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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.
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.
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.
Several mechanisms can break self-tolerance:
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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