Immune deficiencies, infection, and systemic immune disordersDefective B-cell memory in patients with Down syndrome

BackgroundPatients with Down syndrome carry immunologic defects, as evidenced by the increased risks for autoimmune diseases, hematologic malignancies, and respiratory tract infections. Moreover, the low numbers of circulating B cells suggest impaired humoral immunity.ObjectiveWe sought to study how immunodeficiency in patients with Down syndrome results from immunologic defects in the B-cell compartment.MethodsWe studied blood B-cell subset composition, replication history, somatic hypermutation status, and class-switch recombination in 17 children with Down syndrome. Germinal centers and plasma cells were studied in tonsils from 4 additional children with Down syndrome.ResultsBlood transitional B-cell numbers were normal, but naive mature and memory B-cell numbers were reduced despite slightly increased serum B cell-activating factor levels. Germinal centers and plasma cells in tonsils appeared normal, as were serum immunoglobulin levels. CD27+IgD+IgM+ “natural effector” B cells showed reduced proliferation and somatic hypermutation levels, whereas these were normal in CD27+IgD− memory B cells. Furthermore, IgM+ and IgA+, but not IgG+, memory B cells showed impaired molecular signs for antigen selection. The B-cell pattern was highly similar to that of patients with common variable immunodeficiency and a defect in B-cell activation and proliferation.ConclusionChildren with Down syndrome seem capable of normal germinal center and plasma cell formation. Still, blood memory B-cell numbers were reduced and showed impaired molecular maturation of IgA and IgM, which are important for mucosal immunity. The observed molecular defects in circulating IgA and IgM B-cell memory could reflect impaired local responses, which underlie the increased susceptibility to respiratory tract infections of patients with Down syndrome.