Adaptive tolerance: Protection through self-recognition.

Area of Science:

• Immunology
• Autoimmunity
• B cell biology

Background:

• Immunoglobulin gene rearrangement generates self-reactive B cells, necessitating tolerance mechanisms for homeostasis.
• Existing central and peripheral tolerance models do not fully account for the prevalence of autoimmune diseases.
• Recent studies indicate autoreactive B cells can respond, not just be deleted or anergized, in physiological conditions.

Purpose of the Study:

• To propose a novel mechanism for the activation of autoreactive B cells under physiological conditions.
• To introduce the concept of 'adaptive tolerance' mediated by autoantibody production.
• To explore the role of high-affinity IgM autoantibodies in this process.

Main Methods:

• The study proposes a theoretical framework based on recent physiological mouse model findings.
• It discusses the proposed mechanism of autoreactive B cell activation by polyvalent autoantigen complexes.
• Analysis of the role of repeated autoantigen complex encounters in affinity maturation of IgM autoantibodies.

Main Results:

• Autoreactive B cells are activated by polyvalent autoantigen complexes, challenging current tolerance paradigms.
• This activation leads to the production of affinity-matured autoreactive IgM.
• The generated IgM autoantibodies protect self-targets from degradation, a key feature of adaptive tolerance.

Conclusions:

• A novel mechanism termed 'adaptive tolerance' is proposed, involving autoreactive B cell activation and IgM autoantibody production.
• High-affinity IgM autoantibodies play an unexpected role in protecting self-tissues.
• This discovery offers a new perspective on the regulation of autoimmunity and B cell tolerance.