TLRs in Autoimmune Diseases: Complex Role, Potential Target

Toll-like receptors (TLRs) are essential molecules in the immune system, recognizing invaders like bacteria and viruses. Recent research reveals a more intricate role for TLRs in autoimmune diseases.

TLRs and Self-Tolerance:

Normally, TLRs help maintain self-tolerance, preventing the immune system from attacking the body. This is achieved through several mechanisms:

  • T cell silencing: TLR activation can inactivate T cells that might target healthy tissues.
  • Regulatory T cells: TLRs can promote the development and function of regulatory T cells (Tregs) that suppress immune responses to the body's own tissues.
  • Immune ignorance: TLR signaling can contribute to hiding self-antigens from the immune system, preventing a mistaken immune response.

TLRs in the control of self and non-self Ag presentation by DCs.

TLR Dysregulation and Autoimmunity:

However, problems with TLR signaling can lead to autoimmunity:

  • Excessive inflammation: Uncontrolled TLR activation by the body's own molecules can trigger chronic inflammation, a feature of many autoimmune diseases.
  • Mistaken identity: Microbial molecules can resemble the body's own molecules. TLRs targeting these mimics can mistakenly attack healthy tissues.
  • Tolerance loss: Issues with TLR signaling can impair the mechanisms mentioned above, leading to T cell attacks on healthy tissues and Treg dysfunction.

The paradigm of the two-phase IFN-/ induction in systemic autoimmunity.The initiation phase is TLR independent and mediated by apoptotic cell material taken up by a specialized subset of lymphoid DCs, leading to IFN-/ production. Under the effect of IFN-/, lymphoid and myeloid DCs upregulate MHC and costimulatory molecules and differentiate into efficient self-antigen–presenting cells, leading to activation of quiescent autoreactive T helper cells (for example, those specific for RNP-derived peptides). As a result of T-cell help, and the effects of BLys, APRIL and IFN-/, autoreactive B cells (for example, Sm/RNP-specific) proliferate and differentiate into plasma cells. Subsequent to the formation of nucleic acid–containing immune complexes, the amplification phase is induced, which encompasses TLR-dependent IFN-/ induction in pDCs and DCs, and enhanced B-cell proliferation and autoantibody production.

Examples of TLRs and Autoimmunity:

  • TLR2 and TLR4: Linked to rheumatoid arthritis, where they may be activated by self-antigens in joints, causing inflammation.
  • TLR7 and TLR9: Involved in systemic lupus erythematosus (SLE), where they might recognize the body's own nucleic acids and trigger autoimmunity.
  • TLR3: Emerging evidence suggests its role in Sjögren's syndrome, an autoimmune disease affecting glands.

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Toll-like receptors and chronic inflammation in rheumatic diseases: new developments

Treatment Implications:

Understanding TLRs in autoimmunity opens doors for potential treatments:

  • TLR modulators: Specific drugs could activate Tregs to promote tolerance or block excessive inflammatory responses.
  • Targeting TLR pathways: Drugs targeting molecules downstream of TLR signaling are being explored for managing autoimmune diseases.

Conclusion:

TLRs play a complex role in both defending against infections and maintaining self-tolerance. When TLR signaling goes awry, it can contribute to autoimmune diseases. Research into TLR pathways holds promise for developing new therapies to regulate immune responses and restore tolerance in autoimmune conditions.

Learn more about Toll-Like Receptors in this video:


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TLRs in Autoimmune Diseases: Complex Role, Potential Target
Gen store May 27, 2024
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