title: Retinoic acid improves defective TLR9/RP105-induced immune responses in common variable immunodeficiency-derived B cells.
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.
authors.affiliation: Department of Biochemistry, Institute of Basic Medical Sciences, University of Oslo, N-0317 Oslo, Norway;
authors.forename: Randi L
authors.initials: RL
authors.lastname: Indrevær
authors.forename: Kristine L
authors.initials: KL
authors.lastname: Holm
authors.forename: Pål
authors.initials: P
authors.lastname: Aukrust
authors.forename: Liv T
authors.initials: LT
authors.lastname: Osnes
authors.forename: Elin H
authors.initials: EH
authors.lastname: Naderi
authors.forename: Børre
authors.initials: B
authors.lastname: Fevang
authors.forename: Heidi K
authors.initials: HK
authors.lastname: Blomhoff
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000328:Adult; D000368:Aged; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D015703:Antigens, CD / Q000276:immunology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000276:immunology*; D016022:Case-Control Studies; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D017074:Common Variable Immunodeficiency / Q000276:immunology*; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008297:Male; D008875:Middle Aged; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D000074462:Positive Regulatory Domain I-Binding Factor 1; D018168:Receptors, Retinoic Acid / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D051217:Toll-Like Receptor 9; D014212:Tretinoin / Q000494:pharmacology*; D055815:Young Adult
chemical_list: D015703:Antigens, CD; C092722:CD180 protein, human; D007074:Immunoglobulin G; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D051217:Toll-Like Receptor 9; D016753:Interleukin-10; C087042:PRDM1 protein, human; D014212:Tretinoin; D000074462:Positive Regulatory Domain I-Binding Factor 1; D051997:ADP-ribosyl Cyclase 1