Immunology Basics

The immune system defends the body against pathogens, cancer cells, and foreign material while maintaining tolerance to self-tissues. It has two interconnected branches: the innate immune system (rapid, non-specific, no memory) and the adaptive immune system (slower, highly specific, immunological memory).

Innate Immunity

Innate immunity provides immediate (minutes to hours) defence through physical barriers, cellular responses, and soluble mediators. Physical barriers include the intact skin (acidic pH, antimicrobial peptides such as defensins and cathelicidins), mucous membranes, mucociliary escalator, and normal flora that compete with pathogens.

Pattern recognition receptors (PRRs) on innate immune cells detect conserved molecular patterns shared by pathogens but absent from host cells. Toll-like receptors (TLRs) are the prototypic PRRs: TLR4 recognises LPS (with MD2 co-receptor) on macrophage surface; TLR3 recognises dsRNA (viral replication intermediate) in endosomes; TLR9 recognises unmethylated CpG DNA (bacterial/viral) in endosomes. TLR signalling via MyD88 adaptor → IRAK → TRAF6 → IKK → NF-κB activation → pro-inflammatory cytokine transcription (TNF-α, IL-1β, IL-6, IL-12). NOD-like receptors (NLRs) detect intracellular pathogens; NLRP3 forms the inflammasome → caspase-1 activation → IL-1β and IL-18 processing and secretion. RIG-I and MDA5 (RLRs) detect cytoplasmic viral RNA → IRF3/7 phosphorylation → type I interferon (IFN-α/β) production → antiviral state in neighbouring cells.

Innate immune cells: Neutrophils are the most abundant circulating white blood cells (~50–70% of WBCs, 2–7 × 10⁹/L) and are the first responders to infection. They are recruited by chemokines (IL-8/CXCL8, fMLP, C5a) and kill pathogens by: phagocytosis, oxidative burst (NADPH oxidase generates superoxide O₂⁻ → H₂O₂ → myeloperoxidase converts to HOCl), degranulation (proteases, defensins, lactoferrin in granules), and NETs (neutrophil extracellular traps — chromatin + granule proteins). Macrophages are tissue-resident phagocytes (Kupffer cells in liver, microglia in CNS, alveolar macrophages, peritoneal macrophages) derived from monocytes. They phagocytose opsonised pathogens (IgG via FcγR; complement C3b via CR1), kill intracellular organisms, and present antigens. M1 polarisation (LPS + IFN-γ): pro-inflammatory (TNF-α, IL-12, NO). M2 polarisation (IL-4, IL-13): anti-inflammatory, wound healing. Natural killer (NK) cells are cytotoxic lymphocytes of the innate system that kill cells lacking MHC class I (the "missing self" hypothesis) — cancer cells and virus-infected cells that downregulate MHC I to evade CD8⁺ T cells. NK cells release perforin and granzymes. Dendritic cells (DCs) are professional antigen-presenting cells (APCs) that bridge innate and adaptive immunity: they phagocytose pathogens in peripheral tissues, migrate to lymph nodes, and present antigens to naïve T cells.

Complement system: ~30 plasma proteins that can be activated by three pathways — classical (IgM or IgG-antigen complexes activate C1q → C4 → C2 → C3); lectin (mannose-binding lectin binds to mannose on pathogens → MASP-1/2 → C4 → C2 → C3); and alternative (spontaneous C3 hydrolysis on pathogen surfaces). All pathways converge on C3 cleavage to C3a (anaphylatoxin, mast cell degranulation) and C3b (opsonin, binds CR1 on phagocytes). C5 cleavage gives C5a (potent anaphylatoxin and chemotactic factor) and C5b → membrane attack complex (MAC: C5b-6-7-8-9) → pore in bacterial membrane → lysis. Complement deficiency: C3 deficiency → severe bacterial infections; C5-C9 deficiency → Neisseria infections; DAF/CD55 deficiency → paroxysmal nocturnal haemoglobinuria (PNH, complement-mediated haemolysis — treated with eculizumab, anti-C5 antibody).

Adaptive Immunity

Adaptive immunity develops over days–weeks, is highly specific (single antigen epitope), and generates immunological memory (faster, stronger response upon re-exposure). Two major arms: humoral immunity (B cells → antibody production) and cell-mediated immunity (T cells → cytotoxic killing, macrophage activation).

Lymphocyte development: B cells mature in the bone marrow; T cells mature in the thymus. Both undergo somatic DNA recombination (V(D)J recombination) of immunoglobulin (B cells) or TCR (T cells) gene segments by RAG1/RAG2 enzymes → generates vast diversity of antigen receptors (~10¹⁵ different specificities). B cells undergo positive selection (light chain/heavy chain pairing) and negative selection (deletion of autoreactive B cells). T cells undergo positive selection (TCR must recognise self-MHC in the thymic cortex) and negative selection (deletion of T cells with high-affinity TCR for self-MHC + self-peptide in the thymic medulla, mediated by AIRE — autoimmune regulator; AIRE mutations cause APS-1, autoimmune polyendocrinopathy candidiasis ectodermal dystrophy).

T cell activation: Requires two signals from an APC. Signal 1: TCR recognises specific antigen peptide presented in MHC groove (MHC I for CD8⁺ T cells; MHC II for CD4⁺ T cells) → TCR-CD3 complex signalling + co-receptor (CD8 or CD4) binding to MHC. Signal 2 (co-stimulation): CD28 on T cell binds B7 (CD80/CD86) on APC → PI3K/Akt and PKC activation → IL-2 production and proliferation. Without signal 2 → anergy (clonal tolerance). Signal 3: cytokine milieu determines T helper (Th) subset differentiation: IL-12 + IFN-γ → Th1 (produces IFN-γ, activates macrophages, cell-mediated immunity); IL-4 → Th2 (produces IL-4, IL-5, IL-13, drives B cell isotype switching to IgE, eosinophil activation, anti-helminth/allergy); TGF-β + IL-6 → Th17 (produces IL-17, IL-22, mucosal immunity, autoimmunity); TGF-β alone → regulatory T cells (Tregs, FOXP3⁺, suppress autoimmunity). CTLA-4 (CD152) is an inhibitory receptor that competes with CD28 for B7 binding and dampens T cell activation — ipilimumab (anti-CTLA-4) removes this brake to enhance anti-tumour immunity. PD-1 (CD279) is expressed on activated T cells; its ligand PD-L1 (CD274) on tumour cells or APCs delivers an inhibitory signal — pembrolizumab, nivolumab (anti-PD-1), atezolizumab (anti-PD-L1) are checkpoint inhibitors used in multiple cancers.

B cell activation and antibody production: B cells recognise antigen via the BCR (surface immunoglobulin). T-dependent antigens (most proteins) require T cell help: antigen-specific Th2/Tfh cells provide CD40L (binds CD40 on B cell — essential co-stimulatory signal) and cytokines → B cell proliferation, somatic hypermutation (affinity maturation in germinal centres), class-switch recombination (IgM → IgG/IgA/IgE/IgD), and plasma cell/memory B cell differentiation.

Antibody structure and function: IgG (150 kDa): four chains (2 heavy, 2 light) linked by disulfide bonds; Fab region contains CDRs (antigen-binding); Fc region mediates effector functions (opsonisation via FcγR, complement activation via C1q, ADCC). Five isotypes: IgM (pentamer, first response, fixes complement), IgG (most abundant, secondary response, placental transfer, memory), IgA (dimer in secretions, mucosal immunity), IgE (mast cell/basophil binding, allergy, anti-parasite), IgD (B cell surface signalling).