Abstract
The adaptive immune system is shaped by self-recognition, creating a paradox where autoreactivity is essential for immune regulation, yet implicated in autoimmune diseases. Traditionally, B cell selection in the bone marrow (BM) has been viewed through the lens of negative selection, eliminating potentially harmful clones. Emerging evidence challenges this perspective, revealing a subset of B suppressor cells (Bsup) that actively regulate immune homeostasis. Unlike conventional negative selection, C1-specific Bsup cells, which recognize collagen type II (Col2), engage Col2-specific regulatory T cells (Tregs) to suppress inflammation in healthy individuals. This suggests that Bsup play a role in both peripheral and central tolerance, akin to Tregs. However, the molecular mechanisms governing Bsup selection, differentiation, and function remain unknown. Understanding how Bsup distinguish homeostatic from pathogenic autoreactivity could transform autoimmune disease treatment, shifting the focus from eliminating autoreactive B cells to harnessing their regulatory potential for precision immunotherapy.