CoachThe repertoire is made at random and therefore contains receptors for self. Central tolerance removes them where the cells mature: in the thymus, T cells whose receptors bind self peptide–MHC too strongly are killed (negative selection), those that cannot bind MHC at all are also killed (they would be useless), and only the intermediate few per cent leave; a transcription factor, AIRE, makes thymic cells express proteins from every tissue — insulin, thyroglobulin — so that T cells specific for them can be deleted there. B cells that bind self in the marrow are deleted or edit their receptors. Peripheral tolerance handles the rest: a T cell that meets its antigen without costimulation is made unresponsive (anergy) or deleted; and regulatory T cells, defined by the factor FoxP3, actively suppress responses against self and against harmless antigens such as food and commensals. Autoimmunity is the failure of these controls: type 1 diabetes (T cells destroy the cells), multiple sclerosis (myelin), rheumatoid arthritis (joints), lupus (antibodies against nuclear components), thyroid disease; each is associated with particular HLA alleles, which present the relevant self peptides, and some are triggered by infection with a microbe whose peptides resemble a self protein (rheumatic fever after streptococcal infection).
Examples
Example 16.9 (Hypersensitivity, deficiency, transplantation)
Allergy is a Th2 response to a harmless antigen — pollen, peanut, penicillin — that produces IgE; on re-exposure the antigen cross-links IgE on mast cells, which release histamine within minutes, and if the antigen is in the blood the systemic release is anaphylaxis, treated with adrenaline. Immunodeficiency: children lacking RAG or the enzyme ADA make no lymphocytes (severe combined immunodeficiency) and die of infection unless given marrow or gene therapy; HIV destroys CD4 T cells and with them the help every response needs. Transplantation: the recipient’s T cells see the donor’s HLA molecules as foreign, and up to a tenth of all T cells respond — far more than to any pathogen — so grafts are matched at the HLA loci and the recipient is immunosuppressed for life; a graft of marrow can attack its new host instead. And the deliberate uses: the monoclonal antibodies of Chapter 6, the checkpoint inhibitors that release T cells against tumours (Chapter 11), and T cells engineered with a chimaeric receptor for a tumour antigen (CAR-T), which have cured leukaemias that nothing else touched.