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Innate immunity: immediate (minutes to hours), uses germline-encoded receptors, recognises common microbial patterns, has no lasting memory. Components: epithelial barriers, phagocytes, complement, NK cells, cytokines. Adaptive immunity: slower (days), uses somatically generated antigen receptors on lymphocytes (specific for one antigen), shows clonal expansion, memory and tolerance of self. Humoral immunity is mediated by antibodies from B cells; cell-mediated immunity by T cells. The two systems cooperate: innate cells activate lymphocytes, and antibodies and T cells recruit innate effectors.

Barriers: skin and mucosal epithelia, mucus, cilia, acidic secretions, antimicrobial peptides (defensins), and the commensal microbiota. Pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs; for example bacterial lipopolysaccharide, flagellin, viral double-stranded RNA) and damage-associated molecular patterns (DAMPs, released by injured cells). Toll-like receptors (TLRs) are on the cell surface or in endosomes; NOD-like receptors and the inflammasome act in the cytosol; RIG-I-like receptors detect viral RNA; C-type lectins bind carbohydrates. Signalling activates NF-kB and interferon regulatory factors, producing inflammatory cytokines and interferons.

Phagocytes: neutrophils (first to arrive, short-lived) and macrophages (tissue-resident, long-lived). Phagocytosis: recognition (often through opsonins such as antibody and C3b), engulfment into a phagosome, fusion with lysosomes and killing by reactive oxygen species (NADPH oxidase), nitric oxide and enzymes. Defective NADPH oxidase causes chronic granulomatous disease. Complement: plasma proteins activated in cascades: classical (antibody-antigen complexes, C1q), lectin and alternative pathways. All converge on C3 convertase. Effects: opsonisation (C3b), inflammation (C3a and C5a anaphylatoxins) and lysis by the membrane attack complex (C5b-9). NK cells kill cells that lack MHC class I (missing self) or express stress ligands, using perforin and granzymes, and secrete interferon-gamma. Interferons: type I (alpha and beta) induce an antiviral state in cells and activate NK cells.

1. Compare innate and adaptive immunity. 2. What are PAMPs and DAMPs? 3. What are the three effects of complement activation? 4. How do NK cells recognise their targets? 5. What is the role of type I interferons?

1. Innate: fast, non-specific, no memory. Adaptive: slow, antigen-specific, memory. 2. PAMPs: molecular patterns of microbes. DAMPs: molecules released by damaged host cells. 3. Opsonisation, inflammation and cell lysis. 4. By missing MHC class I or stress ligands. 5. They induce an antiviral state and activate NK cells.

MHC (HLA in humans) genes are the most polymorphic in the genome, and each person expresses several alleles. - MHC class I (on all nucleated cells): peptides from cytosolic proteins, generated by the proteasome, transported by TAP into the endoplasmic reticulum, loaded onto class I; recognised by CD8 T cells. - MHC class II (on antigen-presenting cells: dendritic cells, macrophages, B cells): peptides from endocytosed proteins, loaded in endosomes after the invariant chain is removed; recognised by CD4 T cells. - Cross-presentation: dendritic cells present exogenous antigen on class I, which is key for anti-tumour and antiviral CD8 responses. Dendritic cells are the most potent antigen-presenting cells: they capture antigen, migrate to lymph nodes and provide co-stimulation (B7 to CD28).

T cell receptor (TCR): alpha and beta chains, recognises peptide bound to MHC, signals through CD3. Antibody (immunoglobulin): two heavy and two light chains; variable regions (Fab) bind antigen, and the constant region (Fc) defines the class and functions. Classes: IgM (first response, pentamer, activates complement), IgG (main serum antibody, crosses the placenta, opsonises), IgA (mucosal secretions, milk), IgE (mast cell sensitisation, allergy and parasites), IgD. Diversity: V(D)J recombination (RAG1/2 enzymes) combines gene segments; junctional diversity adds more; B cells also undergo somatic hypermutation and class switching (from IgM to other classes, controlled by cytokines, using activation-induced deaminase).

T cells develop in the thymus. Positive selection (cortex) keeps thymocytes whose TCR recognises self-MHC weakly; negative selection (medulla) deletes those binding self peptides strongly (with the transcription factor AIRE expressing tissue antigens). Cells become CD4 or CD8 single positive. B cells develop in the bone marrow, with negative selection of self-reactive clones (receptor editing or deletion). Failure of tolerance leads to autoimmunity.

1. Compare the class I and class II pathways. 2. Name the classes of antibody and one function of each. 3. How does V(D)J recombination generate diversity? 4. What is negative selection? 5. What is cross-presentation?

1. Class I: cytosolic peptides, proteasome and TAP, on all nucleated cells, to CD8 T cells. Class II: endocytosed peptides, on antigen-presenting cells, to CD4 T cells. 2. IgM: early response and complement; IgG: opsonisation and placental transfer; IgA: mucosal defence; IgE: allergy and parasites; IgD: B-cell receptor. 3. Random joining of V, D and J gene segments plus junctional additions. 4. Deletion of thymocytes with high affinity for self peptide-MHC. 5. Presentation of exogenous antigen on MHC class I by dendritic cells.

CD4 helper subsets: Th1 (interferon-gamma; macrophage activation, intracellular microbes), Th2 (IL-4, IL-5, IL-13; parasites, IgE, eosinophils, allergy), Th17 (IL-17; neutrophils, extracellular bacteria and fungi), Tfh (help B cells in germinal centres). Cytotoxic T lymphocytes (CD8) kill infected or tumour cells through perforin and granzymes and Fas ligand. B cell response: T-dependent antigens trigger germinal centre formation in lymph node follicles, with clonal expansion, somatic hypermutation, affinity maturation, class switching and generation of plasma cells and memory B cells.

Regulatory T cells (FOXP3+) suppress responses using IL-10, TGF-beta and CTLA-4. Mutation of FOXP3 causes the IPEX syndrome. Immune checkpoints (CTLA-4, PD-1 and its ligand PD-L1) provide inhibitory signals; blocking them with monoclonal antibodies enhances anti-tumour immunity but can cause autoimmune side effects. Peripheral tolerance mechanisms: anergy (no co-stimulation), deletion by activation-induced cell death, suppression by Tregs and immune privilege in some sites.

- Extracellular bacteria: antibodies, complement, phagocytosis, Th17 and neutrophils. - Intracellular bacteria (Mycobacterium tuberculosis): Th1 and macrophage activation; granuloma formation. - Viruses: type I interferons, NK cells, CD8 T cells, neutralising antibodies. - Fungi: Th17 and neutrophils. - Parasites: Th2, IgE and eosinophils for helminths. Evasion: antigenic variation (influenza, trypanosomes), inhibition of MHC expression (herpes viruses), inhibition of complement, resistance to phagocytosis (capsules), and infecting immune cells (HIV).

1. Name the CD4 helper subsets and their main roles. 2. How do CTLs kill? 3. What is the role of PD-1? 4. What do germinal centres produce? 5. How do herpes viruses evade CD8 T cells?

1. Th1: intracellular microbes; Th2: parasites and allergy; Th17: extracellular bacteria and fungi; Tfh: help B cells. 2. Perforin and granzymes, and Fas ligand. 3. An inhibitory checkpoint receptor on T cells that limits the response. 4. High-affinity class-switched antibodies, plasma cells and memory B cells. 5. They reduce MHC class I expression on infected cells.

- Type I (immediate): IgE on mast cells, degranulation on allergen re-exposure (anaphylaxis, asthma, hay fever, food allergy). Treatment: antihistamines, adrenaline in anaphylaxis, allergen immunotherapy. - Type II (antibody against cell or tissue antigens): complement and phagocyte mediated (haemolytic transfusion reaction, autoimmune haemolytic anaemia, Goodpasture syndrome), or receptor stimulation or blocking (Graves disease, myasthenia gravis). - Type III (immune complexes): deposit in tissues and activate complement (serum sickness, lupus nephritis, post-streptococcal glomerulonephritis). - Type IV (delayed, T cell mediated): 24-72 hours (tuberculin test, contact dermatitis, type 1 diabetes, multiple sclerosis).

Primary (inherited): severe combined immunodeficiency (T and B defects; adenosine deaminase deficiency, X-linked common gamma chain), X-linked agammaglobulinaemia (Bruton tyrosine kinase; recurrent bacterial infections), DiGeorge syndrome (thymic aplasia), chronic granulomatous disease, complement deficiencies (terminal component: Neisseria infections), selective IgA deficiency (the most common). Secondary (acquired): HIV infection (loss of CD4 T cells), malnutrition, cancer and chemotherapy, immunosuppressive drugs, splenectomy. Pattern: antibody defects give recurrent bacterial sinopulmonary infections; T cell defects give opportunistic viral, fungal and protozoal infections.

Transplantation: alloreactive T cells recognise donor MHC. Hyperacute rejection (pre-existing antibodies, minutes to hours), acute rejection (T cells, days to weeks), chronic rejection (months to years, vascular changes). HLA matching and immunosuppression (calcineurin inhibitors such as ciclosporin and tacrolimus, mycophenolate, corticosteroids) prevent rejection. Graft-versus-host disease occurs after bone marrow transplantation. Tumour immunity: tumour antigens (mutated proteins, viral antigens, overexpressed self proteins) are recognised by CD8 T cells and NK cells. Tumours escape by losing MHC class I, secreting immunosuppressive factors and engaging checkpoints. Immunotherapy includes checkpoint inhibitors, CAR T cells and cancer vaccines.

1. Which hypersensitivity type causes anaphylaxis? 2. Give an example of a type III reaction. 3. What infections occur with antibody deficiency and T cell deficiency? 4. What is hyperacute rejection? 5. How can tumours escape T cells?

1. Type I (IgE mediated). 2. Serum sickness, lupus nephritis or post-streptococcal glomerulonephritis. 3. Antibody deficiency: recurrent bacterial infections. T cell deficiency: opportunistic viral, fungal and protozoal infections. 4. Rejection within minutes to hours caused by pre-existing antibodies against donor antigens. 5. By downregulating MHC class I, secreting immunosuppressive molecules and using checkpoint pathways.