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Autoimmunity primer

Autoimmunity occurs when the adaptive immune system’s process of self-tolerance fails, rendering it unable to distinguish between self and non-self antigens – potentially leading to autoimmune diseases.


The immune system protects itself against autoreactive B and T cells via primary and peripheral tolerance. In central tolerance, negative selection results in the clonal deletion of immature lymphocytes in the bone marrow (B cells) and thymus (T cells) that recognize self-antigens with high affinity.

In peripheral tolerance (beyond the lymphoid organs), mature autoreactive lymphocytes are inactivated or killed by mechanisms including anergy, immunological ignorance/antigen sequestration, programmed cell death (PCD) or suppression by regulatory T cells (Tregs).

Tregs, characterized by the expression of FoxP3, exert their tolerogenic effect via cell–cell contact or the release of immunosuppressive factors, such transforming growth factor-β (TGF-β) and IL-101. Rather than keeping the immune system in an ‘off’ state, recent  high-resolution, multiplex analysis has revealed that Tregs respond in a negative feedback manner to suppress autoimmunity2.

Autoimmune response

When these self-tolerance mechanisms fail, the adaptive immune system responds as it would to non-self antigens and mounts an immune response. The body’s inability to eliminate the self-antigen results in a sustained response that leads to chronic inflammation.

  • Autoreactive T helper 1 (Th1) cells release interferon (IFN)γ and interleukin (IL)-17 to activate macrophages that secrete additional cytokines (such tumor necrosis factor (TNF) or IL-1) to cause local inflammation.
  • Autoreactive cytotoxic T (Tc) cells cause extensive tissue damage.
  • Inappropriate T cell responses help autoreactive B cells initiate polyclonal activation and the generation of harmful autoantibodies.
  • Autoantibodies activate the complement system to cause inflammation, bind receptors to block hormone and neurotransmitter signals, or react with antigens in the blood to form complexes3.

Autoimmunity is a natural consequence that arises from the necessity of generating lymphocytes capable of recognizing any antigen. Clonal deletion in central tolerance, typically via apoptosis, is therefore an essential component of safeguarding against autoreactive lymphocytes.

Keeping cells in check

While apoptosis is the primary mechanism for removing autoreactive T cells during their development, regulated necrosis (necroptosis) is involved in eliminating activated T cells. This is essential for maintaining T cell homeostasis, as its deregulation can lead to immunodeficiency or autoimmunity4. Necroptosis, driven by TNF and mediated by receptor interacting protein kinase 3 (RIP3) and its substrate mixed lineage kinase domain-like (MLKL), is suspected to play a crucial role in inflammation and disease pathogenesis5.

Learn more about MLKL and necroptosis in our antibody focus series

Disrupting self-tolerance

Several mechanisms can break self-tolerance:

  • Viral infection of a tissue can activate non-virus-specific T cells, overcoming anergy6.
  • ‘Molecular mimicry’, whereby microbial antigens share epitopes similar to human self-proteins and induce an inflammatory response against the self-antigen7 – support for this causing autoimmune disease is limited8.
  • Immune cells targeting tumors may become or remain active and target healthy cells6. Similarly, ‘immunoediting’ theory suggests that antigens derived from cancer cells containing somatic mutations induce an adaptive immune response and generate cross-reactivity against native proteins9.
  • Damage-associated molecular patterns (DAMPs) (molecules released from stressed or injured cells, such as heat shock proteins, that act as danger signals to alert the immune system) may trigger autoimmunity. Nucleic acids released from dying cells can stimulate toll-like receptors (TLRs) on B cells and promote autoantibody generation6.

Genetic susceptibility

The precise mechanisms leading to the breakdown of self-tolerance and development of autoimmune diseases remain unknown. The major histocompatibility (MHC) genes are highly correlated with a predisposition to autoimmunity: human leukocyte antigen (HLA) class I and II alleles have strong associations with specific autoimmune diseases6,10,11.

As well as HLA genes, genetic variation in the genes encoding CTLA4 (an inhibitory receptor acting as a major negative regulator of T-cell responses) and PTPN22 (a negative regulator of T cell receptor (TCR) signaling), are linked with a risk of developing autoimmunity.

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1.    Josefowicz, S. Z., Lu, L.-F. & Rudensky, A. Y. Regulatory T Cells: Mechanisms of Differentiation and Function. Annu. Rev. Immunol. 30, 531–564 (2012).

2.    Liu, Z. et al. Immune homeostasis enforced by co-localized effector and regulatory T cells. Nature 528, 225–230 (2015).

3.    Fairweather, D. Autoimmune Disease: Mechanisms. Encycl. Life Sci. 1–6 (2007). doi:10.1002/9780470015902.a0020193

4.    Kaczmarek, A., Vandenabeele, P. & Krysko, D. V. Necroptosis: The Release of Damage-Associated Molecular Patterns and Its Physiological Relevance. Immunity 38, 209–223 (2013).

5.    Pasparakis, M. & Vandenabeele, P. Necroptosis and its role in inflammation. Nature 517, 311–320 (2015).

6.    Perumbeti, A. Pathobiology of Human Disease. Pathobiology of Human Disease (2014). doi:10.1016/B978-0-12-386456-7.07906-5

7.    Cusick, M. F., Libbey, J. E. & Fujinami, R. S. Molecular mimicry as a mechanism of autoimmune disease. Clin. Rev. Allergy Immunol. 42, 102–111 (2012).

8.    van Kempen, T. S., Wenink, M. H., Leijten, E. F. a., Radstake, T. R. D. J. & Boes, M. Perception of self: distinguishing autoimmunity from autoinflammation. Nat. Rev. Rheumatol. 1–10 (2015). doi:10.1038/nrrheum.2015.60

9.    Joseph, C. G. et al. Association of the autoimmune disease scleroderma with an immunologic response to cancer. Science 343, 152–7 (2014).

10.  Gough, S. C. L. & Simmonds, M. J. The HLA Region and Autoimmune Disease: Associations and Mechanisms of Action. Curr. Genomics 8, 453–65 (2007).

11.  Smilek, D. E. & St Clair, E. W. Solving the puzzle of autoimmunity: critical questions. F1000Prime Rep. 7, 17 (2015).

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