Adaptive immunity

Both T and B cells arise from haematopoietic stem cells. B cells mature in the bone marrow. T-cell precursors travel to the thymus. In both organs the antigen receptor genes are assembled by V(D)J recombination, started by the recombinase enzymes RAG1 and RAG2 and completed by DNA-repair enzymes, and the cells are then tested for useful and harmless receptors.

B-cell development is ordered as follows. The heavy chain is rearranged first and appears with the surrogate light chain (VpreB and λ5) as the pre-BCR. Pre-BCR signalling stops rearrangement at the other heavy-chain allele (allelic exclusion), so each B cell makes receptors of one specificity. The light chain is then rearranged (κ usually before λ), giving an immature IgM⁺ B cell. Immature cells that bind self-antigen strongly in the marrow undergo receptor editing (a new light-chain rearrangement), clonal deletion or anergy. Surviving cells leave for the spleen and lymph nodes and become mature naive B cells that carry IgM and IgD.

The MHC is a cluster of closely linked genes. In humans it is called HLA and lies on chromosome 6. In mouse it is H-2 on chromosome 17. Its products present peptides to T cells, and they are the main targets of graft rejection. Class I and class II genes are highly polymorphic.

Class III genes lie between class I and II. They code for proteins that do not present antigen, including complement components C2, C4 and factor B, and the cytokines TNF and lymphotoxin.

MHC diversity in a population comes from polygeny (several class I and class II loci) and extreme polymorphism (many alleles per locus), concentrated in the residues that form the peptide groove. Alleles are codominant: a person expresses both parental alleles. A heterozygote therefore has up to six different classical class I molecules (two each of A, B and C), and at least six classical class II molecules (DR, DP and DQ from each parent), often more because some haplotypes carry an extra DRB gene and DQ and DP α and β chains from the two parents can pair in mixed combinations. The set of MHC genes on one chromosome is a haplotype and is usually inherited as a block, because recombination within the complex is rare. Population diversity makes it unlikely that a pathogen can escape presentation in every member of the population. A T cell recognises its peptide only when it is bound to the self-MHC allele it was selected on (MHC restriction).

Cross-presentation is the loading of exogenous antigen onto MHC class I. It is carried out especially by a subset of dendritic cells and primes CD8⁺ T cells against viruses that do not infect dendritic cells and against tumours. Professional antigen-presenting cells (dendritic cells, macrophages, B cells) express class II and co-stimulatory molecules. Dendritic cells are the most effective at activating naive T cells.

In a germinal centre, activation-induced cytidine deaminase (AID) drives both somatic hypermutation of the V genes and class-switch recombination of the constant region. B cells whose mutated receptors bind antigen better are selected, which is affinity maturation. Cells leave as long-lived plasma cells or memory B cells. T-cell cytokines steer the switch: IL-4 favours IgE, TGF-β favours IgA, and IFN-γ favours opsonising IgG subclasses (IgG2a in mice). Absence of CD40 ligand (X-linked) causes hyper-IgM syndrome: IgM is normal or raised but switched isotypes are deficient. Defects in CD40 or AID cause other forms of hyper-IgM syndrome.

Memory T cells include central memory cells (CCR7⁺, home to lymph nodes) and effector memory cells (CCR7⁻, found in blood and peripheral tissues); tissue-resident memory cells stay in one tissue. Memory persists after antigen is cleared and is the basis of immunisation.

An immune response must stop when the antigen is cleared and must not attack self. Regulation works through several mechanisms.

Autoimmunity is an immune response against self and may be organ-specific (Hashimoto thyroiditis, type 1 diabetes, multiple sclerosis) or systemic (SLE, rheumatoid arthritis). Contributing factors include failure of tolerance, molecular mimicry, release of sequestered antigens, certain HLA alleles and inflammation that provides co-stimulation.

HIV is a retrovirus (a lentivirus). Its envelope glycoprotein gp120 binds CD4 and a chemokine co-receptor (CCR5 or CXCR4), and gp41 mediates membrane fusion. Reverse transcriptase makes DNA, integrase inserts it into the host genome, and CD4⁺ T cells, macrophages and dendritic cells are infected. People homozygous for the CCR5-Δ32 deletion are highly resistant to CCR5-using strains. AIDS is defined clinically by opportunistic infections or CD4⁺ counts below 200 cells per microlitre.

In transplantation, a graft from one site to another in the same individual is an autograft, and one between genetically identical individuals is an isograft. Between members of one species it is an allograft, and between species a xenograft. Rejection is driven mainly by differences in MHC, with minor histocompatibility antigens contributing; ABO antigens matter for hyperacute rejection.

Hyperacute rejection (minutes to hours) is due to preformed antibodies against ABO or donor HLA that activate complement on the graft endothelium. Acute rejection (days to weeks) is mainly T-cell mediated, although antibody-mediated acute rejection also occurs. Chronic rejection develops over months to years, with thickening of graft vessels and fibrosis. Cyclosporin A (bound to cyclophilin) and tacrolimus (bound to FKBP12) block calcineurin, so NFAT is not activated and IL-2 gene transcription falls. Rapamycin (bound to FKBP12) inhibits mTOR and so blocks the T-cell proliferation that IL-2 drives.

Graft-versus-host disease (GVHD) occurs when immunocompetent donor T cells in a graft, typically a bone marrow or haematopoietic stem cell graft, attack the tissues of an immunocompromised recipient, especially skin, liver and gut. It needs three conditions: immunocompetent donor cells, host antigens foreign to the donor, and a host unable to reject the donor cells. HLA matching and T-cell depletion of the graft reduce it. The same donor T cells can also attack residual leukaemia cells (graft-versus-leukaemia effect).

Active immunisation gives antigen so the person makes their own response and memory. Passive immunisation gives ready-made antibody (antitoxin, immunoglobulin, maternal IgG across the placenta, anti-D immunoglobulin to prevent Rh haemolytic disease of the newborn). It acts at once but lasts only weeks to a few months and does not create memory.

Adjuvants such as aluminium salts enhance the response by activating innate immunity. Herd immunity protects those unvaccinated when enough of the population is immune that each case infects fewer than one other person on average.