Background: Patients 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. Objective: We sought to study how immunodeficiency in patients with Down syndrome results from immunologic defects in the B-cell compartment. Methods: We 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. Results: Blood 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. Conclusion: Children 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.

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Journal of Allergy and Clinical Immunology
Department of Immunology

Verstegen, R.H.J, Driessen, G.J.A, Bartol, S.J.W, Noesel, C.J.M, Boon, L, van der Burg, M, … van Zelm, M.C. (2014). Defective B-cell memory in patients with Down syndrome. Journal of Allergy and Clinical Immunology. doi:10.1016/j.jaci.2014.07.015