101 · IMM-L3 Lecture 10 · Complement, MHC, Vaccines & Hypersensitivity

Master Logic

• This lecture is one defence pipeline: complement amplifies the signal in body fluids → MHC lifts antigen onto the cell surface → B and T cells recognise and activate → cytokines tune the strength → vaccines are that pipeline replayed on purpose.
• Three “why” questions carry the lecture: why complement needs three routes (different entry points, one outcome); why MHC splits into I and II (endogenous vs exogenous peptide, i.e. CD8 vs CD4); why vaccines come in so many types (immunogenicity vs safety).
• Exam focus: the trigger and the convergence point of each complement route; what C3a, C5a and C3b each do; MHC I/II structure and peptide length; the two antigen-processing routes; T-dependent vs T-independent B-cell activation; the trade-offs between the seven vaccine types; the four hypersensitivity types.

1 · Complement: three routes, one outcome

1.1 Spoken-only additions: the C1 complex, two convertases, tick-over

These are the three things the lecturer said in class that neither the slides nor the note made explicit. The exam is multiple choice, and he said plainly: do not memorise — understand the pathway.

2 · MAC and complement regulation

MAC (membrane attack complex) = C5b → C6 → C7 → C8 → multiple C9 forming a pore that inserts into the pathogen membrane, causing osmotic lysis. C9 polymerisation is the decisive step, so blocking C9 blocks the whole lytic arm.

3 · Three fragments, three jobs

• C3b → opsonisation: coats the pathogen and is recognised by phagocyte CR1, sharply raising phagocytosis. Factor I later trims it to iC3b and C3dg.
• C3a / C5a → inflammation and chemotaxis (anaphylatoxins): raise vascular permeability and recruit neutrophils and monocytes. C5a is among the strongest chemoattractants.
• C5b–C9 → lysis: the MAC punches the membrane directly.

4 · MHC: lifting antigen onto the surface

MHC does not kill anything; it displays. Whether a given antigen is shown to CD8 or CD4 is decided by the structure of the molecule, not by the antigen itself.

4.1 At a glance: MHC I vs MHC II

4.2 The three units of MHC I, and what each does

4.3 Why α3 is the constant unit — and why it matters

• It is non-polymorphic: almost all MHC I polymorphism is concentrated in α1/α2. α3 differs very little between people, which is exactly why CD8 can grip any MHC I.
• It is the CD8 handle: CD8 binding to α3 performs an “MHC check” — confirming that the display stand really is MHC I.
• It is the second contact point: the TCR alone binds MHC–peptide with low affinity; the CD8–α3 contact brings the two cells closer and stabilises the signal, helping the T cell reach its activation threshold.
• But it is not the switch: CD8 binding to α3 only says “this is MHC I”. Whether the T cell fires depends on which peptide the TCR sees. Wrong peptide → CD8 still binds, T cell stays silent.

4.4 The real switch is the peptide

• Empty MHC I is unstable: without a peptide in the groove the molecule is degraded and struggles to reach the surface. So “MHC I on the surface” already implies “a peptide is loaded”.
• Specificity comes from peptide + TCR: MHC is the shared display stand, not the source of specificity; the unique part is the peptide (viral, tumour).
• Peptide length follows groove shape: MHC I is closed at both ends, clamping the peptide → 8–10 aa; MHC II is open, allowing overhang → 13–18 aa.

4.5 MHC II: the same logic, mirrored

• α1 + β1 form the groove (open at both ends) → longer peptides (13–18).
• β2 is the constant domain and the CD4 handle; α2 is constant. Exactly the MHC I logic: variation in the groove, invariance in the handle.
• Both chains are transmembrane (“two legs”), whereas MHC I has only the α chain spanning the membrane and β2m outside (“one leg”).
• Restricted expression: only APCs express MHC II at rest, and IFN-γ up-regulates it — which is why only APCs can show exogenous antigen to CD4.
• Loading is guarded: in the ER the invariant chain (Ii) blocks the groove to prevent premature self-peptide loading; in the endosome it is trimmed to CLIP, and HLA-DM swaps in the antigenic peptide.

4.6 Structure → mechanism, in one table

4.7 Three confusions to kill

1. α3 ≠ β2-microglobulin: both are constant, but α3 is part of the α chain and binds CD8; β2m is a separate small chain that only stabilises.
2. “1 → 8, 2 → 4”: class I → CD8; class II → CD4. Do not guess from Roman numerals.
3. MHC is not the source of antigen specificity: one MHC molecule presents many peptides; specificity comes from the TCR reading the MHC–peptide combination.

4.8 Exam-style reminders the lecturer gave verbally

• C1q recognises Fc, not antigen — the antibody is a bridge that brings complement to the pathogen; antigen recognition still belongs to Fab.
• “One leg vs two legs”: in MHC I only the α chain spans the membrane (β2m does not); in MHC II both α and β do.
• The “MHC check” is not checking the peptide — it confirms that the display stand is a legitimate MHC molecule. Peptide specificity is the TCR's job.
• Red blood cells have no nucleus, which is why “MHC I on all nucleated cells” has exactly one exception.
• β2m is constant and exists to help the α chain fold; it does not bind CD8 (α3 does).
• He stressed the exam is multiple choice: a wrong concept leaves no second chance, so understanding the pathway beats memorising the steps.

5 · The two antigen-processing routes

“Processing” = cutting protein into peptides; “presentation” = loading those peptides onto MHC and shipping them to the surface. Which route runs decides whether the same antigen ends up in front of CD8 or CD4.

6 · B-cell activation: T-dependent vs T-independent

6.1 The seven steps of TD activation: how a B cell earns T-cell help through MHC II

The three-row table above compresses it to “BCR takes up antigen → MHC II → Tfh → CD40L”, but the exam asks which molecule does what at each step, and what fails if it is missing.

6.2 Three signals — and what breaks without each (the note only had CD40L)

6.3 Cytokines choose the isotype (the note said only “cytokines”)

6.4 Germinal centre: how class switching and affinity maturation actually happen

The note lists “class switch, affinity maturation” as nouns. They are the output of three processes inside the germinal centre:

Two exits: plasma cells (short-lived, extrafollicular; long-lived, bone marrow) and memory B cells. That is why antibody can persist for decades and why the secondary response is faster and higher-affinity.

6.5 The two TI subtypes (the note said only “polysaccharide, LPS”)

6.6 Timeline (completely absent from the note)

7 · T-cell activation: three signals

• Signal 1: the TCR recognises MHC–peptide (CD4 binds MHC II, CD8 binds MHC I).
• Signal 2 (co-stimulation): CD28–B7. Without it the cell becomes anergic — this is a mechanism of peripheral tolerance.
• Signal 3 (cytokines): sets the differentiation programme → CD4 becomes TH1/TH2/TH17/Treg; CD8 expands into CTLs under IL-2 (perforin + granzyme).

8 · V(D)J recombination: the whole diversity production line

The handwritten slides break V(D)J into four rules, three loci and two kinds of diversity. The earlier note compressed it to one sentence (“light chain V–J, heavy chain V–D–J”) and lost the detail; this section rebuilds it in slide order.

8.1 Four rules (p31)

1. V = Variable, D = Diversity, J = Joining. The targets are immunoglobulin (Ig), TCR and BCR genes.
2. Each lymphocyte joins one V + one D (heavy chain only) + one J — not all of them.
3. The result is a single V(D)J exon encoding the variable region of the antigen receptor.
4. Functional antigen-receptor genes are made only in developing B or T cells, after randomly chosen segments are brought into contiguity.

8.2 Three loci: segment counts and chromosomes (p32–33)

8.3 Light chain: one recombination (V–J)

An intron separates V from J. Recombination joins the chosen V and J at the DNA level (somatic cell); the intron between J and C is then spliced out → mRNA → translation → VL + CL.

8.4 Heavy chain: two recombinations (D–J, then V–DJ)

The heavy chain does D–J first, then V–DJ — two DNA recombination events, versus one in the light chain. That extra junction is exactly why heavy chains are more diverse.

8.5 One thing that is usually mis-said: V(D)J–C is splicing, not recombination

8.6 Two kinds of diversity: combinatorial vs junctional (p36)

The arithmetic (supplementary): κ 38×5 = 190; λ 33×4 = 132; heavy 45×23×6 = 6,210. Pairing light with heavy already exceeds 10⁶ combinations — before counting junctional addition/deletion.

8.7 Cost and control (supplementary, but commonly examined)

• Non-productive rearrangement → apoptosis, or receptor editing to try again.
• Allelic exclusion: each B cell ends up expressing one BCR, preserving specificity.
• V(D)J changes only the V region; class switching changes only CH. They are separate and never substitute for each other.

8.8 Four exam traps

9 · Cytokines: three modes, six families, seven functions

Properties: small proteins/glycoproteins; short half-life; effective at very low concentration (10⁻¹⁰–10⁻¹⁵ M); require high-affinity receptors.

9.1 Three modes of action

9.2 Six families (slide p42; TGF-β was missing before)

9.3 Seven functions (slide p41, each with examples)

9.4 Six main responses (slide p42, lower half)

Acute inflammation, pro-inflammation, allergy, growth & differentiation, chemotaxis, anti-inflammation / regulation — memorise these six and you can classify any cytokine by its role.

10 · Immunogenicity: why some molecules provoke a response

Antigen = can be recognised; immunogen = can provoke a response. Every immunogen is an antigen, but not the reverse.

11 · Vaccines: replaying the immune response safely

11.1 Definitions and history (Vaccination I–II)

1796, Edward Jenner (1749–1823, English physician): observed that milkwomen who caught cowpox did not get smallpox; inoculated 9-year-old James Phipps with cowpox material, then challenged with smallpox six weeks later — no disease. The word vaccine comes from vaccinia (cowpox virus). In 1980 the WHO declared smallpox eradicated.

1879, Louis Pasteur (1822–1895): chickens given aged, spoiled cholera cultures survived; fresh cultures killed them. Conclusion: attenuated pathogens can confer immunity — the origin of attenuation, about a century after Jenner, but the first explanation of the principle.

11.2 How vaccines work

1. Induce active immunity: immunity and memory similar to natural infection but without the risk of disease.
2. Immunological memory allows rapid recognition and response, preventing or modifying disease.

11.3 Five requirements for a promising vaccine

11.4 Active vs passive immunisation

Active immunity has two routes: natural (after infection) and artificial (vaccination).

11.5 The eight vaccine types in the slides

11.6 Exam traps

12 · Hypersensitivity: the four types (Gell–Coombs)