Naive- and Memory-like CD21^low B Cell Subsets Share Core Phenotypic and Signaling Characteristics in Systemic Autoimmune Disorders

An expansion of CD21^low B cells has been described in a variety of diseases associated with persistent immune stimulation as in chronic infection, immunodeficiency, or autoimmunity. Different developmental stages of CD21^low B cells have been highlighted in specific diseases; however, a systematic comparison of distribution, phenotype, and signaling capacity of these populations has not yet been performed to delineate the pivotal character of this unusual B cell population. Screening of more than 200 patients with autoimmune disease demonstrated that the prevalence of patients with expanded CD21^low B cells varies between diseases. The expansion was frequent in patients with systemic lupus erythematosus, in which it correlated to relative B cell lymphopenia and duration of disease. Different proportions of distinct developmental stages of CD21^low B cells co-occur in nearly all patients with autoimmune disease. Although in most patients, naive-like and CD27^- switched memory B cells were the most prominent CD21^low subpopulations, there was no detectable association of the pattern with the underlying disease. Despite their distinct developmental stage, all CD21^low B cells share a common core phenotype including the increased expression of inhibitory receptors, associated with an elevated constitutive phosphorylation of proximal signaling molecules downstream of the BCR but impaired Ca²⁺ mobilization and NF-κB activation after BCR stimulation. Further, this was accompanied by impaired upregulation of CD69, although CD86 upregulation was preserved. Beyond maturation-associated differences, the common core characteristics of all CD21^low B cell populations suggests either a common ancestry or a shared sustained imprint by the environment they originated in.