Ruud H J Verstegen1, Gertjan J Driessen2, Sophinus J W Bartol3, Carel J M van Noesel4, Louis Boon5, Mirjam van der Burg3, Jacques J M van Dongen3, Esther de Vries6, Menno C van Zelm3. 1. Department of Pediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands. 2. Department of Pediatric Infectious Disease and Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands; Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 3. Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands. 4. Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands. 5. Bioceros B.V., Utrecht, The Netherlands. 6. Department of Pediatrics, Jeroen Bosch Hospital, 's-Hertogenbosch, The Netherlands. Electronic address: e.d.vries@jbz.nl.
Abstract
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.
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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