Toll-like receptor 7-induced naive human B-cell differentiation and immunoglobulin production.
BACKGROUND
Toll-like receptors contribute to the establishment of adaptive immune responses.


OBJECTIVE
The reported studies were conducted to examine the effects of the Toll-like receptor (TLR)-7 ligand, resiquimod, on human naive B-cell differentiation.


METHODS
Naive human B cells were cultured with resiquimod in the presence or absence of IL-2 and IL-10. Secreted IgM and IgG were measured by ELISA, and IL-6, IL-10, and IFN-alpha were measured by a multiplex protein array. Cell proliferation was assessed by measuring [(3)H]thymidine uptake. mRNA for activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts was measured by means of RT-PCR.


RESULTS
Resiquimod induced the production of IgM and, to a lesser extent, IgG by naive human B cells in association with the secretion of IL-6 and IL-10, and a weak proliferative response. IL-2 and IL-10 synergized with resiquimod in markedly augmenting resiquimod-induced IgM and IgG production and proliferation. Resiquimod also stimulated production of IgG by B cells isolated from the blood of a patient with the X-linked hyper-IgM syndrome, with a greater response when these cells were costimulated with IL-2 and IL-10. The stimulated naive B cells from healthy volunteers displayed molecular evidence of immunoglobulin class-switch recombination-namely the appearance of activation-induced cytidine deaminase and I(gamma 1)-C(mu) circle transcripts.


CONCLUSIONS
Perturbation of TLR-7 on naive human B cells can lead to the induction of immunoglobulin class switch and IgG production in the absence of B-cell receptor cross-linking and CD40-CD40L interaction. The results are relevant to vaccine development and mechanisms by which microbial infection may lead to autoimmunity.
Glaum
Mark C
MC
Division of Allergy and Clinical Immunology, University of South Florida College of Medicine, Tampa, FL, USA.
Narula
Shilpi
S
Song
Decheng
D
Zheng
Yi
Y
Anderson
Amy L
AL
Pletcher
C Hank
CH
Levinson
Arnold I
AI
D000328:Adult; D000917:Antibody Formation / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology*; D019013:CD40 Antigens / Q000235:genetics / Q000276:immunology; D023201:CD40 Ligand / Q000235:genetics / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004357:Drug Synergism; D005260:Female; D015322:Gene Rearrangement, B-Lymphocyte / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D006801:Humans; D053307:Hyper-IgM Immunodeficiency Syndrome, Type 1 / Q000235:genetics / Q000276:immunology; D007093:Imidazoles / Q000276:immunology / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology*; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics / Q000276:immunology; D016753:Interleukin-10 / Q000276:immunology / Q000494:pharmacology; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology; D008024:Ligands; D008297:Male; D008875:Middle Aged; D011947:Receptors, Antigen, B-Cell / Q000235:genetics / Q000276:immunology; D051199:Toll-Like Receptor 7 / Q000819:agonists / Q000235:genetics / Q000276:immunology*
D019013:CD40 Antigens; C508609:IL10 protein, human; C508594:IL2 protein, human; C508600:IL6 protein, human; D007093:Imidazoles; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D016898:Interferon-alpha; D007376:Interleukin-2; D015850:Interleukin-6; D008024:Ligands; D011947:Receptors, Antigen, B-Cell; C495348:TLR7 protein, human; D051199:Toll-Like Receptor 7; D016753:Interleukin-10; D023201:CD40 Ligand; C402365:resiquimod