Phosphorothioate‐modified <scp>C</scp>p<scp>G</scp> oligodeoxynucleotides mimic autoantigens and reveal a potential role for <scp>T</scp>oll‐like receptor 9 in receptor revision

Doster, Anne; Ziegler, Saskia; Foermer, Sandra; Rieker, Ralf J.; Heeg, Klaus; Bekeredjian‐Ding, Isabelle

doi:10.1111/imm.12063

Cited by 4 publications

(4 citation statements)

References 54 publications

(112 reference statements)

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“…We and others recently described that syk participates in TLR9‐mediated B‐cell activation . We, therefore, studied CpG ODN‐triggered cytokine secretion in the presence and absence of syk inhibitor piceatannol.…”

Section: Resultsmentioning

confidence: 99%

Ca²⁺‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

et al. 2014

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Suppressory B-cell function controls immune responses and is mainly dependent on IL-10 secretion. Pharmacological manipulation of B-cell-specific IL-10 synthesis could, thus, be therapeutically useful in B-cell chronic lymphocytic leukemia, transplantation, autoimmunity and sepsis. TLR are thought to play a protagonistic role in the formation of IL-10-secreting B cells. The aim of the study was to identify the molecular events selectively driving IL-10 production in TLR9-stimulated human B cells. Our data highlight the selectivity of calcineurin inhibitors in blocking TLR9-induced B-cell-derived IL-10 transcription and secretion, while IL-6 transcription and release, B-cell proliferation, and differentiation remain unaffected. Nevertheless, TLR9-induced IL-10 production was found to be independent of calcineurin phosphatase activity and was even negatively regulated by NFAT. In contrast to TLR9-induced IL-6, IL-10 secretion was highly sensitive to targeting of spleen tyrosine kinase ( Eur. J. Immunol. 2014. 44: 1285-1298 [7]. However, the mechanisms underlying this suppressory B-cell function were less well understood. To date, it is well accepted that the hallmark of B-cell regulatory function is the anti-inflammatory cytokine . IL-10-producing B cells arise in different contexts, among them B-cell chronic lymphocytic leukemia (B-CLL), infections, and the immune response to apoptotic cells [9][10][11]. They can limit ongoing T-cell responses [12]. While exclusive lack of TLR adaptor MyD88 in B lymphocytes leads to development of chronic EAE or aggravation of Salmonella infection [10], loss of B-cell-specific IL-10 drives autoimmunity in TLR9-deficient mice [13].Further reports propose that formation of plasma blasts coincides with release of 14]. This highlights the possibility that in B cells IL-10 production is triggered in an Ag-specific manner and might selectively target Ag-specific T cells. This would discriminate the function of B-cell-derived IL-10 from that produced by myeloid cells. As a consequence, specific pharmacological intervention with B-cell-derived IL-10 could represent a promising strategy to protect from destructive T-cell responses to both auto-and alloantigen while preserving immunity to infection.Transcriptional regulation of IL-10 synthesis is cell type specific [15]. In B cells, IL-10 production has been investigated upon BCR activation and in leukemia. The studies suggest a role of calcium sensors and NFAT transcription factors (TF) [11,16]. However, little is known on the regulation of B-cell-derived IL-10 production and in particular in response to TLR9 stimulation. The objective of the present study was to analyze the molecular mechanisms regulating IL-10 production in B cells challenged with TLR9 agonists. Results CpG oligodeoxynucleotides (ODN) and BCR cross-linking represent potent IL-10 inducersIn this study, we were interested in the molecular mechanisms mediating B-cell-derived release of IL-10 upon stimulation of TLR9. BCR-, TLR-, and CD40-signaling have all been implicate...

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Section: Resultsmentioning

confidence: 99%

Ca²⁺‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

et al. 2014

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“…Consequently, these enzymes become promoters of self-tolerance during lymphocyte differentiation [15]. Once T and B cells mature, RAG expression is turned off and the cells are released to the periphery [15]. However, Gevaert et al [16] very recently provided evidence for local receptor revision in nasal mucosa in CRSwNP.…”

Section: Introductionmentioning

confidence: 99%

“…The overall purpose of these processes lies in diversifying the antigen receptor repertoire and in revising autoreactive receptors to prevent autoimmunity. Consequently, these enzymes become promoters of self‐tolerance during lymphocyte differentiation . Once T and B cells mature, RAG expression is turned off and the cells are released to the periphery .…”

Section: Introductionmentioning

confidence: 99%

Local increase in IgE and class switch recombination to IgE in nasal polyps in chronic rhinosinusitis

Baba

Kondo

Toma-Hirano

et al. 2014

Clin Experimental Allergy

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The current study suggests local class switching to IgE, production of IgE and IgE localization to the surface of mast cells in eosinophilic chronic rhinosinusitis in the Japanese population. The difference in the IgE-related profiles between eosinophilic chronic rhinosinusitis and non-eosinophilic chronic rhinosinusitis suggests heterogeneity in the pathogenesis of chronic rhinosinusitis with nasal polyps.

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“…CD5 expression on B cells is a common feature of both RA and CLL [166] , CD5 expression correlates with RAG activity in B cells of people with autoimmune disease [167] , and RAG is expressed in B cells in the RA synovium [168] . In RA, the appearance of rheumatoid factor (RF, an antibody to Fc-IgG) correlates with the hypogalactosylation of IgG, occuring roughly two years after the appearance of antibodies to citrullinated proteins, but two years before RA diagnosis [169] .…”

Section: Discussionmentioning

confidence: 99%

Coherent Somatic Mutation in Autoimmune Disease

Ross

2014

PLoS ONE

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BackgroundMany aspects of autoimmune disease are not well understood, including the specificities of autoimmune targets, and patterns of co-morbidity and cross-heritability across diseases. Prior work has provided evidence that somatic mutation caused by gene conversion and deletion at segmentally duplicated loci is relevant to several diseases. Simple tandem repeat (STR) sequence is highly mutable, both somatically and in the germ-line, and somatic STR mutations are observed under inflammation.ResultsProtein-coding genes spanning STRs having markers of mutability, including germ-line variability, high total length, repeat count and/or repeat similarity, are evaluated in the context of autoimmunity. For the initiation of autoimmune disease, antigens whose autoantibodies are the first observed in a disease, termed primary autoantigens, are informative. Three primary autoantigens, thyroid peroxidase (TPO), phogrin (PTPRN2) and filaggrin (FLG), include STRs that are among the eleven longest STRs spanned by protein-coding genes. This association of primary autoantigens with long STR sequence is highly significant (). Long STRs occur within twenty genes that are associated with sixteen common autoimmune diseases and atherosclerosis. The repeat within the TTC34 gene is an outlier in terms of length and a link with systemic lupus erythematosus is proposed.ConclusionsThe results support the hypothesis that many autoimmune diseases are triggered by immune responses to proteins whose DNA sequence mutates somatically in a coherent, consistent fashion. Other autoimmune diseases may be caused by coherent somatic mutations in immune cells. The coherent somatic mutation hypothesis has the potential to be a comprehensive explanation for the initiation of many autoimmune diseases.

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Phosphorothioate‐modified CpG oligodeoxynucleotides mimic autoantigens and reveal a potential role for Toll‐like receptor 9 in receptor revision

Cited by 4 publications

References 54 publications

Ca²⁺‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

Ca²⁺‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

Local increase in IgE and class switch recombination to IgE in nasal polyps in chronic rhinosinusitis

Coherent Somatic Mutation in Autoimmune Disease

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Phosphorothioate‐modified CpG oligodeoxynucleotides mimic autoantigens and reveal a potential role for Toll‐like receptor 9 in receptor revision

Cited by 4 publications

References 54 publications

Ca2+‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

Ca2+‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

Local increase in IgE and class switch recombination to IgE in nasal polyps in chronic rhinosinusitis

Coherent Somatic Mutation in Autoimmune Disease

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Ca²⁺‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells

Ca²⁺‐related signaling events influence TLR9‐induced IL‐10 secretion in human B cells