The immune system

The immune system has two complementary arms:

1. Innate (non-specific) immunity. Present from birth, acts within minutes to hours, attacks any pathogen recognised as non-self without prior exposure. Includes:

• Physical barriers — skin, mucus, ciliated epithelium, gastric acid.
• Cellular defence — phagocytes (neutrophils, macrophages, dendritic cells).
• Soluble defences — complement, lysozyme in tears and saliva, antimicrobial peptides.

2. Adaptive (specific) immunity. Develops over days, acts against a specific pathogen, generates memory for faster responses on re-exposure. Carried out by lymphocytes — B cells (humoral response) and T cells (cell-mediated response).

The two systems are deeply connected: phagocytes such as macrophages and dendritic cells act as antigen-presenting cells (APCs), displaying digested pathogen fragments on MHC class II to activate T helper cells — thus bridging innate and adaptive immunity.

The key idea is self vs non-self recognition: all the body's own cells carry MHC (major histocompatibility complex) molecules — 'self markers' — that distinguish them from pathogens. The immune system attacks anything that lacks the correct self markers or carries foreign antigens.

Phagocytes are white blood cells that engulf and digest pathogens. The two main types:

Neutrophils — the most abundant white blood cell (~60% of WBCs). Recognisable by their multi-lobed nucleus (typically 3-5 lobes) and granular cytoplasm. Short-lived (a few days); patrol blood and are first to arrive at infection sites in large numbers. Their lysosomes are packed with hydrolytic enzymes.

Macrophages — derived from monocytes (which leave the blood and differentiate in tissues). Larger and longer-lived than neutrophils, with a kidney-shaped nucleus. Found in tissues — alveolar macrophages in lungs, Kupffer cells in liver, microglia in brain. Crucially, macrophages also act as antigen-presenting cells (APCs).

Steps of phagocytosis:

1. Chemotaxis. Phagocytes detect chemical signals released at the infection site — chemokines from infected tissue, complement components (especially C5a) and bacterial chemicals such as formyl-methionine peptides. They migrate up the concentration gradient towards the pathogen.
2. Recognition + attachment. Receptors on the phagocyte's surface (Toll-like receptors, complement receptors, antibody Fc receptors) recognise non-self surface markers, or recognise antibodies/complement proteins coating the pathogen (opsonisation). This greatly enhances engulfment.
3. Engulfment (endocytosis). The phagocyte's membrane extends pseudopodia around the pathogen and folds inwards. The pathogen ends up enclosed in a vesicle called a phagosome.
4. Lysosome fusion. Cytoplasmic lysosomes — vesicles containing hydrolytic enzymes (proteases, lipases, lysozyme) at low pH (~5) — fuse with the phagosome to form a phagolysosome.
5. Digestion + expulsion. Hydrolytic enzymes digest the pathogen into small soluble products. Useful products are absorbed; debris is exocytosed.
6. Antigen presentation (macrophages and dendritic cells). Pathogen antigen fragments are displayed on MHC class II on the phagocyte's surface. T helper cells with complementary receptors recognise the antigen-MHC complex and are activated, triggering the adaptive immune response.

Lymphocytes carry out the specific (adaptive) immune response. Both B and T lymphocytes are produced in the bone marrow. They differ in where they mature:

• B lymphocytes mature in the bone marrow (B for bone).
• T lymphocytes mature in the thymus (T for thymus).

Mature B and T cells circulate in blood and lymph and accumulate in lymphoid organs (lymph nodes, spleen, MALT). Each lymphocyte carries thousands of identical receptors on its surface — B-cell receptors (membrane-bound antibodies) on B cells, T-cell receptors (TCRs) on T cells. Each lymphocyte's receptor is specific for one antigen, generated by random rearrangement of gene segments during maturation. The total lymphocyte population in the body carries an enormous variety of receptors — perhaps $10^{11}$ different specificities — so that some lymphocyte exists for almost any antigen.

B cells (humoral response).

A B cell with a receptor complementary to a specific antigen binds the antigen. With help from T helper cell cytokines, the B cell is activated and undergoes clonal selection and clonal expansion by mitosis. Daughter cells differentiate into:

• Plasma cells — antibody factories. Short-lived (days) but secrete up to 2000 antibodies per second. Plasma cells have huge amounts of rough endoplasmic reticulum to support this protein synthesis.
• Memory B cells — long-lived (years to decades), give faster secondary response on re-exposure.

B cells fight pathogens in body fluids ('humoral') by producing antibodies that mark, neutralise, agglutinate or activate complement on pathogens.

T cells (cell-mediated response).

T cells act on cells — infected host cells, cancerous cells, transplanted tissue — rather than free pathogens. Two main subtypes:

• T helper cells (CD4+) recognise antigen on MHC class II of antigen-presenting cells. On activation, they undergo clonal expansion and release cytokines that:
  • Activate B cells to differentiate into plasma cells.
  • Activate cytotoxic T cells.
  • Stimulate phagocytes. Memory T helper cells also formed. These cells are the central coordinators of the immune response — destroying them (as HIV does) causes the immune collapse seen in AIDS.
• T cytotoxic cells (CD8+) recognise antigen on MHC class I of infected (or cancerous) host cells. They release perforin (forms pores in the target cell membrane) and granzymes (enter through the pores and trigger apoptosis). Killing infected cells eliminates the source of new virus.
• Memory T cells also formed, giving long-lasting cell-mediated memory.

Clonal selection describes how the immune system uses an enormous pre-existing diversity of lymphocytes rather than making new ones in response to each antigen. Among the body's lymphocytes there is already one (or a few) cell whose receptor happens to be complementary to any incoming antigen. When the antigen arrives, it selects that rare specific cell out of the population — like finding a key for a lock.

Clonal expansion is what happens next: the selected lymphocyte undergoes rapid mitosis, generating thousands of identical daughter cells with the same receptor. Some of these daughters differentiate into effector cells (plasma cells, active T helper, active T cytotoxic) that act immediately; some become memory cells that persist for years.

Because the specific lymphocyte was rare to begin with (~1 in $10^6$), clonal expansion takes time — this is why the primary response has a long lag (5-10 days) before significant antibody appears. Once memory cells are abundant, secondary expansion is much faster.

The body's first encounter with a new antigen triggers a primary response:

• Lag phase of 5-10 days — the rare specific B and T cells must be found and undergo clonal selection and expansion.
• Antibody concentration rises slowly, peaks at a relatively low level after about two weeks, then declines.
• During this response, in addition to plasma and effector T cells, memory B and T cells are produced. These long-lived cells persist for years to decades in the blood, lymph and bone marrow, in much greater numbers than the original rare specific lymphocytes.

A second encounter with the same antigen triggers a secondary response:

• Memory cells are activated immediately — no time wasted searching for rare specific cells.
• Lag is much shorter (1-3 days).
• Antibody concentration rises rapidly and reaches a much higher peak (often 10-100× that of the primary response).
• Antibodies are also of higher affinity (affinity maturation in memory B cells).
• The pathogen is usually eliminated before symptoms appear — the host is immune.

A typical exam graph of antibody concentration vs time has TWO curves — a small primary peak followed by a large, fast secondary peak after re-exposure to the same antigen. If a different antigen is added at the time of re-exposure, only its own (small) primary response is seen — memory is antigen-specific.

This is the basis of vaccination: deliver a non-disease-causing form of the antigen to trigger a primary response and produce memory cells, so that real exposure is met with a rapid secondary response.

Every nucleated cell in the body carries MHC (major histocompatibility complex) molecules — also called self markers — on its surface. MHC molecules are encoded by a highly variable cluster of genes; the combination expressed by each individual is essentially unique (identical twins excepted). MHC molecules display short peptide fragments (~8-12 amino acids) of the cell's internal proteins on the cell surface.

There are two main classes:

• MHC class I — on virtually all nucleated cells. Displays peptides from inside the cell (e.g. viral proteins if the cell is infected). Recognised by T cytotoxic cells (CD8+).
• MHC class II — on antigen-presenting cells (macrophages, dendritic cells, B cells). Displays peptides from external sources (engulfed pathogens). Recognised by T helper cells (CD4+).

During lymphocyte maturation, lymphocytes whose receptors strongly bind self antigens (presented on MHC) are eliminated by apoptosis — a process called clonal deletion or negative selection, in the bone marrow (B cells) and thymus (T cells). The mature lymphocyte repertoire is therefore self-tolerant.

When mature lymphocytes encounter cells displaying non-self antigens — pathogens, cancer-altered antigens, donated organs with different MHC — they recognise the foreign material and trigger an immune response. Transplant rejection is the result of recipient T cells attacking the donor's MHC.

Autoimmune disease. When self-tolerance fails — through escape of self-reactive lymphocytes, breakdown of regulation or molecular mimicry by a pathogen — lymphocytes attack the body's own cells. Examples in the Cambridge specification:

• Type 1 diabetes — T cytotoxic cells destroy insulin-producing β-cells in the pancreatic islets.
• Rheumatoid arthritis — immune attack on the synovium (joint lining) causes chronic inflammation and joint destruction.
• Multiple sclerosis — attack on the myelin sheath of CNS neurones causes patchy demyelination and neurological disability.
• Lupus, Graves' disease, Hashimoto's thyroiditis — further examples.

Treatment of autoimmune disease typically involves immunosuppressive drugs (e.g. corticosteroids, methotrexate, biologics such as anti-TNF antibodies).