RAG1-independent atypical B cell development in chickens: Redefining the role of RAG1 in avian immunology

Recombination-activating gene 1 (RAG1)'s role in chicken B cell development remains unclear, as V(D)J recombination-mediated antibody diversity is limited in birds. While gene conversion in the bursa of Fabricius predominantly generates diversity, RAG1 deficiency disrupts this process and impairs B cell signaling. Using RAG1-deficient chickens, we identified two pathways: a classical RAG1-dependent route and an alternative RAG1-independent pathway unique to birds. Although normal bursal B cell development was impaired, atypical B cells (ABCs) bypassed RAG1 dependence. These ABCs exhibited attenuated ATR-mediated DNA damage responses (DDRs), underscoring ATR's essential role in chicken B cell maturation-distinct from ATM-driven DDR in mammals. ABCs also accumulated in the spleen, expressing IgM composed solely of J and C segments. Notably, they upregulated genes linked to autoimmune pathology, including PI3K and TLR signaling components, autophagy regulators, and inflammatory mediators. These findings reveal an avian-specific, RAG1-independent B cell pathway with profound implications for evolutionary immune adaptation.