TLR9 Activation Is Defective in Common Variable Immune Deficiency

Cunningham‐Rundles, Charlotte; Radigan, Lin; Knight, Adina Kay; Zhang, Li; Bauer, Laura L.; Nakazawa, Atsushi

doi:10.4049/jimmunol.176.3.1978

Cited by 109 publications

(100 citation statements)

References 72 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…There have been reports on defect production of IL-10 in B cells from CVID patients (15), and IL-10 deficiency was suggested to be part of the etiology of the disease (32,33). Taken together with our recent findings that IL-10 is required both for RA-induced proliferation and IgG production in normal B cells stimulated with CpG and anti-RP105 (12), it was interesting to find that the defects in IL-10 secretion from CVID-derived B cells were less pronounced than the nearly complete absence of IgG secretion from the same cells and that, to a large extent, RA was able to restore the deficient TLR9/RP105-mediated IL-10 secretion from the cells.…”

Section: Discussionmentioning

confidence: 99%

“…Diminished TLR9-induced production of IL-10 is one of the B cell defects frequently linked to the reduced IgG production in B cells from CVID patients (15). We showed previously that IL-10 is involved in both RA-induced proliferation and IgG synthesis in B cells stimulated with CpG alone (9) or CpG in combination with anti-RP105 (12).…”

Section: Ra Restores the Deficient Production Of Il-10 In Cvid-derivementioning

confidence: 99%

“…Activation of TLR9 can be achieved in vitro by the use of synthetic CpG oligonucleotides mimicking the CpG-rich bacterial DNA (14). Multiple studies reported defective TLR9 signaling in CVID-derived B cells (15)(16)(17); recently, defective signaling from TLR9 in combination with RP105 (CD180) was reported in three CVID patients (18). The natural ligand for RP105 has not been identified, but anti-RP105 Abs are potent activators of RP105 both in vitro (19) and in vivo (20).…”

Section: Ommon Variable Immunodeficiency (Cvid) Is the Most Commonlmentioning

confidence: 99%

“…Defective TLR9-mediated responses in CVID-derived B cells has been linked to reduced expression of TLR9 itself (15,25); hence, we wished to assess whether the reduced responses to anti-RP105 in the presence of TLR9 stimulation could be accounted for by the reduced expression of RP105 in CVID-derived B cells. To this end, the surface expression of RP105 was determined by flow cytometry of freshly isolated B cells from CVID patients and healthy donors stained with anti-RP105 (CD180).…”

Section: Expression Of Rp105 In Normal and Cvid-derived B Cellsmentioning

confidence: 99%

“…There have been many reports on reduced TLR9-mediated immune responses in B cells from CVID patients (15,25,26) but few and conflicting reports with regard to the proliferative abilities of such cells (16,18,25). Having recently reported that RA enhances TLR9-mediated B cell responses (9), as well as turns anti-RP105 into a potent activator of B cells in the presence of the TLR9-ligand CpG (12), we wished to assess the proliferative response of CVID-derived B cells to CpG and anti-RP105 and to explore the ability of RA to enhance the proliferative response in CVIDderived B cells.…”

Section: Ra Enhances the Proliferation Of B Cells From Cvid Patientsmentioning

confidence: 99%

See 4 more Smart Citations

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Indrevær

Holm

Aukrust

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Ra Restores the Deficient Production Of Il-10 In Cvid-derivementioning

confidence: 99%

Section: Ommon Variable Immunodeficiency (Cvid) Is the Most Commonlmentioning

confidence: 99%

Section: Expression Of Rp105 In Normal and Cvid-derived B Cellsmentioning

confidence: 99%

Section: Ra Enhances the Proliferation Of B Cells From Cvid Patientsmentioning

confidence: 99%

See 3 more Smart Citations

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Indrevær

Holm

Aukrust

et al. 2013

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

Regression of systemic lupus erythematosus after development of an acquired Toll‐like receptor signaling defect and antibody deficiency

Visentini

Conti

Cagliuso

et al. 2009

Arthritis & Rheumatism

View full text Add to dashboard Cite

Toll-like receptor 9 (TLR-9) and TLR-7 may have a role in the production of anti-DNA and anti-RNA autoantibodies, respectively, but murine models do not clearly demonstrate their contribution to the development of systemic lupus erythematosus (SLE). Herein we describe a patient with SLE who had long-lasting remission of her autoimmune disease after development of an antibody deficiency resembling common variable immunodeficiency (CVID). After CVID had developed, antidouble-stranded DNA antibodies disappeared, although antinuclear antibodies remained positive for >10 years. In vitro studies revealed that the patient's B cells proliferated poorly and failed to differentiate into plasmablasts after stimulation of either TLR-9 or TLR-7, providing evidence for an acquired defect of the signaling pathway downstream of these TLRs. These observations suggest, although indirectly, that signaling through TLR-9 and TLR-7 is important in the pathogenesis of human SLE, and indicate that investigation of potential treatment strategies with TLR antagonists is warranted.

show abstract

Primary blood neutrophils express a functional cell surface Toll‐like receptor 9

et al. 2013

View full text Add to dashboard Cite

Polymorphonuclear leukocytes (PMNs) represent one of the first lines of defense against pathogens. TLR9 is normally expressed in endosomes/lysosomes where it is activated by pathogen-derived DNA. Here we show that freshly isolated human and mouse primary PMNs express TLR9 at the cell surface ex vivo. Moreover, surface TLR9 expression is upregulated upon activation of PMNs with different stimuli and not only TLR9 agonists. Importantly, surface TLR9 is processed, active, and functional. TLR9 ligands, oligonucleotides containing unmethylated CpG motifs, indeed bind to surface TLR9 and binding was strongly observed at the cell surface of human cells expressing surface TLR9 and at the surface of WT but not TLR9-deficient mouse PMNs. Finally, CpG oligonucleotides cross-linked onto a solid phase and having no access to intracellular TLR9 are able to trigger cell surface TLR9 and induce neutrophil activation, even when endosomal acidification is inhibited. This is the first demonstration of a functional TLR9 expressed at the cell surface of human primary cells. This pathway may be triggered when pathogenderived TLR9 ligands cannot reach the endosome, offering a rescue mechanism for neutrophil activation.Keywords: Activation r Cell-surface expression r Functionality r Neutrophils r TLR9 See accompanying Commentary by MiyakeAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPolymorphonuclear cells (PMNs) are the first cells recruited at inflammation sites. They play a central role in host defense and their accumulation at sites of acute infection or tissue injury is a critical component of inflammation [1]. PMNs have recently been Correspondence: Dr. Patrice Decker e-mail: patrice.decker@univ-paris13.fr reported to induce chemotaxis of the pro-inflammatory Th17 lymphocytes [2] and to stimulate plasmacytoid dendritic cells (DCs) to produce 4]. Importantly, PMNs have been suggested to link innate and adaptive immunity [5][6][7] by influencing, e.g. DCs. PMN activation may thus favor adaptive immunity but may also represent a double-edged sword in promoting responses that may lead to tissue injury or autoimmunity. * These authors contributed equally to this work. Eur. J. Immunol. 2013Immunol. . 43: 2101Immunol. -2113 TLR9 is activated in endosomal/lysosomal compartments by unmethylated CpG motifs present in pathogen-derived DNA [8] as well as in synthetic oligonucleotides (ODNs). Nevertheless, vertebrate DNA can also trigger TLR9 under certain circumstances although TLR9-independent pathways are triggered in addition [9]. For instance, mammalian DNA activates innate immunity in a TLR-independent manner [10]. Moreover, natural phosphodiester ODNs lacking CpG motifs activate TLR9 upon enforced endosomal translocation [11]. Actually, the sugar backbone of natural phosphodiester DNA has been shown to determine recognition by TLR9 [12]; the rules governing TLR9 activation are therefore complicated. Furthermore, all the aforementioned results refer to intr...

show abstract

TLR9 Activation Is Defective in Common Variable Immune Deficiency

Cited by 109 publications

References 72 publications

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Retinoic Acid Improves Defective TLR9/RP105-Induced Immune Responses in Common Variable Immunodeficiency–Derived B Cells

Regression of systemic lupus erythematosus after development of an acquired Toll‐like receptor signaling defect and antibody deficiency

Primary blood neutrophils express a functional cell surface Toll‐like receptor 9

Contact Info

Product

Resources

About