Immunoglobulin

TMU set Immunoglobulin as a definition in 2019 and Antibody in 2020. That is not the examiner being lazy — it is a test of whether you know the two words are not interchangeable. Most students use them as synonyms and lose the mark that depends on the difference.

The distinction is one of function versus structure. An antibody is defined by what it does: it is made by a B cell in response to an antigen, and it binds that antigen. An immunoglobulin is defined by what it looks like: a globulin with antibody activity, or with a structure similar to an antibody molecule. That second clause is where they come apart.

Every immunoglobulin monomer is the same Y-shaped four-chain unit: two identical heavy chains and two identical light chains, held together by disulfide bonds. Everything else in this unit — the classes, the enzyme fragments, the functions — is a consequence of that architecture, so it is worth getting the numbers exactly right.

The five heavy chains give the five classes, in the same order: γ→IgG, α→IgA, μ→IgM, δ→IgD, ε→IgE. Light chains come in only two flavours, κ and λ, and here is the detail examiners like: both types occur in all five classes, but any one immunoglobulin molecule contains only one type of light chain — never one κ and one λ.

Domains and the immunoglobulin superfamily

Split each chain lengthwise by how much its sequence varies between different antibodies and you get the whole logic of the molecule. The N-terminal end varies enormously — this is the variable (V) region, and it is what binds antigen. The C-terminal end is nearly the same in every antibody of a given class — the constant (C) region — and it is what talks to the rest of the immune system.

Look closely inside the variable region and the variability is not spread evenly. It is concentrated into three short stretches in each of V_H and V_L. These are the hypervariable regions (HVR), and because they fold into the surface that is complementary to the epitope, they have a second and more descriptive name: complementarity-determining regions (CDRs). The less variable stretches between them are the framework regions (FR1–FR4), and their job is to hold the CDRs in the right place.

Now count. Each V_H contributes 3 CDRs and each V_L contributes 3, so one antigen-binding site is built from six CDRs across two chains. And since a monomer has two arms, each Ig monomer has two antigen-binding sites. That number drives everything about valence in the next section — and it is why an intact antibody can cross-link two antigens while a single Fab fragment cannot.

The hinge region

Between C_H1 and C_H2 sits a short flexible stretch — the hinge — present in γ, α and δ chains, so in IgG, IgA and IgD. It is rich in proline, and that has two consequences that matter for the rest of this unit.

First, flexibility. The two arms can swing, so an antibody can grip two epitopes that are not a fixed distance apart. When it does, the molecule shifts from a T shape to a Y shape — and that conformational change is what exposes the complement-binding site. Complement is not activated by free antibody, only by antibody that has actually bound antigen, and the hinge is the mechanical reason why. Second, proline-rich sequences are susceptible to proteolytic cleavage, which is exactly what papain and pepsin exploit in the next section.

J chain and secretory piece

This is Section V question 2, worth 6 marks and set identically in both papers we hold. It is also the classic experiment that proved what the two halves of an antibody do. Two enzymes cut IgG in almost the same place — and the tiny difference between them produces completely different fragments.

An antibody is itself a protein, so it can be an antigen to somebody else's immune system. The antigenic determinants it carries fall into three levels, distinguished by who differs from whom — and the three names are examinable as a set.

The subclasses are worth a line of their own, because a fill-in-the-blank asks which classes have them. IgG has four subclasses (IgG1–IgG4) and IgA has two (IgA1, IgA2). Light chains have subtypes too — κ1/κ2 and λ1/λ2.

The functions divide exactly along the structural line drawn in §3: what the V region does, and what the Fc does. Answer any 'functions of antibody' question with that two-part structure and the marks follow the headings.

1 · Mediated by the V region — recognition

The variable regions bind antigen with high specificity — one epitope to one binding site, two sites per monomer. The direct consequence is neutralisation: an antibody coating a virus stops it attaching to its receptor, an antibody bound to a toxin blocks the active site, an antibody on a Gram-negative bacterium blocks adhesion. Note that neutralisation needs nothing else — no complement, no cells. Binding alone does the job, which is exactly why F(ab′)₂ fragments still work as antitoxin.

2 · Mediated by the Fc portion — effector function

• Activation of complement. The C1q-binding site is in C_H2 of IgG (IgG1, IgG2, IgG3) and C_H3 of IgM. Antigen + IgG/IgM + C1q activates the classical pathway; aggregated Ig can activate the alternative pathway.
• Opsonisation. Phagocytes carry Fcγ receptors, so a microbe coated in specific IgG is bound and ingested far more efficiently. IgG is the principal opsonising antibody.
• ADCC — antibody-dependent cell-mediated cytotoxicity. NK cells and other leucocytes carry FcγR; they bind IgG already coating a target cell and lyse it. The antibody supplies the specificity, the NK cell supplies the killing.
• Mediating type I hypersensitivity. IgE binds high-affinity Fcε receptors on mast cells and basophils; cross-linking by allergen triggers degranulation.
• Crossing the placenta or mucosa. IgG (IgG1, IgG3, IgG4) crosses the placenta via placental Fc receptors; sIgA crosses into external secretions.

Two MCQs and most of Section II blank 5 come from this table. Learn it by the superlatives — most abundant, largest, first, only one that crosses the placenta, rarest — because that is how the examiner asks.

Immunise an animal and it responds to every epitope on the antigen at once, with many different B-cell clones each making its own antibody. The antiserum you collect is therefore a mixture — a polyclonal antibody. Useful, cheap, and different in every batch.

A monoclonal antibody is the product of a single B-cell clone, specific for a single epitope, and identical forever. The obstacle is that a normal B cell will not grow indefinitely in culture. The solution — Köhler and Milstein's 1975 hybridoma method, which you met as the proof of clonal selection in Unit 1 — is to fuse the antibody-producing B cell with a myeloma cell. The hybrid inherits the B cell's specificity and the tumour cell's immortality.

The exam map for this unit — the richest in the subject

The three-second version