopic disease.
- "A child with recurrent infections — what pattern suggests B-cell vs T-cell vs phagocyte vs complement deficiency?" → Pattern recognition table is high-yield.
- "Classify hypersensitivity reactions" → Gell & Coombs with clinical examples and timing.
- "Explain why splenectomy increases infection risk" → Encapsulated organisms, loss of splenic macrophage filtration function.
Common Exam Pitfalls
- Confusing IgE sensitisation with clinical allergy — high IgE ≠ allergy; need symptoms on exposure.
- Forgetting that innate immunity has NO memory — NK cells are innate, not adaptive, despite being lymphocytes.
- Mixing up MHC class I vs II — Class I = all nucleated cells, CD8+ T cells; Class II = APCs, CD4+ T cells. Erythrocytes express NEITHER.
- Overlooking complement deficiency causing autoimmunity — early classical pathway deficiency → SLE (not just infections).
- Assuming HIV only affects CD4+ T cells — it also affects other parts of the immune system.
High Yield Summary
• Innate = immediate, non-specific, no memory (barriers, phagocytes, NK, complement, cytokines); Adaptive = delayed, specific, memory (T cells, B cells, antibodies). Innate stimulates adaptive.
• PAMPs recognised by PRRs (TLRs, NLRs, RLRs). MHC class I → CD8+ CTLs; MHC class II → CD4+ Th cells.
• Th1 (IFN-γ, IL-12) → cell-mediated / intracellular; Th2 (IL-4, IL-5) → humoral / IgE / parasites; Th17 (IL-23, IL-1β) → neutrophilic / mucosal. Reciprocal inhibition.
• Hygiene hypothesis: ↓Th1 stimulation → hyperactive Th2 → atopy.
• Complement: Classical (Ab-Ag), Lectin (MBL), Alternative (spontaneous). Early deficiency → SLE; terminal → Neisseria.
• Hypersensitivity: Type I (IgE, minutes), Type II (cytotoxic Ab), Type III (immune complex), Type IV (T-cell, delayed > 1h). Differentiate by timing and lesion nature.
• PID: B-cell defect → encapsulated bacteria; T-cell → viruses/PCP/fungi; Phagocyte → catalase +ve organisms; Complement → encapsulated bacteria + autoimmunity.
• Secondary immunodeficiency: HIV (CD4↓), drugs, DM, cirrhosis, malignancy, splenectomy, extremes of age, pregnancy, malnutrition.
• HLA matching crucial in transplant; anti-HLA antibodies → rejection.
• Immune system is a double-edged sword: defence vs allergy, autoimmunity, and malignancy.
Active Recall - Immune System Overview
[1] Lecture slides: GC 100. Defense against microbes.pdf (pp. 3–5, 30, 34–35) [2] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 169) [3] Senior notes: Jerry's immunodeficiencies.pdf (p. 2) [4] Senior notes: Ryan Ho Respiratory.pdf (p. 96) [5] Senior notes: Adrian Lui Pediatrics Notes.pdf (p. 169) [6] Senior notes: Block A - Treatments for skin diseases (eczema, psoriasis and urticaria).pdf (p. 35) [7] Senior notes: Block A - Treatments for skin diseases (eczema, psoriasis and urticaria).pdf (pp. 8–9) [8] Lecture slides: Laboratory Diagnostic Investigations Seminar_Tissue typing and transplant immunology_2025 - Dr J Kwok.pdf (pp. 105, 108, 128) [9] Senior notes: Block A - Fundamentals of Allergology.pdf (p. 3) [10] Lecture slides: Laboratory Diagnostic Investigations Seminar_Tissue typing and transplant immunology_2025 - Dr J Kwok.pdf (p. 18) [11] Senior notes: MBBS Final MB (Medicine) (Felix PY Lai).pdf (p. 1717); MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 711) [12] Senior notes: MBBS Final MB (Pediatrics) (Felix PY Lai).pdf (p. 639) [13] Lecture slides: GC 093. Urticaria, angioedema and anaphylaxis.pdf [14] Senior notes: Maksim Medicine Notes.pdf (p. 74) [15] Lecture slides: Adrian Lui Obstetric Notes.pdf (p. 116) [16] Senior notes: Gen Clerk Anaes + Microbiology Summary.pdf (p. 36)
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