Non-Specific and Innate Immunity

Spec mapping: AQA 7402 Section 3.2.4 — defence against disease: non-specific (innate) immunity (refer to the official AQA specification document for exact wording).

The immune system is conventionally divided into two arms: the non-specific (innate) immune system — fast, hard-wired, present in all animals — and the specific (adaptive) immune system — slower, antigen-tailored, with memory, found in vertebrates. This lesson covers the innate arm: how the body distinguishes 'self' from 'non-self' at the molecular level, the physical and chemical barriers that prevent infection in the first place, the phagocytic cells that engulf pathogens that breach those barriers, the complement and inflammatory mechanisms that amplify the response, and the antigen-presentation step that hands the baton to adaptive immunity (which lesson 8 covers in detail). Innate immunity is not a poor relation to adaptive immunity — it deals with the overwhelming majority of microbial encounters before adaptive immunity is even required. Without innate immunity, our adaptive system would be overwhelmed within hours.

Key Definition: An antigen is any molecule, usually a protein or glycoprotein, that is recognised by the immune system and can elicit an immune response. Self-antigens are molecules on an organism's own cells that the immune system tolerates; non-self antigens (foreign antigens) belong to pathogens, toxins, transplanted tissue or cancer-altered cells. Innate immunity is the first-line, non-specific defence that does not depend on prior exposure and does not generate immunological memory.

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Self vs Non-Self Recognition

Every nucleated cell in the human body displays self-antigens on its surface. The immune system must distinguish these from foreign antigens. Failure to make this distinction underlies autoimmune disease; failure to detect foreign antigens results in persistent infection.

Major Histocompatibility Complex (MHC) Markers

The principal self-antigens are MHC molecules (in humans called HLA — human leucocyte antigens), a family of glycoproteins encoded by the most polymorphic region of the human genome.

• MHC class I is displayed on the surface of virtually all nucleated cells in the body (red blood cells lack a nucleus and so display no MHC). MHC I presents short peptide fragments derived from intracellular proteins.

  • In a healthy uninfected cell, MHC I shows normal self-peptides — the immune system tolerates the cell.
  • In a virus-infected cell, MHC I displays viral peptide fragments — alerting cytotoxic T cells (CD8⁺) to destroy the cell (a process that bridges innate and adaptive immunity, covered in lesson 8).
  • Some cancers downregulate MHC I to evade T-cell surveillance — but loss of MHC I is itself a signal that triggers natural killer (NK) cells, a innate lymphocyte described below.

• MHC class II is displayed only on antigen-presenting cells (APCs) — macrophages, dendritic cells, B lymphocytes. MHC II presents peptide fragments derived from extracellular pathogens that the APC has engulfed and digested.

  • This presentation activates helper T cells (CD4⁺), initiating the adaptive immune response.

A key consequence: MHC I monitors what is happening inside a cell (intracellular threats: viruses, intracellular bacteria, cancer); MHC II monitors what the cell has eaten (extracellular threats engulfed by phagocytosis).

Pattern Recognition

Innate immune cells recognise pathogens not by specific antigens but by broadly shared pathogen-associated molecular patterns (PAMPs) — conserved microbial features such as bacterial lipopolysaccharide (LPS), peptidoglycan, flagellin and viral double-stranded RNA. These are detected by pattern recognition receptors (PRRs), of which the Toll-like receptors (TLRs) are the best-characterised family. TLR4, for example, recognises LPS; TLR3 recognises viral dsRNA. PAMP–PRR binding triggers signalling cascades that release inflammatory cytokines and activate phagocytosis. This recognition is broad (it covers many species) but is genetically hard-wired rather than antigen-specific.

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First Line — Physical and Chemical Barriers

The innate defence starts before infection occurs: external surfaces present a battery of physical and chemical obstacles.

Skin

• The stratum corneum is a dry, keratinised layer of dead cells, mechanically tough and largely impermeable to microbes.
• Sebaceous glands secrete sebum, a slightly acidic (pH ~5.5) oily mixture that inhibits bacterial growth.
• Commensal bacteria (e.g., Staphylococcus epidermidis) competitively exclude pathogens by occupying surface niches and producing inhibitory peptides.

Mucous Membranes

• The respiratory, gastrointestinal, urinary and reproductive tracts are lined with mucous membranes.
• Mucus, secreted by goblet cells, traps inhaled or ingested microbes.
• Cilia on respiratory epithelial cells beat in coordinated waves (the mucociliary escalator), sweeping trapped particles upward to the throat, where they are swallowed.

Stomach Acid

• Gastric parietal cells secrete HCl, producing a pH of ~1.5–3.5 in the stomach.
• This acidity destroys the vast majority of ingested microbes by denaturing their enzymes and disrupting membranes.
• Some pathogens (e.g., Helicobacter pylori) have evolved acid-resistance mechanisms.

Antimicrobial Secretions

• Lysozyme is an enzyme present in tears, saliva, nasal secretions and breast milk. It hydrolyses the β-1,4 glycosidic bond between N-acetylmuramic acid and N-acetylglucosamine in peptidoglycan, lysing Gram-positive bacteria.
• Defensins are short antimicrobial peptides that disrupt microbial membranes.
• Lactoferrin in breast milk and neutrophils sequesters iron, depriving bacteria of an essential nutrient.

Commensal Microbiota

• The body harbours an estimated 10¹³–10¹⁴ commensal microbial cells, predominantly in the gut.
• These commensals occupy niches that pathogens would otherwise colonise, produce inhibitory compounds (short-chain fatty acids, bacteriocins), and educate the developing immune system.

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Second Line — Inflammation

When barriers fail and microbes enter tissues, the second line of defence is the inflammatory response.

Cardinal Signs

The Roman writer Aulus Cornelius Celsus described inflammation by four cardinal signs — calor (heat), rubor (redness), tumor (swelling) and dolor (pain). A fifth sign, functio laesa (loss of function), was later added.

Mechanism

1. Damaged tissues and resident innate cells (mast cells, tissue-resident macrophages) release inflammatory mediators including histamine, prostaglandins, and chemokines.
2. Vasodilation of local arterioles increases blood flow — explaining warmth and redness.
3. Increased capillary permeability allows plasma and circulating immune cells to leak into the tissue — explaining swelling.
4. Pain results from the action of bradykinin and prostaglandins on local sensory nerve endings.
5. Neutrophils are the first leucocytes recruited to the site of infection, followed by monocytes that mature into tissue macrophages.

Inflammation aims to deliver phagocytes, antibodies and complement to the infection site, dilute toxins, and facilitate antigen transport to draining lymph nodes.

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Phagocytosis — The Cellular Workhorse

Phagocytosis (literally "cell eating") is the engulfment of solid particles >0.5 µm by professional phagocytes. It is the principal innate cellular mechanism for destroying bacteria and large pathogens.

Phagocytic Cell Types

Cell type	Origin	Lifespan	Role
Neutrophil	Bone marrow → blood	Hours–days in tissue	First responder; short-lived; numerous
Macrophage	Monocyte → tissue	Months	Long-lived; antigen presentation via MHC II; tissue residency
Dendritic cell	Bone marrow	Variable	Specialised APC; bridge to adaptive immunity

Mechanism

1. Detection. Phagocytes locate pathogens via PRRs (e.g., TLRs) recognising PAMPs, or by binding opsonins — antibodies (IgG) or complement fragments (C3b) that have coated the pathogen surface. Opsonisation dramatically increases phagocytic efficiency by acting as a molecular handle.
2. Engulfment. Pseudopodia (actin-driven cytoplasmic extensions) flow around the pathogen, fusing to form a phagosome.
3. Phagosome maturation. The phagosome acidifies (V-ATPase pumps protons in), reaching pH ~4.5.
4. Lysosome fusion. Lysosomes fuse with the phagosome to form a phagolysosome. The lysosomal cargo includes acid hydrolases (proteases, lipases, nucleases), lysozyme, defensins and the enzymes producing reactive oxygen species (NADPH oxidase generates superoxide, which is converted to hydrogen peroxide and hypochlorite).
5. Digestion. The pathogen is dismantled into its molecular constituents.
6. Antigen presentation. In macrophages and dendritic cells, peptide fragments are loaded onto MHC II molecules and displayed at the cell surface, where they are scanned by helper T cells — the link to adaptive immunity (lesson 8).

Why Multiple Phagocyte Types?

Neutrophils provide rapid, abundant phagocytosis at the cost of a short lifespan. Macrophages provide sustained surveillance and antigen presentation. Dendritic cells are the most efficient antigen-presenters and the main initiators of T-cell responses. Their division of labour is a recurring theme of innate immunity.

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The Complement System

The complement system is a cascade of ~30 plasma proteins that "complement" antibody-mediated immunity but is itself a fundamentally innate mechanism. Most complement proteins circulate as inactive zymogens; activation by a microbial surface triggers a sequential proteolytic cascade.

Three Activation Pathways

• Classical pathway — initiated by antibody binding to antigen (a bridge between adaptive and innate, requiring antibody from B cells).
• Lectin pathway — initiated by mannose-binding lectin recognising microbial carbohydrates.
• Alternative pathway — spontaneous activation on microbial surfaces lacking host regulatory proteins.

All three converge on C3 cleavage into C3a and C3b.

Effector Functions

• Opsonisation. C3b coats microbial surfaces, providing a handle for phagocyte receptors and enhancing phagocytosis.
• Inflammation. C3a and C5a are anaphylatoxins — they recruit and activate phagocytes and trigger mast cell degranulation, amplifying inflammation.
• Membrane attack complex (MAC). Late complement proteins (C5b–9) polymerise to form a pore in microbial membranes, causing osmotic lysis — particularly effective against Gram-negative bacteria.

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Natural Killer Cells

Natural killer (NK) cells are large, granular lymphocytes of the innate system that kill virally infected and cancer-altered cells.

• NK cells express both activating receptors (recognising stress-induced ligands on infected/transformed cells) and inhibitory receptors (recognising self MHC I).
• A healthy cell expresses normal MHC I → inhibitory signal wins → NK cell does not kill.
• A virus-infected or tumour cell that has downregulated MHC I (to evade T cells) loses the inhibitory signal → NK cell kills it via perforin/granzyme release (perforin pores the membrane; granzymes enter and trigger apoptosis).

This "missing self" recognition is innate complementing the adaptive system's MHC-I-dependent killing — viruses cannot win by either expressing or hiding MHC I.

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Antigen Presentation — Bridge to Adaptive Immunity

After phagocytosis and digestion, antigen-presenting cells (macrophages, dendritic cells) load peptide fragments onto MHC class II molecules in the endocytic pathway and present them at the cell surface.

• Dendritic cells migrate from peripheral tissues to lymph nodes, where naive helper T cells circulate.
• Each helper T cell carries a unique T-cell receptor (TCR); the rare T cell whose TCR matches the presented peptide–MHC II complex is activated.
• The activated helper T cell then directs the adaptive immune response — orchestrating B-cell activation, cytotoxic T-cell activation, and macrophage activation (covered in lesson 8).

This handover step is what makes the innate system not merely a holding action but a decisive instructor of adaptive immunity. Vaccines work in part by ensuring this handover step occurs in a controlled context.

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Mermaid Diagram — Innate Immune Pathway

flowchart TD
  P[Pathogen breach] --> Bar{Barriers}
  Bar -- crossed --> Inf[Inflammation: histamine, vasodilation]
  Inf --> Recruit[Neutrophil + macrophage recruitment]
  Recruit --> Phag[Phagocytosis + phagolysosome]
  Phag --> Kill[Pathogen destroyed]
  Phag --> APC[Antigen presentation MHC II]
  APC --> Adaptive[Activate adaptive immunity]
  Inf --> Comp[Complement cascade]
  Comp --> MAC[Membrane attack complex]
  Comp --> Op[Opsonisation by C3b]
  Recruit --> NK[NK cells: 'missing self']

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Blood Group Antigens — A Worked Example of Self Recognition

The ABO blood group system demonstrates self/non-self recognition at the level of cell-surface glycolipid antigens.

Blood group	Antigens on RBCs	Antibodies in plasma
A	A antigen	Anti-B antibodies
B	B antigen	Anti-A antibodies
AB	A + B antigens	None
O	None	Anti-A + anti-B

Mismatched transfusion → recipient antibodies bind donor RBC antigens → agglutination → blockage of small vessels and haemolysis. Group O is the universal donor (no surface antigens to attack); AB is the universal recipient (no antibodies to bind donor cells). The Rhesus (Rh) system parallels this but anti-Rh antibodies are not present naturally — they only develop after exposure (clinically relevant in haemolytic disease of the newborn; managed by anti-D immunoglobulin prophylaxis).

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Specimen Exam Question — 25-mark Synoptic Essay

Specimen question modelled on the AQA paper format (Paper 3 essay style)

Discuss the contribution of non-specific (innate) immunity to defence against pathogens, evaluating its strengths and limitations relative to specific (adaptive) immunity. [25 marks]

AO breakdown: AO1 (knowledge) 5 marks; AO2 (application) 10 marks; AO3 (analysis and evaluation) 10 marks.

Grade C model answer