Unit 1: Fundamentals of the immune system

I. Orientation: the immune system as a defence network

The immune system is the collection of cells, tissues, and soluble molecules that discriminate self from non-self and neutralise pathogens, damaged cells, and malignancies. It operates across two integrated tiers — rapid non-specific defence and slower antigen-specific defence — both drawn from a common cellular origin in the bone marrow.

• Antigen: any molecule recognised by lymphocyte receptors or antibody; typically a protein or polysaccharide with a defined epitope (the exact bound region).
• Self/non-self discrimination: governed by MHC (major histocompatibility complex) molecules displaying peptides; failure produces autoimmunity.
• Clonal selection: each lymphocyte bears one receptor specificity; antigen binding drives proliferation of that clone alone.
• Immunological memory: re-exposure gives a faster, larger response — the basis of vaccination.
• Two-tier design: innate immunity (immediate, fixed) supports and instructs adaptive immunity (delayed, specific, memory-forming).

II. Types of Immunity

Innate and adaptive arms of defence

Immunity is classified by whether protection is inborn or acquired, and by whether it is generated actively or transferred passively.

A. Innate versus adaptive immunity

Two contrasting arms differ in speed, specificity, and memory.

1. Innate (natural) immunity: present from birth, responds within minutes to hours.
   • Barriers: skin keratin, mucus, lysozyme in tears, low stomach pH (~2).
   • Recognition: pattern-recognition receptors (e.g. Toll-like receptors) detect conserved PAMPs such as bacterial LPS.
   • No memory: identical response on every exposure.
2. Adaptive (acquired) immunity: develops over 4–7 days on first exposure.
   • Specificity: unique receptors generated by V(D)J recombination.
   • Memory: long-lived memory cells give an anamnestic secondary response.

B. Active and passive immunity

Acquired immunity is subdivided by the source of the protective agent.

• Active immunity: host's own immune system is stimulated to make antibodies — via infection (natural) or vaccination (artificial); durable because memory forms.
• Passive immunity: pre-formed antibodies are transferred — maternal IgG across the placenta and IgA in milk (natural), or antiserum injection such as anti-tetanus immunoglobulin (artificial); immediate but short-lived (weeks), with no memory.

III. Differentiation of Stem Cells

Haematopoiesis and lineage commitment

All immune cells arise from a single pluripotent haematopoietic stem cell (HSC) in the bone marrow through progressive lineage restriction.

A. Differentiation of stem cells

Haematopoiesis proceeds from self-renewing HSC to committed progenitors under cytokine control.

• Pluripotent HSC: self-renews and gives rise to two committed progenitors.
• Common myeloid progenitor (CMP): yields erythrocytes, platelets (from megakaryocytes), granulocytes, monocytes, and mast cells.
• Common lymphoid progenitor (CLP): yields T cells, B cells, NK cells, and some dendritic cells.
• Cytokine regulation: growth factors direct fate — e.g. erythropoietin drives red-cell lineage, IL-7 drives lymphoid commitment, GM-CSF drives granulocyte/monocyte output.

IV. Cells of the Immune System

Effectors of innate and adaptive defence

The functional cells divide into myeloid effectors (mostly innate) and lymphoid cells (mostly adaptive), each identified by morphology and surface markers.

A. Cells of the immune system

Each cell type carries out a defined role signalled by characteristic CD markers.

• Neutrophils: most abundant leukocyte (~60%); multilobed nucleus; phagocytose bacteria and form the pus of acute inflammation.
• Macrophages: tissue-resident phagocytes derived from blood monocytes; phagocytose debris and act as antigen-presenting cells (APCs).
• Dendritic cells: the most potent APC; capture antigen in tissues and migrate to lymph nodes to prime naïve T cells.
• Eosinophils and basophils: eosinophils attack helminths; basophils and tissue mast cells release histamine in allergy.
• T lymphocytes: thymus-matured; CD4⁺ helper T cells coordinate responses via cytokines, CD8⁺ cytotoxic T cells kill infected cells.
• B lymphocytes: carry surface immunoglobulin; differentiate into antibody-secreting plasma cells.
• Natural killer (NK) cells: large granular lymphocytes that kill virus-infected and tumour cells lacking normal MHC-I, without prior sensitisation.

V. Primary Lymphoid Organs

Sites of lymphocyte generation and maturation

Primary (central) lymphoid organs are where lymphocytes are produced and mature into functional, self-tolerant cells before antigen contact.

A. Primary lymphoid organs

Two organs supply the immune repertoire and enforce self-tolerance.

1. Bone marrow: site of all haematopoiesis and of complete B-cell maturation.
   • B-cell selection: immature B cells binding self-antigen strongly are deleted (negative selection) to prevent autoreactivity.
   • Output: mature naïve B cells and all progenitors exit via blood.
2. Thymus: bilobed organ above the heart where T cells mature; most active before puberty, then involutes.
   • Positive selection: thymocytes able to recognise self-MHC in the cortex survive.
   • Negative selection: thymocytes reacting strongly to self-peptide in the medulla are deleted.
   • Outcome: MHC-restricted, self-tolerant CD4⁺ or CD8⁺ T cells.

VI. The Lymphatic System

The circulatory route of immune surveillance

The lymphatic system is the network of vessels and fluid that returns interstitial fluid to the blood and carries antigens and lymphocytes to lymphoid tissue.

A. Lymphatic system

A one-way drainage network channels antigen to organised immune sites.

• Lymph: interstitial fluid collected from tissues; carries antigens, APCs, and lymphocytes.
• Lymphatic capillaries and vessels: thin, blind-ended vessels with one-way valves; flow driven by muscle movement, not a central pump.
• Ducts: vessels converge on the thoracic duct and right lymphatic duct, which empty into the subclavian veins, rejoining blood.
• Surveillance function: funnelling lymph through nodes ensures antigen from any tissue meets patrolling lymphocytes — the link between periphery and adaptive response.

VII. Secondary Lymphoid Organs

Sites where adaptive responses are initiated

Secondary (peripheral) lymphoid organs are where mature lymphocytes encounter antigen and mount responses; they are strategically placed at sites of antigen entry.

A. Secondary lymphoid organs

Each organ traps antigen from a distinct route and provides zones for lymphocyte activation.

• Lymph nodes: bean-shaped filters on lymphatic vessels; trap antigen from tissues.
  • B-cell zone: follicles in the cortex, containing germinal centres where B cells proliferate and mature.
  • T-cell zone: the paracortex, rich in dendritic cells presenting antigen.
• Spleen: filters blood-borne antigens.
  • White pulp: lymphoid tissue for immune responses.
  • Red pulp: removes aged erythrocytes.
• Mucosa-associated lymphoid tissue (MALT): guards mucosal surfaces — includes tonsils, Peyer's patches of the gut, and appendix; samples luminal antigens.

VIII. The Humoral Response

Antibody-mediated adaptive immunity

The humoral response is the arm of adaptive immunity mediated by antibodies secreted by plasma cells, effective against extracellular pathogens and toxins.

A. Humoral response

Antigen recognition by B cells culminates in antibody secretion and memory.

• Activation: a B cell binds antigen through its surface immunoglobulin; a CD4⁺ helper T cell recognising the same antigen provides costimulation and cytokines.
• Differentiation: activated B cells proliferate in germinal centres and become plasma cells (antibody factories) or long-lived memory B cells.
• Antibody structure: Y-shaped glycoprotein of two heavy and two light chains; the variable Fab regions bind antigen, the constant Fc region recruits effectors.

        antigen-binding sites
           \        /
            Fab    Fab      <- variable region (specificity)
             \    /
              \  /
              |  |          <- Fc region (effector function)
     complement / phagocyte binding

• Antibody classes (isotypes):
  • IgG: most abundant in serum; crosses placenta; dominates the secondary response.
  • IgM: pentamer; first antibody made in a primary response; strong complement activator.
  • IgA: dimer in secretions (saliva, milk, mucus); mucosal defence.
  • IgE: binds mast cells; mediates allergy and antiparasite defence.
  • IgD: surface receptor on naïve B cells.
• Effector mechanisms:
  • Neutralisation: antibody blocks a toxin or viral binding site.
  • Opsonisation: Fc-coated microbes are phagocytosed more readily.
  • Complement activation: IgM/IgG trigger the classical pathway, forming the membrane-attack complex that lyses the target.
• Primary versus secondary response:
  1. Primary: 4–7 day lag; IgM appears first, then modest IgG.
  2. Secondary: memory cells give a response within 1–3 days; rapid, high-titre IgG of higher affinity (affinity maturation), giving lasting protection.