What Rheumatologists Should Know about B Cell Tolerance & Autoimmunity

“In recent years, B cells have been identified as major drivers of systemic auto­immunity emphasizing the importance of maintaining B cell tolerance,” says Shaun W. Jackson, MBChB, MD, a pediatric nephrologist and rheuma­tologist at Seattle Children’s and principal investigator at its Center for Immunity and Immunotherapies (CIIT). Dr. Jackson is also a professor of pediatrics at the University of Washington School of Medicine, Seattle, and an adjunct professor in its Department of Laboratory Medicine and Pathology.

Dr. Jackson is the co-author of a review that is part of a series on immunology for rheumatologists published in Arthritis & Rheumatology (A&R).¹ In this new installment, Dr. Jackson and co-author Sivasankaran M. Ponnan, PhD, a post­doctoral researcher in Dr. Jackson’s lab at CIIT, review the mechanisms employed by the immune system to create B cells that respond to diverse pathogens while preserving immune tolerance, and how these mechanisms shape the understanding of autoimmune pathogenesis.²

Insights for Rheumatologists 

“A key feature of B cell tolerance that may not be recognized by rheumatologists is that healthy individuals have autoreactive B cells as part of a normal B cell repertoire. For this reason, multiple overlapping mechanisms act in concert to prevent the activation of autoreactive B cells and the production of harmful autoantibodies,” Dr. Jackson explains. “This review describes these coordinated processes that ensure the formation of a diverse yet self-tolerant antibody repertoire.

Dr. Shaun W. Jackson

“Prior reviews have described how genetic variants impacting B cell signaling pathways contribute to loss of tolerance and autoimmune pathogenesis. A key takeaway from the current article is the important role that neoantigens (i.e., altered self) play in precipitating breaks in B cell tolerance,” Dr. Jackson says.

The review initially presents a clinical case of a patient with two rare diseases, Alport syndrome, a genetic disorder leading to slowly progressive kidney dysfunction and hearing loss, and de novo anti-glomerular basement membrane (GBM) disease, an autoimmune disorder leading to rapidly progressive glomerulonephritis. To clarify the immunopathology of the case, the authors examine the fundamentals of B cell tolerance, comprising central, peripheral and germinal center B cell tolerance. They discuss the regulatory role of T cells in B cell tolerance, clonal redemption and anergic B cell maintenance, and the disruptions to B cell tolerance in autoimmunity.

Along with a graphical abstract and over 60 references, the review includes two detailed figures and legends demonstrating the central and peripheral mechanisms of B cell tolerance, and the contribution of neoantigens to breaks in B cell tolerance. 

Case Presentation 

The case presentation follows a 27-year-old male patient with end-stage renal disease secondary to X-linked Alport syndrome. After three years on hemodialysis, he received a deceased donor kidney transplant. Post-transplant, the patient initially presented with stable creatinine levels of around 1.2 mg/dL. At 10 months post-transplant, he developed an acute onset of hematuria, proteinuria and rapidly deteriorating allograft function, with a creatinine level rising to 4.6 mg/dL over one week. 

Dysmorphic red blood cells (RBCs) and RBC casts were detected by urinalysis. Allograft biopsy revealed linear deposition of immunoglobulin G along the GBM. Crescent formation presented in 60% of the glomeruli along with high titer circulating anti-GBM antibodies. 

The findings confirmed the diagnosis of de novo anti-GBM disease in a kidney allograft, but the rheumatology team mulled the immunopathology of the case.

“The development of two rare, and seemingly unrelated, kidney diseases in one patient raises interesting questions pertinent to the pathogenesis of humoral autoimmunity,” write Dr. Jackson and Dr. Ponnan. 

Layered Checkpoints in B Cell Tolerance

Central tolerance eliminates most highly autoreactive B cells, but B cell tolerance is maintained in the periphery. 

Central tolerance occurs in the bone marrow. It comprises clonal deletion of high-affinity self-reactive B cells and receptor editing of these cells to modify B cell receptor binding. During peripheral tolerance, self-reactive mature B cells become functionally unresponsive to antigens. These anergic B cells also show a reduced ability to access B cell follicles in secondary lymphoid organs and have short lifespans.

“These anergic B cells could potentially become activated and enter a germinal center response if they successfully acquire T cell help,” the authors explain. “For this reason, a key peripheral tolerance checkpoint limits the recruitment of self-reactive B cells into germinal centers during initial cognate interactions between T helpers and B cells.”

During germinal center tolerance, de novo autoreactive B cells generated by somatic hypermutation are deleted. B cell tolerance is also regulated by T cells via the central deletion of potential B cell helpers and the control of germinal center responses, influenced by the balance of T follicular helper and regulatory cells. 

Despite the potential for autoreactive B cells to escape inhibitory control, the immune system maintains cells with low self-antigen affinity in a functional anergy state. The authors explain the reason for this is that “many pathogens express surface epitopes that mimic self-antigens,” so “a repertoire entirely devoid of self-reactivity would leave ‘gaps’ in immune coverage rendering individuals vulnerable to invasive pathogens.”

“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

1. 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.
2. 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.