Background: Germinal centres (GCs) are critical for generating high-affinity antibodies while avoiding the generation of antibodies which bind to self-targets and cause autoimmunity. However, the mechanisms that restrain self-reactivity in GCs are poorly understood, despite their relevance in the context of autoantibody generation following infectious threats, for example Streptococcal infections, which can lead to Rheumatic Heart Disease.
Objective: We aimed to characterize the molecular pathways that govern self-reactive GC B cell responses to foreign antigens mimicking self-proteins.
Methods: Using single-cell RNA sequencing integrated with antibody repertoire analysis in murine models with defined self- and foreign-antigen affinities, we traced the molecular activation and evolution of self-reactive B cells within the GC.
Results: Our analysis identified a distinct molecular signature associated with self-reactive GC B cells, including transcriptional and cellular pathways linked to the modulation of self-reactivity. These signatures shifted as B cells acquired mutations that reduced self-binding, even at the expense of foreign antigen affinity.
Conclusion: These findings provide new insights into the mechanisms by which GCs mitigate self-reactivity, offering potential targets for preventing autoantibody generation following infectious agents.