Antigen recognition: antibodies, receptors and MHC
مُقدَّم| English | المعنى |
|---|---|
| antibody/ˈæntɪbɒdi/ | A protein produced by immune cells that binds to a particular antigen and helps the immune system respond to it. |
| V(D)J recombination | V(D)J recombination |
| clonal selection/ˈkləʊnl sɪˈlekʃn/ | clonal selection |
| T-cell receptor | T-cell receptor |
| major histocompatibility complex | major histocompatibility complex |
| affinity maturation | affinity maturation |
| HLA | HLA |
Antibodies against a molecule invented last year
- You can make antibodies against a chemical that did not exist when you were born. With about 20 000 genes, how can the body be ready for anything?
- The answer is a library of gene segments shuffled in each lymphocyte, and a display system that shows T cells what is inside every cell.
The antibody
- An antibody 抗体 has two heavy chains and two light chains. The variable ends bind antigen; the constant part decides the class and the job.
- IgM comes first, IgG is the main blood antibody and crosses the placenta, IgA guards mucosa and milk, IgE sits on mast cells, and IgD marks naive B cells.
Match each antibody class to its main role.
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The constant region decides where the antibody goes and what it does.
Shuffling gene segments
- V(D)J recombination 基因片段重排 joins one V, one D and one J segment for the heavy chain, and one V and one J for the light chain. Joins are trimmed and random bases are added, which multiplies the possibilities past 10¹¹.
- Each B cell makes just one receptor. When antigen binds it, that clone is chosen to grow: clonal selection 克隆选择.
T cells see peptides in MHC
- The T-cell receptor T细胞受体 never sees free antigen. It sees a short peptide held in a major histocompatibility complex 主要组织相容性复合体 (MHC) molecule on a cell surface.
- MHC class I, on almost all nucleated cells, shows what the cell is making to CD8 T cells. MHC class II, on dendritic cells, macrophages and B cells, shows what the cell has eaten to CD4 T cells.
A virus is making proteins inside a liver cell. How do T cells find out?
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MHC class I, on nearly all nucleated cells, shows what the cell is making; CD8 T cells inspect it.
A T-cell receptor can bind a whole protein floating in the blood.
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T cells see only short peptides held in MHC molecules on a cell surface.
Better antibody over weeks
- The first IgM is a pentamer with 10 binding sites but low affinity. In germinal centres, B cells switch class to IgG and mutate their receptors; the best binders survive.
- This affinity maturation 亲和力成熟 raises affinity 10- to 1000-fold over weeks to months, which is why a later vaccine dose gives better antibody.
Why does antibody bind more tightly weeks after a first exposure?
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Affinity maturation is mutation plus selection, and it raises affinity 10- to 1000-fold.
HLA: the most variable genes
- Human MHC genes are called HLA 人类白细胞抗原 and are the most variable genes in the body. They are inherited as two blocks, one haplotype from each parent.
- So a brother or sister has a 1/4 chance of sharing both haplotypes (a full match), 1/2 of sharing one, and 1/4 of sharing none.
What is the chance, as a percentage, that a brother shares neither HLA haplotype with his sister?
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He must get the other haplotype from both parents, 1/2 × 1/2 = 1/4 = 25%.
Worked example: counting combinations
- Heavy chain: about 40 V × 23 D × 6 J = 5520 combinations. Light chains: about 200 kappa + 120 lambda = 320.
- Pairs: 5520 × 320 ≈ 1.8 × 10⁶ from joining alone. Trimming and added bases at each join push the total past 10¹¹.
With 40 V, 23 D and 6 J segments, how many heavy-chain combinations can joining alone make?
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40 × 23 × 6 = 5520.
Worked example: finding a matched sibling
- (Fictional) A patient needs a stem-cell donor and has two brothers. Each has a 3/4 chance of NOT being a full HLA match.
- Chance that at least one matches: $1 - (3/4)^2 = 7/16 \approx 44\%$. More siblings raise the chance, but never to certainty.
A patient has two siblings. What is the chance, as a percentage, that at least one is a full HLA match?
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1 − (3/4)² = 1 − 9/16 = 7/16 = 43.75%.
Three common slips
- "Antibodies kill microbes." They neutralise and mark; complement and phagocytes do the killing.
- "T cells recognise free antigen." Only peptide held in MHC.
- Mixing up the MHC classes. Class I shows what a cell makes (to CD8); class II shows what it has eaten (to CD4).
Recap
- Antibody: two heavy + two light chains; IgM first, IgG blood and placenta, IgA mucosa, IgE mast cells.
- V(D)J recombination plus junctional changes give over 10¹¹ receptors; one clone, one receptor.
- T cells see peptide in MHC: class I to CD8, class II to CD4. A sibling is a full HLA match with chance 1/4.