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PH-IM12

Tolerance and autoimmunity

How the immune system learns to leave the body alone, through central and peripheral tolerance, how genes and triggers break that tolerance, and how the resulting autoimmune response injures one organ or many.

By the end, you can

  • Explain central tolerance in the thymus and bone marrow, and the peripheral checkpoints that back it up.
  • Describe how HLA and other genes, sex and environmental triggers contribute to autoimmunity.
  • Explain molecular mimicry, modified self, bystander activation and epitope spreading.
  • Relate autoimmune injury to the hypersensitivity mechanisms, using rheumatoid arthritis as an example.
  • Distinguish organ-specific from systemic autoimmune disease, and interpret autoantibodies as markers.
  • Recognise the lymphocytic tissue picture of organ-specific autoimmunity and the antinuclear antibody patterns, and explain how immunosuppressants and biologics act on the mechanism by target.

What it is

Autoimmunity is an adaptive immune response against the body’s own antigens. It develops when self-tolerance, the mechanisms that delete or restrain self-reactive lymphocytes, fails in a person with susceptibility genes, often after an environmental trigger. Autoimmune diseases are organ-specific (one organ, as in Hashimoto thyroiditis) or systemic (many organs, as in lupus).

2 types to tell apart
Organ-specific
The target antigen is confined to one tissue: Hashimoto thyroiditis, Graves disease, type 1 diabetes, myasthenia gravis, autoimmune gastritis.
Systemic
The target antigens are widespread, such as nuclear antigens, so many organs are inflamed: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjögren syndrome.

Normal function

Learning to leave the body alone

Lymphocytes make their antigen receptors by shuffling gene segments at random, so some inevitably recognise self. In the , developing T cells meet self-antigens, including many tissue proteins made there under the control of the AIRE gene. Those that bind strongly die by apoptosis (negative selection), and some become regulatory T cells instead. Developing B cells are checked in a similar way in the bone marrow. This is central tolerance.

Central tolerance is incomplete, so peripheral tolerance backs it up. A T cell that meets its antigen without the co-stimulatory signals of an activated antigen-presenting cell becomes unresponsive (anergy); regulatory T cells, which depend on the transcription factor FOXP3, suppress others; and repeatedly activated cells can be deleted by apoptosis.

The is largest in childhood and is largely replaced by fat in adults, by which time most of the T-cell repertoire has been selected.

Point to it on the model
Checkpoints of self-toleranceSchematic
  1. NormalRandom receptor generationSome new lymphocytes recognise self
  2. central tolerance
    NormalNegative selection in the thymus and marrowStrongly self-reactive cells die; AIRE displays tissue proteins
    NormalSome become regulatory T cellsFOXP3-positive
  3. escaped cells reach the tissues
    NormalAnergyAntigen without co-stimulation switches the cell off
    NormalSuppressionRegulatory T cells, IL-10, TGF-β
    NormalDeletionApoptosis after repeated activation
  4. OutcomeSelf-toleranceSelf-reactive cells exist but stay harmless

Some antigens are also kept largely out of reach of immune cells, as in the eye and testis.