Defective B-cell memory in patients with Down syndrome

J Allergy Clin Immunol. 2014 Dec;134(6):1346-1353.e9. doi: 10.1016/j.jaci.2014.07.015. Epub 2014 Aug 23.

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.

Keywords: B cell; Down syndrome; IgA; IgM; antibody; common variable immunodeficiency; plasma cell; selection; somatic hypermutation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • B-Lymphocyte Subsets / immunology
  • B-Lymphocytes / immunology*
  • Cell Differentiation
  • Child
  • Child, Preschool
  • Common Variable Immunodeficiency / immunology
  • Down Syndrome / immunology*
  • Female
  • Germinal Center
  • Humans
  • Immunoglobulin A / immunology*
  • Immunoglobulin Class Switching
  • Immunoglobulin G / immunology
  • Immunoglobulin M / immunology*
  • Immunologic Memory*
  • Lymphocyte Count
  • Male
  • Palatine Tonsil / cytology
  • Palatine Tonsil / immunology
  • Plasma Cells / cytology

Substances

  • Immunoglobulin A
  • Immunoglobulin G
  • Immunoglobulin M