Immune system

All immune cells arise from haematopoietic stem cells. Primary (central) lymphoid organs are where lymphocytes are produced and become mature but antigen-naive. Secondary (peripheral) lymphoid organs are where naive lymphocytes meet antigen and where adaptive responses start.

Cells of the myeloid lineage (neutrophils, eosinophils, basophils, mast cells, monocytes/macrophages, most dendritic cells) mainly drive innate responses. Cells of the lymphoid lineage are B cells, T cells (CD4 helper, CD8 cytotoxic) and NK cells. Dendritic cells are the most efficient antigen-presenting cells for activating naive T cells, and they link innate and adaptive immunity.

Innate immunity is immediate, uses germline-encoded receptors and has no antigen-specific memory. The first lines are barriers: skin, mucus, cilia, low gastric pH, lysozyme, defensins and commensal flora. When these are breached, pattern-recognition receptors (PRRs) detect conserved microbial molecules (PAMPs) or damage signals (DAMPs).

TLR signalling through adaptor proteins activates NF-κB, which switches on genes for inflammatory cytokines (TNF-α, IL-1, IL-6) and co-stimulatory molecules. All TLRs except TLR3 use the adaptor MyD88; TLR3 uses TRIF, and TLR4 can use both. Sensing of viral nucleic acid also activates IRF transcription factors and type I interferons.

The main phagocytes are neutrophils (short-lived, first to arrive at a site of infection) and macrophages (long-lived, and they also present antigen to T cells).

NK cells are lymphocytes without antigen-specific receptors. They kill virus-infected and tumour cells that have lost MHC class I (the 'missing self' idea), because their inhibitory receptors then go unengaged, and they are triggered by activating receptors (for example NKG2D) that bind stress-induced ligands. They kill with perforin and granzymes, secrete IFN-γ, and can perform antibody-dependent cellular cytotoxicity (ADCC) through the Fc receptor CD16 (FcγRIII).

Inflammation shows redness, heat, swelling and pain. Mast cells and macrophages release histamine, prostaglandins, leukotrienes and cytokines; bradykinin comes from the kinin system. Vasodilation and increased vascular permeability bring fluid, complement and antibodies into the tissue. In the liver, IL-6 (with IL-1 and TNF-α) induces acute-phase proteins such as C-reactive protein, serum amyloid A, fibrinogen and mannose-binding lectin.

Cytokines are small secreted proteins that act on cells through specific receptors, locally (autocrine, paracrine) or sometimes systemically (endocrine). They are pleiotropic (one cytokine, many effects) and redundant (different cytokines, same effect), and they can act in synergy or antagonism. Chemokines are a family of small cytokines that direct cell migration by binding G-protein-coupled receptors; they are grouped by their conserved cysteines into CC, CXC, CX3C and C classes.

Complement is a set of plasma proteins, made mainly by the liver, that are activated in a cascade of proteolytic cleavages. Convention: the smaller fragment of a cleaved component is 'a' and the larger is 'b' (so C3a is small and C3b large). The exception here is C2a, which is taken as the larger fragment, giving the classical convertase as C4b2a. Some texts instead call the larger C2 fragment C2b and write the convertase as C4b2b. All three pathways converge on cleavage of C3.

C1q is activated only when it binds at least two Fc regions close together. One antigen-bound pentameric IgM is therefore enough, but IgG must be bound at two neighbouring sites on the antigen.

An antibody (immunoglobulin) is a Y-shaped molecule of two identical heavy (H) chains and two identical light (L) chains joined by disulphide bonds. Each chain has a variable (V) domain and constant (C) domains. The V domains of an H and an L chain together form one antigen-binding site. Within each V domain, three complementarity-determining regions (CDRs) are the hypervariable loops that contact the antigen, so each site has six CDRs. IgG, IgA and IgD have three CH domains and a flexible hinge between CH1 and CH2; IgM and IgE have four CH domains and no hinge. Light chains are κ or λ (never both in one antibody); the heavy-chain type defines the class.

The body makes an enormous repertoire of antibodies from a limited number of genes. In the germline, the genes for the V region are split into segments. In developing B cells, V(D)J recombination joins one V, one D and one J segment for the heavy chain, and one V and one J segment for each light chain (κ or λ). Light chains have no D segments.

After antigen activates a mature B cell (with T-cell help) in a germinal centre, two further changes occur. Both need activation-induced cytidine deaminase (AID), which deaminates cytosine to uracil in DNA; RAG proteins are not involved.

Cytokines direct which class is chosen: IL-4 leads to IgE (and IgG4 in humans), IFN-γ favours IgG classes, TGF-β favours IgA. A naive B cell expresses IgM and IgD together from one long transcript by alternative splicing; this needs no DNA change. Defects in CD40L or in AID cause hyper-IgM syndrome, with high IgM and little IgG, IgA or IgE.

Humoral immunity is mediated by antibodies: neutralisation of toxins and viruses, opsonisation for phagocytosis, complement activation and ADCC. Most protein antigens need T-cell help: a CD4 follicular helper T cell recognises peptide on the B cell's MHC class II and delivers CD40L and cytokines (such as IL-21). This leads to antibody production, memory B cells and plasma cells. Cell-mediated immunity is mediated by T cells and the macrophages they activate.

MHC class I is on almost all nucleated cells and presents peptides from cytosolic (endogenous) proteins to CD8 T cells. MHC class II is on professional antigen-presenting cells (dendritic cells, macrophages, B cells) and presents peptides from endocytosed (exogenous) proteins to CD4 T cells.

T-independent antigens, such as bacterial polysaccharides and LPS, carry many repeated epitopes that cross-link B-cell receptors and activate B cells without T-cell help. The response is mainly IgM, with little class switching, little affinity maturation and little memory.

A polyclonal antibody preparation (for example, antiserum from an immunised animal) is a mixture of antibodies from many B-cell clones, recognising many epitopes of one antigen. A monoclonal antibody comes from a single B-cell clone: every molecule is identical and binds one epitope.

Monoclonal antibodies are used in diagnostics (ELISA, immunofluorescence, flow cytometry, pregnancy tests), in affinity purification and in therapy. Mouse antibodies trigger an immune response in humans, so therapeutic antibodies are engineered: chimeric (mouse V region, human C region), humanised (only the CDRs, with a few framework residues, from mouse) or fully human (from transgenic mice or phage display). The naming scheme used for most antibodies approved so far marks these with the endings -omab (mouse), -ximab (chimeric), -zumab (humanised) and -umab (human); newer names follow a revised scheme without these markers. Polyclonal antibodies are used for antivenoms and antitoxins, and as secondary antibodies in detection.