[Durgical](https://durgical.com/en/) › [DurgiPedia](https://durgical.com/en/durgipedia/) › [Immunology](https://durgical.com/en/immunology/) › [Autoimmunity](https://durgical.com/en/immunology/#a-autoimmunity) › Immune tolerance and how autoimmunity begins

[Immunology](https://durgical.com/en/immunology/) · [Autoimmunity](https://durgical.com/en/immunology/#a-autoimmunity)

# 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](https://durgical.com/en/anatomy/thymus/)

## Key points

- Central tolerance: thymus (T cells, AIRE) and bone marrow (B cells, receptor editing).
- Peripheral tolerance: anergy without costimulation, CTLA-4 and PD-1, Fas-mediated death, FOXP3 regulatory T cells.
- AIRE defect = APECED: candidiasis, hypoparathyroidism, adrenal insufficiency.
- FOXP3 defect = IPEX: enteropathy, diabetes and eczema in infant boys.
- Checkpoint inhibitors for cancer release tolerance and cause immune-related adverse events.

## 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 |

## Memory aid

Two schools and three police officers: thymus and marrow teach; anergy, deletion and regulatory T cells patrol afterwards.

## 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.

[Add to my cards (4)](https://durgical.app/estudiar/?add=/en/immunology/immune-tolerance-and-how-autoimmunity-begins/)

## See it in 3D

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

- [Thymus](https://durgical.com/en/anatomy/thymus/)

## Related

- [Regulatory T cell (Treg, FOXP3)](https://durgical.com/en/immunology/regulatory-t-cell/)
- [T-cell development: positive and negative selection](https://durgical.com/en/immunology/t-cell-development-positive-and-negative-selection/)
- [Thymus: where T cells learn](https://durgical.com/en/immunology/thymus-where-t-cells-learn/)
- [B cell and plasma cell](https://durgical.com/en/immunology/b-cell-and-plasma-cell/)
- [T-cell activation: two signals and superantigens](https://durgical.com/en/immunology/t-cell-activation-two-signals-and-superantigens/)
- [Molecular mimicry and post-infectious autoimmunity](https://durgical.com/en/immunology/molecular-mimicry-and-post-infectious-autoimmunity/)
- [HLA associations with disease](https://durgical.com/en/immunology/hla-associations-with-disease/)
- [Autoantibodies: the table to know](https://durgical.com/en/immunology/autoantibodies-the-table-to-know/)

## Related conditions

- [Type 1 diabetes mellitus](https://durgical.com/en/conditions/type-1-diabetes-mellitus/)
- [Adrenal insufficiency](https://durgical.com/en/conditions/adrenal-insufficiency/)
- [Systemic lupus erythematosus](https://durgical.com/en/conditions/systemic-lupus-erythematosus/)

[← All of immunology](https://durgical.com/en/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](https://pmc.ncbi.nlm.nih.gov/articles/PMC3367546/) (Cold Spring Harbor Perspectives in Biology (PMC), 2012); [Autoimmune responses are directed against self antigens](https://www.ncbi.nlm.nih.gov/books/NBK27155/) (Garland Science (Janeway's Immunobiology, 5th ed., NCBI Bookshelf), 2001).

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Representative model, for educational purposes only.

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Source: https://durgical.com/en/immunology/immune-tolerance-and-how-autoimmunity-begins/
License: CC BY 4.0 (https://creativecommons.org/licenses/by/4.0/). Cite as: DurgiPedia (durgical.com), https://durgical.com/en/immunology/immune-tolerance-and-how-autoimmunity-begins/