Bruton’s Tyrosine Kinase Mediates the Synergistic Signalling between TLR9 and the B Cell Receptor by Regulating Calcium and Calmodulin
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{"title"=>"Bruton's Tyrosine Kinase Mediates the Synergistic Signalling between TLR9 and the B Cell Receptor by Regulating Calcium and Calmodulin", "type"=>"journal", "authors"=>[{"first_name"=>"Elaine F.", "last_name"=>"Kenny", "scopus_author_id"=>"54927074500"}, {"first_name"=>"Susan R.", "last_name"=>"Quinn", "scopus_author_id"=>"36470896400"}, {"first_name"=>"Sarah L.", "last_name"=>"Doyle", "scopus_author_id"=>"7101941609"}, {"first_name"=>"Paul M.", "last_name"=>"Vink", "scopus_author_id"=>"7006242414"}, {"first_name"=>"Hans", "last_name"=>"van Eenennaam", "scopus_author_id"=>"56086884000"}, {"first_name"=>"Luke A J", "last_name"=>"O'Neill", "scopus_author_id"=>"7103393094"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"sgr"=>"84881493902", "issn"=>"19326203", "isbn"=>"1932-6203 (Electronic)\\r1932-6203 (Linking)", "pmid"=>"23967355", "doi"=>"10.1371/journal.pone.0074103", "pui"=>"369566653", "scopus"=>"2-s2.0-84881493902"}, "id"=>"e2be11e8-d011-374e-a5e2-c4c2c9498a7d", "abstract"=>"B cells signal through both the B cell receptor (BCR) which binds antigens and Toll-like receptors (TLRs) including TLR9 which recognises CpG DNA. Activation of TLR9 synergises with BCR signalling when the BCR and TLR9 co-localise within an auto-phagosome-like compartment. Here we report that Bruton's tyrosine kinase (BTK) is required for synergistic IL6 production and up-regulation of surface expression of MHC-class-II, CD69 and CD86 in primary murine and human B cells. We show that BTK is essential for co-localisation of the BCR and TLR9 within a potential auto-phagosome-like compartment in the Namalwa human B cell line. Downstream of BTK we find that calcium acting via calmodulin is required for this process. These data provide new insights into the role of BTK, an important target for autoimmune diseases, in B cell activation.", "link"=>"http://www.mendeley.com/research/brutons-tyrosine-kinase-mediates-synergistic-signalling-between-tlr9-b-cell-receptor-regulating-calc", "reader_count"=>27, "reader_count_by_academic_status"=>{"Student > Doctoral Student"=>3, "Researcher"=>6, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>4, "Professor"=>2}, "reader_count_by_user_role"=>{"Student > Doctoral Student"=>3, "Researcher"=>6, "Student > Ph. D. Student"=>7, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>1, "Student > Bachelor"=>4, "Professor"=>2}, "reader_count_by_subject_area"=>{"Unspecified"=>2, "Biochemistry, Genetics and Molecular Biology"=>2, "Agricultural and Biological Sciences"=>16, "Medicine and Dentistry"=>2, "Chemistry"=>1, "Immunology and Microbiology"=>4}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>2}, "Chemistry"=>{"Chemistry"=>1}, "Immunology and Microbiology"=>{"Immunology and Microbiology"=>4}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>16}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>2}, "Unspecified"=>{"Unspecified"=>2}}, "reader_count_by_country"=>{"Netherlands"=>1, "Austria"=>1, "India"=>1}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1169353"], "description"=>"<p>Primary murine B cells were isolated from the spleens of wild type mice, and stimulated with (A) CpG, anti-IgM or both for 48 hr, (B) LPS, anti-IgM or both for 48 hr at the concentrations shown or (C) pre-treated for 1 hr with the indicated concentrations of the BTK inhibitor and then stimulated with CpG, anti-IgM or both for 48 hr. The supernatants were then collected and IL6 production was measured by ELISA. (A) Data show mean ± standard deviation of a single experiment carried out in triplicate and are representative of three independent experiments. (B) Data show mean ± S.E.M of three independent experiments, each carried out in triplicate. (C) Data show mean ± S.E.M of three independent experiments each carried out in triplicate in which the concentration of IL6 produced by CpG and anti-IgM was set to 100% and all other simulations were normalised to this. IL6 levels induced maximally by CpG and anti-IgM ranged from 5–8.5 ng/ml across different mice. ***, p < 0.005, **, p < 0.01, * p < 0.05, not significant (NS) p > 0.05; significant differences between cells treated with DMSO control or BTK inhibitor and stimulated with CpG, anti-IgM or CpG plus anti-IgM.</p>", "links"=>[], "tags"=>["synergistic", "il6", "tlr9", "bcr", "stimulation", "murine"], "article_id"=>772182, "categories"=>["Biological Sciences"], "users"=>["Elaine F. Kenny", "Susan R. Quinn", "Sarah L. Doyle", "Paul M. Vink", "Hans van Eenennaam", "Luke A. J. O’Neill"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0074103.g001", "stats"=>{"downloads"=>0, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BTK_is_required_for_synergistic_IL6_production_in_response_to_TLR9_and_BCR_stimulation_in_primary_murine_B_cells_/772182", "title"=>"BTK is required for synergistic IL6 production in response to TLR9 and BCR stimulation in primary murine B cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:00:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169354"], "description"=>"<p>Primary human B cells were stimulated with (A) CpG, anti-IgM or both for 48 hr, (B) pre-treated for 1 hr with the indicated concentrations of the BTK inhibitor and then stimulated with CpG, anti-IgM or both for 48 hr. The supernatants were then collected and IL6 production was measured by ELISA. (A) Data show mean ± standard deviation of a single experiment carried out in triplicate and are representative of three independent experiments. (B) Data show mean ± S.E.M of three independent experiments each carried out in triplicate in which the concentration of IL6 produced by CpG and anti-IgM was set to 100% and all other simulations were normalised to this. IL6 levels induced maximally by CpG and anti-IgM ranged from 1–2.5 ng/ml across different donors. ***, p < 0.005, **, p < 0.01, * p < 0.05, not significant (NS) p > 0.05; significant differences between cells treated with DMSO control or BTK inhibitor and stimulated with CpG, anti-IgM or CpG plus anti-IgM. (C–D) Primary human B cells were stimulated for 24 hr with anti-IgM or CpG plus anti-IgM, stained with an anti-CD69 antibody or with an anti-CD86 antibody and analysed by FACS. Median fluorescent intensities (MFI) are shown. Data show mean ± spread of biological duplicate determinations. Results are representative of two independent experiments. (E) Primary human B cells were stimulated for 48 hr with CpG, anti-IgM, both or IL4, stained with an anti-FITC-MHC-class-II antibody or with an anti-FITC-IgG isotype control antibody and analysed by FACS. Mean fluorescent intensities (MFI) of stimulated versus stimulated plus inhibitor are shown. Results are representative of three independent experiments. (F) The mean fluorescence intensities from three independent experiments were combined to confirm that the BTK inhibitor significantly affected surface expression of MHC-II. Data show ± S.E.M of three independent experiments.</p>", "links"=>[], "tags"=>["synergistic", "il6", "activation", "tlr9", "bcr", "stimulation"], "article_id"=>772183, "categories"=>["Biological Sciences"], "users"=>["Elaine F. Kenny", "Susan R. Quinn", "Sarah L. Doyle", "Paul M. Vink", "Hans van Eenennaam", "Luke A. J. O’Neill"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0074103.g002", "stats"=>{"downloads"=>1, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BTK_is_required_for_synergistic_IL6_production_and_B_cell_activation_in_response_to_TLR9_and_BCR_stimulation_in_primary_human_B_cells_/772183", "title"=>"BTK is required for synergistic IL6 production and B cell activation in response to TLR9 and BCR stimulation in primary human B cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:00:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169355"], "description"=>"<p>Namalwa B cells were pre-treated with the BTK inhibitor for 1 hr and stimulated with (A) FITC-labelled CpG, (B) Alexa-fluor 647-labelled anti-IgM or (C) both for 16 hr. The cells were then examined by confocal microscopy. To confirm that BTK was required for this co-localisation 50 cells stimulated with CpG and anti-IgM were examined and the number of specks containing both proteins was counted yielding an average of 1.4 specks/cell. This was repeated for 50 cells pre-treated with the BTK inhibitor prior to CpG and anti-IgM stimulation and these cells contained an average of 3.5 specks/cell. A 2x2 contingency table chi-squared test was carried out on the total number of specks giving a <i>p</i> value of <0.001 indicating that TLR9 and the BCR were located in significantly more regions in the BTK inhibitor treated cells. Data are representative of at least four independent experiments (bars 5 µM) in which a minimum of 50 cells were examined.</p>", "links"=>[], "tags"=>["igm-dependent", "co-localisation", "tlr9", "bcr", "namalwa"], "article_id"=>772184, "categories"=>["Biological Sciences"], "users"=>["Elaine F. Kenny", "Susan R. Quinn", "Sarah L. Doyle", "Paul M. Vink", "Hans van Eenennaam", "Luke A. J. O’Neill"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0074103.g003", "stats"=>{"downloads"=>1, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_BTK_is_required_for_IgM_dependent_co_localisation_of_TLR9_and_the_BCR_in_Namalwa_B_cells_/772184", "title"=>"BTK is required for IgM-dependent co-localisation of TLR9 and the BCR in Namalwa B cells.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:00:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169357"], "description"=>"<p>Primary human B cells were pre-treated for 1 hr with (A) the PLC-γ2 inhibitor U-73122 or (D) the IP-3 receptor inhibitor, Xestospongin C. The cells were then stimulated with CpG, anti-IgM or both for 48 hr. The supernatants were collected and IL6 production was measured by ELISA. Data show mean ± S.E.M of three independent experiments each carried out in triplicate in which the concentration of IL6 produced by CpG and anti-IgM was set to 100% and all other simulations were normalised to this. Results are representative of three independent experiments. IL6 levels induced maximally by CpG and anti-IgM ranged from 0.6–1.5 ng/ml across different donors. ***, p < 0.005, **, p < 0.01, * p < 0.05, not significant (NS) p > 0.05; significant differences between cells treated with DMSO control or BTK inhibitor and stimulated with CpG, anti-IgM or CpG plus anti-IgM. (B) Primary human and Namalwa B cells were incubated with the BTK inhibitor for 1 hr, stimulated with CpG, anti-IgM or both for 30 min and the cell lysates were examined for phospho-PLC-γ2 and β-actin by SDS-PAGE and Western Blot analysis. Densitometric analysis of band intensities was determined, where each band was normalised to its β-actin and the relative intensity (R.I.) of the bands over the non-stimulated control (in lane 1) were calculated. (C) Namalwa human B cells were incubated with the BTK inhibitor for 30 min. The cells were then incubated with Fluo-3AM, a fluorescent calcium indicator, for 20 min. Basal levels of calcium were measured for 40 sec, the cells were stimulated with CpG, anti-IgM, both or ionomycin and analysed by FACS for a total of 200 sec. Mean fluorescent intensities (MFI) of stimulated versus stimulated plus inhibitor are shown. Results are representative of three independent experiments.</p>", "links"=>[], "tags"=>["ip-3", "tlr9", "bcr", "synergistic", "il6"], "article_id"=>772186, "categories"=>["Biological Sciences"], "users"=>["Elaine F. Kenny", "Susan R. Quinn", "Sarah L. Doyle", "Paul M. Vink", "Hans van Eenennaam", "Luke A. J. O’Neill"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0074103.g004", "stats"=>{"downloads"=>0, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_PLC_947_2_and_IP_3_are_required_for_TLR9_and_BCR_synergistic_IL6_production_/772186", "title"=>"PLC-γ2 and IP-3 are required for TLR9 and BCR synergistic IL6 production.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:00:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169358"], "description"=>"<p>Primary human B cells were pre-treated for 1 hr with (A) the BTK inhibitor or (B) the Ca<sup>2+</sup> chelator BAPTA and stimulated with CpG, anti-IgM, thapsigargin, CpG & anti-IgM and CpG & thapsigargin for 48 hr. Supernatants were collected and IL6 production was measured by ELISA. Data show mean ± S.E.M of three independent experiments each carried out in triplicate in which the concentration of IL6 produced by CpG and anti-IgM was set to 100% and all other simulations were normalised to this. IL6 levels induced maximally by CpG and anti-IgM ranged from 0.6-1.8 ng/ml across different donors. ***, p < 0.005, **, p < 0.01, * p < 0.05, not significant (NS) p > 0.05; significant differences between cells treated with DMSO control or BTK inhibitor and stimulated with CpG, anti-IgM, thapsigargin, CpG plus anti-IgM or CpG plus thapsigargin. (C) Namalwa B cells were pre-treated with BAPTA, incubated with Fluo-3AM and calcium flux was measured in response to the ligands indicated by FACS. Mean fluorescent intensities (MFI) of stimulated versus stimulated plus inhibitor are shown. (D) Namalwa B cells were pre-treated with BAPTA and stimulated for 16 hr with Alexa fluor-647-labelled anti-IgM. The cells were then examined by confocal microscopy (bars 5 µM) and a minimum of 50 cells were examined. To confirm that calcium was required for this pooling of the BCR 50 cells stimulated with anti-IgM were examined and the number of specks was counted yielding an average of 1.8 specks/cell. This was repeated for 50 cells pre-treated with BAPTA prior to stimulation and these cells contained an average of 5.5 specks/cell. A 2x2 contingency table chi-squared test was carried out on the total number of specks giving a <i>p</i> value of <0.001 indicating that the BCR was located in significantly more regions of the BAPTA treated cells. Results are representative of three independent experiments.</p>", "links"=>[], "tags"=>["tlr9", "bcr"], "article_id"=>772188, "categories"=>["Biological Sciences"], "users"=>["Elaine F. Kenny", "Susan R. Quinn", "Sarah L. Doyle", "Paul M. Vink", "Hans van Eenennaam", "Luke A. J. O’Neill"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0074103.g005", "stats"=>{"downloads"=>0, "page_views"=>3, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Calcium_is_required_for_TLR9_and_BCR_synergy_/772188", "title"=>"Calcium is required for TLR9 and BCR synergy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:00:29"}
  • {"files"=>["https://ndownloader.figshare.com/files/1169360"], "description"=>"<p>(A) Primary human B cells were pre-treated for 1 hr with W7 and stimulated with CpG, anti-IgM, or CpG & anti-IgM for 48 hr. Supernatants were collected and IL6 production was measured by ELISA. Data show mean ± S.E.M of three independent experiments each carried out in triplicate in which the concentration of IL6 produced by CpG and anti-IgM was set to 100% and all other simulations were normalised to this. IL6 levels induced maximally by CpG and anti-IgM ranged from 2.5–4 ng/ml across different donors. ***, p < 0.005, **, p < 0.01, * p < 0.05, not significant (NS) p > 0.05; significant differences between cells treated with DMSO control or BTK inhibitor and stimulated with CpG alone, anti-IgM alone or CpG plus anti-IgM. Namalwa B cells were stimulated for 16 hr with FITC-CpG, Alexa fluor-647-labelled anti-IgM, in the absence (B) or presence of 3 µM W7 (C), fixed and stained for EEA1. The cells were then examined by confocal microscopy (bars 5 µM) and a minimum of 50 cells were examined. To confirm that calmodulin was required for the co-localisation of TLR9, EEA1 and the BCR 50 cells stimulated with CpG plus anti-IgM were examined and the number of fluorescent specks were counted yielding an average of 1.7 specks/cell. This was repeated for 50 cells pre-treated with W7 prior to stimulation and these cells contained an average of 4.6 specks/cell. A 2x2 contingency table chi-squared test was carried out on the total number of specks giving a <i>p</i> value of <0.001 indicating that TLR9, the BCR and EEA1 were located in significantly more regions of the W7 treated cells. Results are representative of three independent experiments.</p>", "links"=>[], "tags"=>["calcium", "calmodulin", "tlr9", "bcr"], "article_id"=>772189, "categories"=>["Biological Sciences"], "users"=>["Elaine F. Kenny", "Susan R. Quinn", "Sarah L. Doyle", "Paul M. Vink", "Hans van Eenennaam", "Luke A. J. O’Neill"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0074103.g006", "stats"=>{"downloads"=>4, "page_views"=>27, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_The_calcium_sensor_calmodulin_is_essential_for_TLR9_and_BCR_synergy_/772189", "title"=>"The calcium sensor calmodulin is essential for TLR9 and BCR synergy.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-08-14 02:00:29"}

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Relative Metric

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