Immune tolerance and how autoimmunity begins !

Process

Tolerance is how the immune system learns not to attack the body. Autoimmunity begins when those safety checks fail.

Updated 2026-11-01

See it in 3D: Thymus

What it is

Random gene rearrangement creates some T and B cells that recognise self. Central tolerance removes most of them while they mature, in the thymus for T cells and in the bone marrow for B cells. Peripheral tolerance silences the ones that escape: they become unresponsive (anergy), die, or are held back by regulatory T cells. Autoimmune disease appears when genes, especially HLA, and triggers such as infection, drugs or smoking break these checks for a particular self antigen.

Key facts

Most autoimmune diseases are more common in women.
Identical twins are concordant more often than siblings who share HLA, showing that non-HLA genes and environment also matter.
Epitope spreading: tissue damage exposes new self antigens, and the response widens over time.
Autoantibodies can appear years before symptoms, as in lupus and type 1 diabetes.

Step by step

Thymus: T cells that bind self too strongly die (negative selection) or become regulatory T cells.
AIRE lets thymic medullary cells display proteins from other organs (insulin, thyroid proteins) so reactive T cells are removed.
Bone marrow: self-reactive B cells edit their receptor, die or become anergic.
Periphery: a T cell that sees antigen without costimulation (CD28 to B7) becomes anergic.
CTLA-4 and PD-1 brake activated T cells; Fas-mediated death removes repeatedly stimulated cells.
FOXP3+ regulatory T cells suppress self-reactive cells through IL-10, TGF-beta and contact.
Autoimmunity: a susceptible person, a trigger and a broken check let self-reactive cells expand and spread to new epitopes.

When a single tolerance gene fails

Defect	Syndrome	Main features
AIRE	APECED (autoimmune polyendocrine syndrome type 1)	Chronic mucocutaneous candidiasis, hypoparathyroidism, adrenal insufficiency
FOXP3	IPEX	Severe enteropathy, early type 1 diabetes and eczema in infant boys (X-linked)
Fas or Fas ligand	Autoimmune lymphoproliferative syndrome (ALPS)	Large lymph nodes and spleen, autoimmune cytopenias
CTLA-4 or PD-1 blocked by drugs	Immune checkpoint inhibitor side effects	Colitis, thyroiditis, hepatitis, pneumonitis, skin rash

Test yourself

Think of the answer, then tap the question to see it.

What does AIRE do in the thymus?

It makes medullary epithelial cells express proteins normally found only in other organs, so T cells that react to them are removed before leaving the thymus.

What happens to a T cell that recognises its antigen without costimulation?

It becomes anergic: it stays alive but stops responding. Costimulation such as CD28 binding B7 on an activated antigen-presenting cell is needed for full activation.

A baby boy has severe diarrhea, eczema and diabetes in the first months of life. Which gene is likely affected?

FOXP3, causing IPEX syndrome. Without FOXP3, regulatory T cells fail and autoimmunity hits the gut, skin and islets.

Why can cancer checkpoint inhibitors cause colitis or thyroiditis?

They block CTLA-4 or PD-1, brakes that normally keep self-reactive T cells quiet, so autoimmunity can appear in many organs.

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See it in 3D

The structures of Durgical's 3D anatomy where it is found.

Thymus

← All of immunology

Educational content on the immune system; not a treatment or individual vaccination guide and no substitute for a health professional's advice. No doses are given.

Sources: T-Cell Tolerance: Central and Peripheral (Cold Spring Harbor Perspectives in Biology (PMC), 2012); Autoimmune responses are directed against self antigens (Garland Science (Janeway's Immunobiology, 5th ed., NCBI Bookshelf), 2001).

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Representative model, for educational purposes only.