An autoimmunity primer

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

Self-tolerance

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 recognise 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, characterised by the expression of FoxP3, exert their tolerogenic effect via cell–cell contact or the release of immunosuppressive factors, such as 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 autoimmunity.

Autoimmune response

When these self-tolerance mechanisms fail, the adaptive immune system responds as it would to nonself-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 as tumour 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 complexes.

Autoimmunity is a natural consequence that arises from the necessity of generating lymphocytes capable of recognising 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 autoimmunity. 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 pathogenesis.

Disrupting self-tolerance

Several mechanisms can break self-tolerance:

• Viral infection of a tissue can activate non-virus-specific T cells, overcoming anergy.
• ‘Molecular mimicry’, whereby microbial antigens share epitopes similar to human self-proteins and induce an inflammatory response against the self-antigen. Support for this causing autoimmune disease is limited.
• Immune cells targeting tumours may become or remain active and target healthy cells. Similarly, the ‘immunoediting’ theory suggests that antigens derived from cancer cells containing somatic mutations induce an adaptive immune response and generate cross-reactivity against native proteins.
• 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 generation.

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 diseases.

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) signalling) are linked with a risk of developing autoimmunity.

Image credit: ©FreeImages.com/Kurhan

Originally published here.