Extrafollicular IgD⁻CD27⁻CXCR5⁻CD11c⁻ DN3 B cells infiltrate inflamed tissues in autoimmune fibrosis and in severe COVID-19

Although therapeutic B cell depletion dramatically resolves inflammation in many diseases in which antibodies appear not to play a central role, distinct extrafollicular pathogenic B cell subsets that accumulate in disease lesions have hitherto not been identified. The circulating immunoglobulin D (IgD)⁻CD27⁻CXCR5⁻CD11c⁺ DN2 B cell subset has been previously studied in some autoimmune diseases. A distinct IgD⁻CD27⁻CXCR5⁻CD11c⁻ DN3 B cell subset accumulates in the blood both in IgG4-related disease, an autoimmune disease in which inflammation and fibrosis can be reversed by B cell depletion, and in severe COVID-19. These DN3 B cells prominently accumulate in the end organs of IgG4-related disease and in lung lesions in COVID-19, and double-negative B cells prominently cluster with CD4⁺ T cells in these lesions. Extrafollicular DN3 B cells may participate in tissue inflammation and fibrosis in autoimmune fibrotic diseases, as well as in COVID-19.