“Clonal redemption provides a mechanism for these anergic B cells to be safely recruited into protective immune responses,” they add.
Neoantigens & Autoimmunity
Autoimmunity can result when the immune system encounters previously hidden, or absent, antigens or those that are modified versions of self-proteins. Breaks in B cell tolerance may be triggered by several factors, such as a genetic predisposition toward B cell activation, T cell tolerance defects or the emergence of neoantigens.
Neoantigens can initiate breaks in B cell tolerance, as demonstrated in the case presentation of Alport syndrome, which is caused by mutations in genes encoding subunits of type IV collagen proteins. The kidney allograft introduced the patient to previously absent collagen IV antigens, triggering an alloimmune response. This led to the development of de novo anti-GBM disease targeting the kidney allograft.
“The notion that neoantigens can initiate breaks in immune tolerance applies to various autoimmune diseases. For example, post-translational modifications of self-proteins can create novel epitopes recognized as foreign by the immune system. A classic example is the citrullination of proteins in rheumatoid arthritis, leading to the production of anti-citrullinated protein antibodies that drive inflammation and joint damage,” the authors write.
Additional mechanisms for B cell tolerance breaks through the formation of neoantigens include molecular mimicry, in which pathogen-associated foreign antigens have a similar structure or sequence to self-antigens. An example of this is Guillain-Barré syndrome, in which Campylobacter jejuni antigens resemble nerve gangliosides. Cancer neoantigens can also initiate breaks in B cell tolerance, such as with POLR3A mutations in paraneoplastic scleroderma.
“Understanding the mechanisms shaping the B cell repertoire and governing the maintenance of B cell tolerance is paramount for developing effective strategies to prevent and treat humoral autoimmunity,” Dr. Jackson and Dr. Ponnan conclude.
Katie Robinson is a medical writer in New York.
References
- Bucala R, Solomon DH. Immunology for the rheumatologist: Arthritis & Rheumatology introduces a new problem-based immunology review series with great educational potential. Arthritis Rheumatol. 2024 Jan;76(1):9–10.
- Ponnan SM, Jackson SW. Mechanisms of B cell tolerance in health and autoimmunity. Arthritis Rheumatol. 2025 July 10. Epub ahead of print.
Disclosures
Dr. Jackson is a current or previous consultant for Amgen, Merck, IgM BioSciences, Sail BioMedicines, Bristol-Myers Squib, Variant Bio and ChemoCentryx Inc.