Open Access

Mika Pohlen, Francesco Basile, Alexander Glassmann, Harald Illges

• Background: Soluble CD21 (sCD21) is the product of metalloprotease-mediated proteolysis of CD21, a mechanism in which the entire extracellular domain of CD21 is shed from the cell surface. Through its retained ligand-binding ability and presence in human serum, sCD21 joins the growing list of surface proteins shed from the leukocyte cell surface which allows modulation of the immune response. Summary: sCD21 plays a multifaceted role in the body, including the promotion of inflammatory responses through receptor-ligand interactions with monocyte CD23, acting as a decoy receptor during Epstein-Barr virus infection preventing lymphoproliferation, and suppression of IgG and IgE responses by competitively inhibiting cell surface CD21. Clinical studies have shown that in comparison with healthy individuals, levels of sCD21 in serum are significantly altered in various diseases, highlighted by diverse viral infections, B-cell leukemias, and autoimmune disorders. Key Messages: Although findings of prevalence and functionality suggest sCD21 to be a key modulator of cellular and humoral immunity, questions remain about its origins and the regulation of its responses. Here, we aim to clarify and connect the advances in understanding sCD21 over time with emphasis on its generation by surface cleavage, binding partners, and functional roles. We also provide an outlook on its clinical significance and usage as a diagnostic target and therapeutic biomarker to monitor treatment efficacy in the context of chronic autoimmune disorders.