Retinoic acid improves defective TLR9/RP105-induced immune responses in common variable immunodeficiency-derived B cells

J Immunol. 2013 Oct 1;191(7):3624-33. doi: 10.4049/jimmunol.1300213. Epub 2013 Sep 4.

Abstract

Common variable immunodeficiency (CVID) is a disease that is characterized primarily by low levels of serum Igs, resulting in a high incidence of infections. It also has been associated with impaired B cell signaling via TLR9 and reduced serum levels of vitamin A. Given the established link between vitamin A deficiency and increased susceptibility to infections, we investigated the ability of the vitamin A metabolite all-trans retinoic acid (RA) to restore the defective immune responses in CVID-derived B cells activated through the TLRs TLR9 and RP105. We demonstrate that RA almost normalizes proliferation and IL-10 secretion in patient-derived B cells. IgG secretion is also partially restored, but to a more moderate extent. This can be explained by impaired RA-mediated isotype switching in TLR9/RP105-stimulated CVID-derived B cells owing to reduced induction of activation-induced deaminase. Accordingly, these B cells secreted higher levels of IgM than did normal B cells, and RA augmented IgM secretion. The ability of RA to improve critical immune parameters in CVID-derived B cells stimulated through TLR9 and RP105 support the possibility of combining RA with TLR stimulation for the treatment of CVID.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase 1 / metabolism
  • Adult
  • Aged
  • Antibody Formation / drug effects
  • Antibody Formation / immunology
  • Antigens, CD / immunology*
  • B-Lymphocytes / cytology
  • B-Lymphocytes / drug effects*
  • B-Lymphocytes / immunology*
  • Case-Control Studies
  • Cell Differentiation / drug effects
  • Cell Differentiation / immunology
  • Cell Proliferation / drug effects
  • Common Variable Immunodeficiency / immunology*
  • Female
  • Humans
  • Immunoglobulin G / immunology
  • Immunoglobulin G / metabolism
  • Interleukin-10 / biosynthesis
  • Lymphocyte Activation / drug effects
  • Lymphocyte Activation / immunology
  • Male
  • Middle Aged
  • Plasma Cells / drug effects
  • Plasma Cells / immunology
  • Plasma Cells / metabolism
  • Positive Regulatory Domain I-Binding Factor 1
  • Receptors, Retinoic Acid / metabolism
  • Repressor Proteins / metabolism
  • Toll-Like Receptor 9
  • Tretinoin / pharmacology*
  • Young Adult

Substances

  • Antigens, CD
  • CD180 protein, human
  • Immunoglobulin G
  • Receptors, Retinoic Acid
  • Repressor Proteins
  • Toll-Like Receptor 9
  • Interleukin-10
  • PRDM1 protein, human
  • Tretinoin
  • Positive Regulatory Domain I-Binding Factor 1
  • ADP-ribosyl Cyclase 1