Systemic autoimmune rheumatic diseases are characterized by persistent immune activation and clinical heterogeneity, yet the molecular processes sustaining and diversifying pathogenic immune states remain incompletely understood. Here, we investigate somatic genome diversification as a potential driver of immune variation and disease progression. Using Systemic Lupus Erythematosus as a model disease, we generated a subset-resolved map of somatic mutations across B-cell subsets from 35 patients. Double-negative (DN) B cells carried the highest mutational burden, which was associated with disease duration and immunosuppressive therapy, rather than with disease activity. Integration with single-cell transcriptomes linked DN mutations to dysregulated signalling and proteostasis. Notably, DN cells harboured mutations in genes recurrently altered in B-cell lymphomas. Together, these findings identify somatic genome diversification as a feature of pathogenic B-cell subsets and provide a resource for understanding how chronic stimulation and therapeutic pressure shape the clonal evolution of autoimmunity.
Shiba, Y., Kossinna, P., Caloren, L., Pijpers, L., Li, X., Ashouri, A., Nie, J. I., Bonilla, D., Whittall-Garcia, L. P., Wither, J. E., Gladman, D. D., Touma, Z., Venturutti, L., Gaiti, F.
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