The ‘activated naïve’ B cell phenotype with enriched CD21lo B cells has previously been described in the contexts of immunodeficiency, such as CVID [38, 46] and chronic HIV infection [47], autoimmunity such as Hepatitis C virus-associated mixed cryoglobulinemia [48], rheumatoid arthritis [49] or systemic lupus erythematosus [50, 51], as well as monogenic causes of immune dysregulation (e.g. CTLA4, NFKB1, and LRBA haploinsufficiency [39]). Here, CTLA4 is linked to rheumatoid arthritis.