Primary Immune Response (Cambridge AS & A‑Level Biology – Topic 11 Immunity)
1. Overview
The primary immune response is the first encounter of the immune system with a previously unseen antigen. It proceeds from the innate (non‑specific) defence, through activation of the adaptive (specific) arm, to the generation of effector mechanisms and long‑lived immunological memory.
2. Key Definitions
Antigen – any substance that can be recognised by an immune‑receptor (antibody or T‑cell receptor).
Self‑antigen – normal host molecules that are tolerated.
Non‑self antigen – foreign molecules (pathogen proteins, toxins, transplanted tissue, etc.) that can trigger an immune response.
Immunological memory – long‑lived B‑ and T‑lymphocytes that respond more rapidly and strongly on re‑exposure to the same antigen.
Major Histocompatibility Complex (MHC) – cell‑surface proteins that present peptide fragments: MHC II to CD4⁺ T‑helper cells, MHC I to CD8⁺ cytotoxic T cells.
3. Cells of the Innate Immune System
- Macrophages
- Patrol tissues; recognise pathogen‑associated molecular patterns (PAMPs) via pattern‑recognition receptors (PRRs).
- Engulf and digest microbes (phagocytosis); process antigens.
- Load peptide fragments onto MHC II and migrate to draining lymph nodes to present them to naïve CD4⁺ T‑helper (Th) cells.
- Secrete cytokines (IL‑12, TNF‑α, IL‑1β) that polarise T‑cell responses.
- Dendritic cells (DCs)
- Most potent professional antigen‑presenting cells (APCs).
- Capture antigen in peripheral tissue, process it, and travel to lymph nodes where they present peptide‑MHC II to naïve Th cells.
- Provide strong co‑stimulatory signals (CD80/86‑CD28) – essential for the initiation of the adaptive response.
- Neutrophils
- First responders (minutes after injury); phagocytose and kill microbes by oxidative burst and granule enzymes.
- Can form neutrophil extracellular traps (NETs) that immobilise bacteria.
- Short‑lived (≈ 6–8 h) but crucial for early control of infection.
4. Sequence of Events in a Primary Immune Response
- Antigen entry & innate detection
- Microbe breaches a barrier (skin, mucosa).
- Neutrophils arrive, phagocytose and release antimicrobial substances.
- Macrophages (and dendritic cells) ingest the pathogen, degrade it, and migrate to the nearest lymph node.
- Antigen processing & presentation
- Peptide fragments are loaded onto MHC II in endosomes.
- Peptide‑MHC II complexes travel to the cell surface and are displayed to naïve CD4⁺ Th cells.
- Activation of naïve T‑helper (CD4⁺) cells
- Th cell TCR recognises the specific peptide‑MHC II complex.
- Co‑stimulatory interaction (CD80/86 on APC ↔ CD28 on Th) provides the second signal.
- Th cells proliferate and differentiate (Th1, Th2, Th17) according to the cytokine milieu:
- IL‑12 → Th1 (cell‑mediated immunity)
- IL‑4 → Th2 (humoral immunity)
- IL‑6/TGF‑β → Th17 (extracellular bacteria & fungi)
- Clonal expansion of Th cells & cytokine release
- IL‑2 – autocrine growth factor for Th cells.
- IFN‑γ – activates macrophages, promotes Th1 responses.
- IL‑4, IL‑5, IL‑13 – assist B‑cell activation and class‑switching to IgE/IgG1.
- IL‑21 – supports B‑cell differentiation into plasma cells.
- Activation of naïve B‑lymphocytes
- Surface immunoglobulin (B‑cell receptor) binds soluble antigen.
- B cell internalises, processes, and presents the same peptide on MHC II.
- Interaction with an activated Th cell (CD40 ↔ CD40L) plus cytokines (IL‑4, IL‑21) provides full activation.
- Differentiation of B cells
- Plasma cells – secrete large amounts of antibody. First antibody is IgM (pentameric, high avidity). Later, with cytokine signals, class‑switch recombination produces IgG, IgA or IgE.
- Memory B cells – long‑lived, retain high‑affinity surface Ig; ready to become plasma cells on re‑exposure.
- Activation of cytotoxic T‑killer (CD8⁺) cells
- Infected cells display pathogen‑derived peptides on MHC I.
- Naïve CD8⁺ T cells recognise peptide‑MHC I via their TCR; activation is enhanced by IL‑2 and IFN‑γ from Th1 cells.
- Activated CTLs migrate to the infection site and induce apoptosis of the target cell (perforin/granzyme or Fas‑FasL pathways).
- Effector phase & pathogen clearance
- Antibodies – neutralise toxins, block attachment, opsonise microbes for phagocytosis, agglutinate particles, and activate the classical complement pathway (IgM is especially efficient at C1q binding).
- Macrophages – become more microbicidal under IFN‑γ stimulation (enhanced oxidative burst, production of nitric oxide).
- CTLs – eliminate virus‑infected or intracellular bacterial cells.
- Generation of immunological memory
- Memory B cells retain high‑affinity Ig receptors.
- Memory CD4⁺ Th and CD8⁺ CTL cells persist as long‑lived circulating or tissue‑resident cells.
- On re‑exposure, the secondary response is faster (≈ 24 h) and larger (predominantly IgG), providing protection.
5. Roles of the Key Cells (Summary)
| Cell Type | Primary Function in Primary Response | Antigen Presentation | Key Cytokines / Products |
|---|
| Neutrophil | Rapid phagocytosis, oxidative burst, NET formation | — (innate) | Reactive oxygen species, elastase, myeloperoxidase |
| Macrophage | Phagocytosis, antigen processing, cytokine production, microbicidal activation | MHC II to CD4⁺ Th cells | IL‑12, TNF‑α, IL‑1β |
| Dendritic cell | Most potent APC; initiates adaptive response | MHC II to CD4⁺ Th cells (strong co‑stimulation) | IL‑12, IL‑6, high CD80/86 expression |
| B‑lymphocyte | Antigen‑specific recognition; differentiates into plasma & memory cells | MHC II to CD4⁺ Th cells (after internalising antigen) | Receives IL‑4, IL‑21 from Th cells |
| Plasma cell | High‑volume secretion of antibodies (IgM → class‑switched IgG/IgA/IgE) | — | Immunoglobulins (IgM, IgG, IgA, IgE) |
| T‑Helper (CD4⁺) | Orchestrates adaptive response; provides help to B cells and CD8⁺ CTLs | MHC II on APCs | IL‑2, IFN‑γ, IL‑4, IL‑5, IL‑13, IL‑21 |
| T‑Killer / Cytotoxic (CD8⁺) | Kills infected cells by apoptosis | MHC I on infected cells | Perforin, granzyme B, IFN‑γ, TNF‑α |
6. Antibody Structure, Class‑Switch Recombination & Functions
- Basic structure – two identical heavy chains (H) and two identical light chains (L) linked by disulphide bonds.
- Regions
- Variable (V) region – forms the antigen‑binding site (Fab).
- Constant (C) region – determines the antibody class (Fc) and mediates effector functions.
- Primary‑response antibody – IgM is the first class produced; pentameric, giving high avidity and efficient activation of the classical complement pathway.
- Class‑switch recombination (CSR)
- Triggered by cytokines from Th cells:
- IL‑4 → switch to IgE (allergy, helminths) or IgG1 (mouse) / IgG4 (human).
- IFN‑γ → switch to IgG (IgG2 in mouse, IgG1/IgG3 in human) – good for opsonisation and complement.
- TGF‑β → switch to IgA – important for mucosal immunity.
- CSR changes the heavy‑chain constant region (µ → γ, α, ε) without altering antigen specificity.
- Major antibody classes & principal actions
- IgM – complement activation (classical pathway), early neutralisation, agglutination.
- IgG – opsonisation, neutralisation, complement activation (classical), crosses placenta.
- IgA – secretory IgA protects mucosal surfaces (gut, respiratory tract).
- IgE – binds mast cells/basophils; mediates defence against parasites and allergic reactions.
- IgD – surface receptor on mature naïve B cells (optional syllabus point).
- Mechanisms of antibody‑mediated protection
- Neutralisation – blocks receptor binding sites on toxins or viruses.
- Opsonisation – coats microbes, enhancing phagocytosis via Fc receptors.
- Complement activation – C1q binds IgM (or IgG) → cascade → membrane‑attack complex.
- Agglutination – cross‑links multiple pathogens, facilitating clearance.
7. Monoclonal Antibodies – Hybridoma Technique
- Immunise a mouse (or other suitable animal) with the antigen of interest.
- After a primary response, harvest spleen B cells that produce the desired antibody.
- Fuse the B cells with an immortal myeloma cell line using polyethylene glycol (PEG). The resulting hybrid cells (hybridomas) combine antibody production with unlimited growth.
- Culture hybridomas in selective HAT medium; each surviving clone secretes a single (monoclonal) antibody.
- Screen clones for specificity, expand the chosen line, and purify the antibody for research, diagnostic or therapeutic use (e.g., trastuzumab, rituximab).
8. Memory Cells – Why the Secondary Response Is Faster
- Memory B cells – retain high‑affinity surface Ig; on re‑exposure they rapidly differentiate into plasma cells, producing large amounts of IgG within ~24 h.
- Memory T cells
- CD4⁺ memory Th cells reside in secondary lymphoid tissue and quickly release cytokines.
- CD8⁺ memory CTLs circulate or remain in peripheral tissues; they can kill infected cells immediately.
- Both memory populations can persist for years, providing long‑term protection.
9. Active vs. Passive Immunity (Natural & Artificial)
| Type | Source of Antibodies / Cells | Duration of Protection | Cambridge‑style Example |
|---|
| Active natural immunity | Host’s own immune response after infection | Years to lifelong (memory cells) | Recovery from chickenpox, measles |
| Active artificial immunity (vaccination) | Host’s response to a vaccine (live‑attenuated, killed, subunit, toxoid) | Usually years; boosters may be needed | MMR, BCG, tetanus toxoid |
| Passive natural immunity | Maternal antibodies transferred across placenta (IgG) or via breast‑milk (IgA) | Weeks to a few months | Newborn protection against diphtheria, measles |
| Passive artificial immunity | Administration of pre‑formed antibodies (serum, immunoglobulin, monoclonal antibodies) | Days to weeks | Anti‑rabies immunoglobulin, monoclonal antibody therapy for COVID‑19 |
10. Principles of Vaccination & Types of Vaccines
- Introduce an antigen that is recognised by the immune system but does not cause disease.
- Stimulate a primary response that generates memory B and T cells.
- Provide long‑lasting protection with minimal risk.
- Common vaccine categories (Cambridge examples):
- Live‑attenuated – e.g., measles, mumps, rubella (MMR).
- Inactivated/killed – e.g., Salk polio vaccine.
- Subunit or toxoid – e.g., diphtheria‑tetanus‑pertussis (DTP) toxoids.
- Recombinant protein – e.g., hepatitis B surface antigen.
- Viral vector & mRNA – modern platforms (useful context, not required for AS/A‑Level).
11. Quick Revision Checklist
- Define antigen, self‑ vs non‑self.
- Describe the roles of neutrophils, macrophages and dendritic cells in the innate phase.
- Recall the 10‑step sequence of a primary immune response.
- Identify cytokines that link Th cells to B cells (IL‑4, IL‑21) and to CTLs (IL‑2, IFN‑γ).
- State the order of antibody classes produced (IgM → class‑switched IgG/IgA/IgE) and the cytokine cues for each switch.
- Explain how memory B and T cells accelerate the secondary response.
- Contrast active (natural & artificial) with passive immunity.
- List the main types of vaccines and the principle behind each.
- Outline the hybridoma method for producing monoclonal antibodies.
- Remember the four principal antibody actions: neutralisation, opsonisation, complement activation, agglutination.
12. Suggested Flow Diagram (for classroom hand‑out)
Pathogen entry → Neutrophil response → Macrophage/DC antigen capture → Antigen presentation (MHC II) → Naïve CD4⁺ Th activation → Cytokine release → B‑cell activation → Plasma cell (IgM → class‑switched IgG/IgA/IgE) & memory B cell; parallel CD8⁺ CTL activation → target cell killing. Arrows from memory B/T cells → faster secondary response.