Do human B-1 lymphocytes truly exist?

phenotype. This discovery was vigorously debated, but their existence and equivalence to murine B-1 cells has gained acceptance in recent years. These human B-1 cells are present in blood, skin, pleural and peritoneal cavities, the spleen, and several fetal tissues. They exhibit tonic intracellular signaling and spontaneously secrete antibodies that share certain specificities with classical natural antibodies (e.g., against phosphorylcholine or bacterial polysaccharides). However, they also differ from murine B-1 cells in several aspects, including somatic hypermutation and spontaneous secretion of IgG. Several questions remain unresolved regarding their tissue residency, developmental origin during fetal life, and contribution to immune homeostasis. Moreover, evidence addressing their involvement in infectious, inflammatory, and immune-mediated diseases, remains limited and sometimes controversial, although most studies suggest a protective role. In this review, we critically examine these open questions, highlight areas of consensus and debate, and outline future directions necessary to better define the biology and clinical relevance of human B-1 cells.