Matthew C Cook

Publications (29)329.69 Total impact

• Article: Roquin-2 Shares Functions with Its Paralog Roquin-1 in the Repression of mRNAs Controlling T Follicular Helper Cells and Systemic Inflammation.

  Alvin Pratama, Roybel R Ramiscal, Diego G Silva, Souvik K Das, Vicki Athanasopoulos, Jessica Fitch, Natalia K Botelho, Pheh-Ping Chang, Xin Hu, Jennifer J Hogan, Paula Maña, David Bernal, Heinrich Korner, Di Yu, Christopher C Goodnow, Matthew C Cook, Carola G Vinuesa
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  ABSTRACT: Accumulation of T follicular helper (Tfh) cells and proinflammatory cytokines drive autoantibody-mediated diseases. The RNA-binding protein Roquin-1 (Rc3h1) represses the inducible costimulator ICOS and interferon-γ (IFN-γ) in T cells to prevent Tfh cell accumulation. Unlike Rc3h1(san) mice with a mutation in the ROQ domain of Roquin-1, mice lacking the protein, paradoxically do not display increased Tfh cells. Here we have analyzed mice with mutations that eliminate the RING domain from Roquin-1 or its paralog, Roquin-2 (Rc3h2). RING or ROQ mutations both disrupted Icos mRNA regulation by Roquin-1, but, unlike the ROQ mutant that still occupied mRNA-regulating stress granules, RING-deficient Roquin-1 failed to localize to stress granules and allowed Roquin-2 to compensate in the repression of ICOS and Tfh cells. These paralogs also targeted tumor necrosis factor (TNF) in nonlymphoid cells, ameliorating autoantibody-induced arthritis. The Roquin family emerges as a posttranscriptional brake in the adaptive and innate phases of antibody responses.
  Immunity 04/2013; · 21.64 Impact Factor
• Article: Autoimmunity in primary antibody deficiency is associated with protein tyrosine phosphatase nonreceptor type 22 (PTPN22).

  Gary Y J Chew, Umang Sinha, Paul A Gatenby, Theo Demalmanche, Stephen Adelstein, Roger Garsia, Pravin Hissaria, Martyn A French, Anastasia Wilson, Belinda Whittle, Philippa Kirkpatrick, D Sean Riminton, David A Fulcher, Matthew C Cook
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  ABSTRACT: BACKGROUND: The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients. OBJECTIVE: We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD. METHODS: We genotyped rs2476601 (g.1858C>T), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes. RESULTS: C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P = .0014; odds ratio, 3.64; 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21(low) B cells. CONCLUSION: The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD.
  The Journal of allergy and clinical immunology 07/2012; · 9.17 Impact Factor
• Article: Functional STAT3 deficiency compromises the generation of human T follicular helper cells.

  Cindy S Ma, Danielle T Avery, Anna Chan, Marcel Batten, Jacinta Bustamante, Stephanie Boisson-Dupuis, Peter D Arkwright, Alexandra Y Kreins, Diana Averbuch, Dan Engelhard, [......], Sharon Choo, Joanne M Smart, Jane Peake, Melanie Wong, Paul Gray, Matthew C Cook, David A Fulcher, Jean-Laurent Casanova, Elissa K Deenick, Stuart G Tangye
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  ABSTRACT: T follicular helper (Tfh) cells are critical for providing the necessary signals to induce differentiation of B cells into memory and Ab-secreting cells. Accordingly, it is important to identify the molecular requirements for Tfh cell development and function. We previously found that IL-12 mediates the differentiation of human CD4(+) T cells to the Tfh lineage, because IL-12 induces naive human CD4(+) T cells to acquire expression of IL-21, BCL6, ICOS, and CXCR5, which typify Tfh cells. We have now examined CD4(+) T cells from patients deficient in IL-12Rβ1, TYK2, STAT1, and STAT3 to further explore the pathways involved in human Tfh cell differentiation. Although STAT1 was dispensable, mutations in IL12RB1, TYK2, or STAT3 compromised IL-12-induced expression of IL-21 by human CD4(+) T cells. Defective expression of IL-21 by STAT3-deficient CD4(+) T cells resulted in diminished B-cell helper activity in vitro. Importantly, mutations in STAT3, but not IL12RB1 or TYK2, also reduced Tfh cell generation in vivo, evidenced by decreased circulating CD4(+)CXCR5(+) T cells. These results highlight the nonredundant role of STAT3 in human Tfh cell differentiation and suggest that defective Tfh cell development and/or function contributes to the humoral defects observed in STAT3-deficient patients.
  Blood 03/2012; 119(17):3997-4008. · 9.90 Impact Factor
• Source

  Available from: Tri Giang Phan

  Article: Molecular pathogenesis of EBV susceptibility in XLP as revealed by analysis of female carriers with heterozygous expression of SAP.

  Umaimainthan Palendira, Carol Low, Anna Chan, Andrew D Hislop, Edwin Ho, Tri Giang Phan, Elissa Deenick, Matthew C Cook, D Sean Riminton, Sharon Choo, Richard Loh, Frank Alvaro, Claire Booth, H Bobby Gaspar, Alessandro Moretta, Rajiv Khanna, Alan B Rickinson, Stuart G Tangye
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  ABSTRACT: X-linked lymphoproliferative disease (XLP) is a primary immunodeficiency caused by mutations in SH2D1A which encodes SAP. SAP functions in signalling pathways elicited by the SLAM family of leukocyte receptors. A defining feature of XLP is exquisite sensitivity to infection with EBV, a B-lymphotropic virus, but not other viruses. Although previous studies have identified defects in lymphocytes from XLP patients, the unique role of SAP in controlling EBV infection remains unresolved. We describe a novel approach to this question using female XLP carriers who, due to random X-inactivation, contain both SAP(+) and SAP(-) cells. This represents the human equivalent of a mixed bone marrow chimera in mice. While memory CD8(+) T cells specific for CMV and influenza were distributed across SAP(+) and SAP(-) populations, EBV-specific cells were exclusively SAP(+). The preferential recruitment of SAP(+) cells by EBV reflected the tropism of EBV for B cells, and the requirement for SAP expression in CD8(+) T cells for them to respond to Ag-presentation by B cells, but not other cell types. The inability of SAP(-) clones to respond to Ag-presenting B cells was overcome by blocking the SLAM receptors NTB-A and 2B4, while ectopic expression of NTB-A on fibroblasts inhibited cytotoxicity of SAP(-) CD8(+) T cells, thereby demonstrating that SLAM receptors acquire inhibitory function in the absence of SAP. The innovative XLP carrier model allowed us to unravel the mechanisms underlying the unique susceptibility of XLP patients to EBV infection in the absence of a relevant animal model. We found that this reflected the nature of the Ag-presenting cell, rather than EBV itself. Our data also identified a pathological signalling pathway that could be targeted to treat patients with severe EBV infection. This system may allow the study of other human diseases where heterozygous gene expression from random X-chromosome inactivation can be exploited.
  PLoS Biology 11/2011; 9(11):e1001187. · 11.45 Impact Factor
• Article: Foxp3⁺ regulatory T cells exert asymmetric control over murine helper responses by inducing Th2 cell apoptosis.

  Lei Tian, John A Altin, Lydia E Makaroff, Dean Franckaert, Matthew C Cook, Christopher C Goodnow, James Dooley, Adrian Liston
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  ABSTRACT: Foxp3(+) regulatory T cells play a pivotal role in maintaining self-tolerance and immune homeostasis. In the absence of regulatory T cells, generalized immune activation and multiorgan T cell-driven pathology occurs. Although the phenomenon of immunologic control by Foxp3(+) regulatory T cells is well recognized, the comparative effect over different arms of the immune system has not been thoroughly investigated. Here, we generated a cohort of mice with a continuum of regulatory T-cell frequencies ranging from physiologic levels to complete deficiency. This titration of regulatory T-cell depletion was used to determine how different effector subsets are controlled. We found that in vivo Foxp3(+) regulatory T-cell frequency had a proportionate relationship with generalized T-cell activation and Th1 magnitude, but it had a surprising disproportionate relationship with Th2 magnitude. The asymmetric regulation was associated with efficient suppression of Th2 cells through additional regulations on the apoptosis rate in Th2 cells and not Th1 cells and could be replicated by CTLA4-Ig or anti-IL-2 Ab. These results indicate that the Th2 arm of the immune system is under tighter control by regulatory T cells than the Th1 arm, suggesting that Th2-driven diseases may be more responsive to regulatory T-cell manipulation.
  Blood 06/2011; 118(7):1845-53. · 9.90 Impact Factor
• Article: Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3-positive regulatory versus T(H)2 effector cells to cause allergy.

  John A Altin, Lei Tian, Adrian Liston, Edward M Bertram, Christopher C Goodnow, Matthew C Cook
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  ABSTRACT: Allergy, the most common disease of immune dysregulation, has a substantial genetic component that is poorly understood. Although complete disruption of T-cell receptor (TCR) signaling causes profound immunodeficiency, little is known about the consequences of inherited genetic variants that cause partial quantitative decreases in particular TCR-signaling pathways, despite their potential to dysregulate immune responses and cause immunopathology. We sought to elucidate how an inherited decrease in TCR signaling through CARD11, a critical scaffold protein that signals to nuclear factor κB (NF-κB) transcription factors, results in spontaneous selective accumulation of large numbers of T(H)2 cells. "Unmodulated" mice carry a Card11 single nucleotide variant that decreases but does not abolish TCR/CD28 signaling to induce targets of NF-κB. The consequences of this mutation on T-cell subset formation in vivo were examined, and its effects within effector versus regulatory T-cell subsets were dissected by the adoptive transfer of wild-type cells and by the examination of forkhead box protein 3 (Foxp3)-deficient unmodulated mice. Unlike the pathology-free boundary points of complete Card11 sufficiency or deficiency, unmodulated mice have a specific allergic condition characterized by increased IgE levels and dermatitis. The single nucleotide variant partially decreases both the frequency of Foxp3(+) regulatory T cells and the efficiency of effector T-cell formation in vivo. These intermediate effects combine to cause a gradual and selective expansion of T(H)2 cells. Inherited reduction in the efficiency of TCR-NF-κB signaling has graded effects on T-cell activation and Foxp3(+) regulatory T-cell suppression that result in selective T(H)2 dysregulation and allergic disease.
  The Journal of allergy and clinical immunology 02/2011; 127(5):1277-85.e5. · 9.17 Impact Factor
• Article: Blood relatives of follicular helper T cells.

  Carola G Vinuesa, Matthew C Cook
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  ABSTRACT: Expression of the chemokine receptor CXCR5 identifies B follicular helper T cells. In this issue of Immunity, Morita et al. (2011) describe a heterogeneous circulating CXCR5(+)CD4(+) B cell helper population overrepresented in juvenile dermatomyositis patients.
  Immunity 01/2011; 34(1):10-2. · 21.64 Impact Factor
• Source

  Available from: Stuart G Tangye

  Article: IL-27 supports germinal center function by enhancing IL-21 production and the function of T follicular helper cells.

  Marcel Batten, Nandhini Ramamoorthi, Noelyn M Kljavin, Cindy S Ma, Jennifer H Cox, Hart S Dengler, Dimitry M Danilenko, Patrick Caplazi, Melanie Wong, David A Fulcher, Matthew C Cook, Cecile King, Stuart G Tangye, Frederic J de Sauvage, Nico Ghilardi
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  ABSTRACT: Maturation and selection of high-affinity B cell clones in the germinal center (GC) relies on support from T follicular helper (T(FH)) cells. T(FH) cells are characterized by their localization to the B cell follicle and their high expression of the costimulatory molecules ICOS and PD1 and the cytokine IL-21, which promotes immunoglobulin (Ig) class switching and production by B cells. We show that the heterodimeric cytokine IL-27 is critical for the function of T(FH) cells and for normal and pathogenic GC responses. IL-27 signaling to T cells results in the production of IL-21, a known autocrine factor for the maintenance of T(FH) cells, in a STAT3-dependent manner. IL-27 also enhances the survival of activated CD4(+) T cells and the expression of T(FH) cell phenotypic markers. In vivo, expression of the IL-27Rα chain is required to support IL-21 production and T(FH) cell survival in a T cell-intrinsic manner. The production of high-affinity antibodies is reduced, and pristane-elicited autoantibodies and glomerulonephritis are significantly diminished, in Il27ra(-/-) mice. Together, our data show a nonredundant role for IL-27 in the development of T cell-dependent antibody responses.
  Journal of Experimental Medicine 12/2010; 207(13):2895-906. · 13.85 Impact Factor
• Article: Heterophile interference accounts for method-specific dsDNA antibodies in patients receiving anti-TNF treatment.

  Jalila Alshekaili, Candice Li, Matthew C Cook
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  ABSTRACT: To evaluate analytical explanations for the highly reported incidence of antibodies to dsDNA in patients receiving TNF antagonists. Sixty serum samples from patients receiving biological anti-TNF medication were assessed for the presence of dsDNA antibodies using three standard diagnostic platforms [ELISA, IIF and multiplex bead array (MBA)], before and after treatment to block heterophile antibodies. Results were compared with those obtained using serum samples from patients with SLE. We identified significant method-specific discrepancies in the estimation of dsDNA antibodies in patients receiving TNF antagonists. dsDNA antibodies were frequent according to ELISA and IIF, but rare according to MBA. Blockade of heterophile antibodies resulted in a significant reduction in titres of dsDNA antibodies detected by IIF. In contrast, there was a much greater consistency for dsDNA antibody results in SLE, especially for those present in high titre, and blockade of heterophile antibodies did not result in a change between the two paired samples by IIF or MBA. There is a significant method-specific variation in the detection of dsDNA antibodies in patients receiving TNF antagonists, due in part to the effects of heterophile antibodies.
  Rheumatology (Oxford, England) 02/2010; 49(5):891-7. · 4.24 Impact Factor
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  Available from: Jane Elizabeth Peake

  Article: B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans.

  Danielle T Avery, Elissa K Deenick, Cindy S Ma, Santi Suryani, Nicholas Simpson, Gary Y Chew, Tyani D Chan, Umamainthan Palendira, Jacinta Bustamante, Stéphanie Boisson-Dupuis, [......], Joachim Roesler, Peter D Arkwright, Pravin Hissaria, D Sean Riminton, Melanie Wong, Robert Brink, David A Fulcher, Jean-Laurent Casanova, Matthew C Cook, Stuart G Tangye
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  ABSTRACT: Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
  Journal of Experimental Medicine 01/2010; 207(1):155-71. · 13.85 Impact Factor
• Article: Expansion of circulating T cells resembling follicular helper T cells is a fixed phenotype that identifies a subset of severe systemic lupus erythematosus.

  Nicholas Simpson, Paul A Gatenby, Anastasia Wilson, Shreya Malik, David A Fulcher, Stuart G Tangye, Harinder Manku, Timothy J Vyse, Giovanna Roncador, Gavin A Huttley, Christopher C Goodnow, Carola G Vinuesa, Matthew C Cook
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  ABSTRACT: In the sanroque mouse model of lupus, pathologic germinal centers (GCs) arise due to increased numbers of follicular helper T (Tfh) cells, resulting in high-affinity anti-double-stranded DNA antibodies that cause end-organ inflammation, such as glomerulonephritis. The purpose of this study was to examine the hypothesis that this pathway could account for a subset of patients with systemic lupus erythematosus (SLE). An expansion of Tfh cells is a causal, and therefore consistent, component of the sanroque mouse phenotype. We validated the enumeration of circulating T cells resembling Tfh cells as a biomarker of this expansion in sanroque mice, and we performed a comprehensive comparison of the surface phenotype of circulating and tonsillar Tfh cells in humans. This circulating biomarker was enumerated in SLE patients (n = 46), Sjögren's syndrome patients (n = 17), and healthy controls (n = 48) and was correlated with disease activity and end-organ involvement. In sanroque mice, circulating Tfh cells increased in proportion to their GC counterparts, making circulating Tfh cells a feasible human biomarker of this novel mechanism of breakdown in GC tolerance. In a subset of SLE patients (14 of 46), but in none of the controls, the levels of circulating Tfh cells (defined as circulating CXCR5+CD4+ cells with high expression of Tfh-associated molecules, such as inducible T cell costimulator or programmed death 1) were increased. This cellular phenotype did not vary with time, disease activity, or treatment, but it did correlate with the diversity and titers of autoantibodies and with the severity of end-organ involvement. These findings in SLE patients are consistent with the autoimmune mechanism in sanroque mice and identify Tfh effector molecules as possible therapeutic targets in a recognizable subset of patients with SLE.
  Arthritis & Rheumatism 01/2010; 62(1):234-44. · 7.87 Impact Factor
• Article: Dysregulation of germinal centres in autoimmune disease.

  Carola G Vinuesa, Iñaki Sanz, Matthew C Cook
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  ABSTRACT: In germinal centres, somatic hypermutation and B cell selection increase antibody affinity and specificity for the immunizing antigen, but the generation of autoreactive B cells is an inevitable by-product of this process. Here, we review the evidence that aberrant selection of these autoreactive B cells can arise from abnormalities in each of the germinal centre cellular constituents--B cells, T follicular helper cells, follicular dendritic cells and tingible body macrophages--or in the supply of antigen. As the progeny of germinal centre B cells includes long-lived plasma cells, selection of autoreactive B cells can propagate long-lived autoantibody responses and cause autoimmune diseases. Elucidation of crucial molecular signals in germinal centres has led to the identification of novel therapeutic targets.
  Nature Reviews Immunology 12/2009; 9(12):845-57. · 32.25 Impact Factor
• Article: Primary immune deficiencies affecting lymphocyte differentiation: lessons from the spectrum of resulting infections.

  Matthew C Cook, Stuart G Tangye
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  ABSTRACT: Understanding primary immunodeficiencies has elucidated many aspects of human immunity and susceptibility to infections. Recently, defects have been identified that result in deficiencies of terminally differentiated subsets of lymphocytes including deficiencies of memory B cells, NKT cells and T(h)17 T cells. Together with defects specific to T(h)1 responses, these disorders revealed that dedicated pathogen-specific mechanisms exist for prevalent human pathogens, and that some host defence strategies are remarkably specific. Deficiency of T(h)17 cells confirms that this subset of effector T cells is important for defence at epithelial surfaces. The clinical phenotype includes devastating complications from infection with Staphylococcus aureus. Since the microbial load at human epithelial surfaces is substantial and enormously diverse, this specificity could hold clues that are important for understanding first the complex symbiosis with mucosal commensals and second for understanding the consequences of manipulating these populations in inflammatory diseases.
  International Immunology 09/2009; 21(9):1003-11. · 3.41 Impact Factor
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  Available from: PubMed Central

  Article: Follicular helper T cells are required for systemic autoimmunity.

  Michelle A Linterman, Robert J Rigby, Raphael K Wong, Di Yu, Robert Brink, Jennifer L Cannons, Pamela L Schwartzberg, Matthew C Cook, Giles D Walters, Carola G Vinuesa
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  ABSTRACT: Production of high-affinity pathogenic autoantibodies appears to be central to the pathogenesis of lupus. Because normal high-affinity antibodies arise from germinal centers (GCs), aberrant selection of GC B cells, caused by either failure of negative selection or enhanced positive selection by follicular helper T (T(FH)) cells, is a plausible explanation for these autoantibodies. Mice homozygous for the san allele of Roquin, which encodes a RING-type ubiquitin ligase, develop GCs in the absence of foreign antigen, excessive T(FH) cell numbers, and features of lupus. We postulated a positive selection defect in GCs to account for autoantibodies. We first demonstrate that autoimmunity in Roquin(san/san) (sanroque) mice is GC dependent: deletion of one allele of Bcl6 specifically reduces the number of GC cells, ameliorating pathology. We show that Roquin(san) acts autonomously to cause accumulation of T(FH) cells. Introduction of a null allele of the signaling lymphocyte activation molecule family adaptor Sap into the sanroque background resulted in a substantial and selective reduction in sanroque T(FH) cells, and abrogated formation of GCs, autoantibody formation, and renal pathology. In contrast, adoptive transfer of sanroque T(FH) cells led to spontaneous GC formation. These findings identify T(FH) dysfunction within GCs and aberrant positive selection as a pathway to systemic autoimmunity.
  Journal of Experimental Medicine 03/2009; 206(3):561-76. · 13.85 Impact Factor
• Article: Insights into the role of STAT3 in human lymphocyte differentiation as revealed by the hyper-IgE syndrome.

  Stuart G Tangye, Matthew C Cook, David A Fulcher
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  ABSTRACT: "Experiments of nature" due to single gene mutations resulting in human immunodeficiency states have revealed critical roles for several genes in regulating lymphocyte development and the generation of protective immunity. Recently, heterozygous mutations in STAT3 were found to cause autosomal dominant hyper-IgE syndrome, a condition affecting not only the immune system but also other mesenchymal and ectodermal tissues, including bones, cranium, teeth, and skin. STAT proteins operate to integrate signals from surface receptors, including cytokine receptors, that regulate growth and differentiation of multiple cell lineages. In this article, we will review how the study of STAT3 deficiency in humans and mice has highlighted nonredundant roles of STAT3, and of specific cytokines, in diverse cellular processes such as antimicrobial immunity and protection at epithelial barriers, the generation of functional humoral immune responses, bone formation, and keratinocyte biology.
  The Journal of Immunology 02/2009; 182(1):21-8. · 5.79 Impact Factor
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  Available from: Stuart G Tangye

  Article: Deficiency of Th17 cells in hyper IgE syndrome due to mutations in STAT3.

  Cindy S Ma, Gary Y J Chew, Nicholas Simpson, Archana Priyadarshi, Melanie Wong, Bodo Grimbacher, David A Fulcher, Stuart G Tangye, Matthew C Cook
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  ABSTRACT: Hyper-immunoglobulin E syndrome (HIES) is a primary immune deficiency characterized by abnormal and devastating susceptibility to a narrow spectrum of infections, most commonly Staphylococcus aureus and Candida albicans. Recent investigations have identified mutations in STAT3 in the majority of HIES patients studied. Despite the identification of the genetic cause of HIES, the mechanisms underlying the pathological features of this disease remain to be elucidated. Here, we demonstrate a failure of CD4+ T cells harboring heterozygous STAT3 mutations to generate interleukin 17-secreting (i.e., T helper [Th]17) cells in vivo and in vitro due to a failure to express sufficient levels of the Th17-specific transcriptional regulator retinoid-related orphan receptor t. Because Th17 cells are enriched for cells with specificities against fungal antigens, our results may explain the pattern of infection susceptibility characteristic of patients with HIES. Furthermore, they underscore the importance of Th17 responses in normal host defense against the common pathogens S. aureus and C. albicans.
  Journal of Experimental Medicine 08/2008; 205(7):1551-7. · 13.85 Impact Factor
• Article: STAT3 is required for IL-21-induced secretion of IgE from human naive B cells.

  Danielle T Avery, Cindy S Ma, Vanessa L Bryant, Brigitte Santner-Nanan, Ralph Nanan, Melanie Wong, David A Fulcher, Matthew C Cook, Stuart G Tangye
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  ABSTRACT: The production of immunoglobulin E (IgE) is tightly regulated. This is evidenced by the fact that it comprises less than 0.0001% of serum Ig, and aberrant production causes atopic conditions, including allergy, rhinitis, and anaphylaxis. Interleukin-4 (IL-4) is a well-characterized inducer of IgE by human and murine B cells, whereas interferon-gamma can antagonize this effect. IL-21 has also been recognized for its ability to suppress IL-4-induced IgE production by murine B cells. Here, we identified IL-21 as an inducer of IgE production by CD40L-stimulated human naive B cells. Furthermore, there was a striking synergy between IL-4 and IL-21 on inducing IgE secretion by CD40L-stimulated human B cells, such that the levels detected under these conditions exceeded those induced by IL-4 or IL-21 alone by more than 10-fold. IL-21 induced activation of STAT3 and analysis of B cells from patients with loss-of-function STAT3 mutations revealed that the ability of IL-21 to induce IgE secretion, and augment that driven by IL-4, was STAT3-dependent. These findings highlight a fundamental difference between the regulation of IgE production by human and murine B cells and have implications for the dysregulated production of IgE in conditions characterized by extremely high levels of serum IgE.
  Blood 06/2008; 112(5):1784-93. · 9.90 Impact Factor
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  Available from: Michael A Mcguckin

  Article: Aberrant mucin assembly in mice causes endoplasmic reticulum stress and spontaneous inflammation resembling ulcerative colitis.

  Chad K Heazlewood, Matthew C Cook, Rajaraman Eri, Gareth R Price, Sharyn B Tauro, Douglas Taupin, David J Thornton, Chin Wen Png, Tanya L Crockford, Richard J Cornall, Rachel Adams, Masato Kato, Keats A Nelms, Nancy A Hong, Timothy H J Florin, Christopher C Goodnow, Michael A McGuckin
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  ABSTRACT: MUC2 mucin produced by intestinal goblet cells is the major component of the intestinal mucus barrier. The inflammatory bowel disease ulcerative colitis is characterized by depleted goblet cells and a reduced mucus layer, but the aetiology remains obscure. In this study we used random mutagenesis to produce two murine models of inflammatory bowel disease, characterised the basis and nature of the inflammation in these mice, and compared the pathology with human ulcerative colitis. By murine N-ethyl-N-nitrosourea mutagenesis we identified two distinct noncomplementing missense mutations in Muc2 causing an ulcerative colitis-like phenotype. 100% of mice of both strains developed mild spontaneous distal intestinal inflammation by 6 wk (histological colitis scores versus wild-type mice, p < 0.01) and chronic diarrhoea. Monitoring over 300 mice of each strain demonstrated that 25% and 40% of each strain, respectively, developed severe clinical signs of colitis by age 1 y. Mutant mice showed aberrant Muc2 biosynthesis, less stored mucin in goblet cells, a diminished mucus barrier, and increased susceptibility to colitis induced by a luminal toxin. Enhanced local production of IL-1beta, TNF-alpha, and IFN-gamma was seen in the distal colon, and intestinal permeability increased 2-fold. The number of leukocytes within mesenteric lymph nodes increased 5-fold and leukocytes cultured in vitro produced more Th1 and Th2 cytokines (IFN-gamma, TNF-alpha, and IL-13). This pathology was accompanied by accumulation of the Muc2 precursor and ultrastructural and biochemical evidence of endoplasmic reticulum (ER) stress in goblet cells, activation of the unfolded protein response, and altered intestinal expression of genes involved in ER stress, inflammation, apoptosis, and wound repair. Expression of mutated Muc2 oligomerisation domains in vitro demonstrated that aberrant Muc2 oligomerisation underlies the ER stress. In human ulcerative colitis we demonstrate similar accumulation of nonglycosylated MUC2 precursor in goblet cells together with ultrastructural and biochemical evidence of ER stress even in noninflamed intestinal tissue. Although our study demonstrates that mucin misfolding and ER stress initiate colitis in mice, it does not ascertain the genetic or environmental drivers of ER stress in human colitis. Characterisation of the mouse models we created and comparison with human disease suggest that ER stress-related mucin depletion could be a fundamental component of the pathogenesis of human colitis and that clinical studies combining genetics, ER stress-related pathology and relevant environmental epidemiology are warranted.
  PLoS Medicine 04/2008; 5(3):e54. · 16.27 Impact Factor
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  Available from: Herbert C Morse

  Article: Axon growth and guidance genes identify T-dependent germinal centre B cells.

  Di Yu, Matthew C Cook, Dong-Mi Shin, Diego G Silva, Jennifer Marshall, Kai-Michael Toellner, Wendy L Havran, Pico Caroni, Michael P Cooke, Herbert C Morse, Ian C M MacLennan, Christopher C Goodnow, Carola G Vinuesa
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  ABSTRACT: Selection of B cells subjected to hypermutation in germinal centres (GC) during T cell-dependent (TD) antibody responses yields memory cells and long-lived plasma cells that produce high affinity antibodies biased to foreign antigens rather than self-antigens. GC also form in T-independent (TI) responses to polysaccharide antigens but failed selection results in GC involution and memory cells are not generated. To date there are no markers that allow phenotypic distinction of T-dependent and TI germinal centre B cells. We compared the global gene expression of GC B cells purified from mice immunized with either TD or TI antigens and identified eighty genes that are differentially expressed in TD GC. Significantly, the largest cluster comprises genes involved in growth and guidance of neuron axons such as Plexin B2, Basp1, Nelf, Shh, Sc4mol and Sult4alpha. This is consistent with formation of long neurite (axon and dendrite)-like structures by mouse and human GC B cells, which may facilitate T:B cell interactions within GC, affinity maturation and B cell memory formation. Expression of BASP1 and PLEXIN B2 protein is very low or undetectable in resting and TI GC B cells, but markedly upregulated in GC B cells induced in the presence of T cell help. Finally we show some of the axon growth genes upregulated in TD-GC B cells including Basp1, Shh, Sult4alpha, Sc4mol are also preferentially expressed in post-GC B cell neoplasms.
  Immunology and Cell Biology 02/2008; 86(1):3-14. · 3.66 Impact Factor
• Article: Genetic analysis of systemic autoimmunity.

  Carola G Vinuesa, Matthew C Cook
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  ABSTRACT: Even for complex diseases with high rates of monozygotic twin concordance, disease-associated alleles remain elusive. One explanation is that multiple common genetic variants with weak effects cause these diseases and identification of any single allele requires large cohorts. Conversely, if the allelic spectrum of complex disease is heterogeneous, strong effects of rare variants might be offset by their presence in only a small proportion of the patient population. Lupus (SLE) is a systemic autoimmune disease, with significant monozygotic twin concordance, protean clinical manifestations, and production of high-affinity pathogenic autoantibodies. This complex phenotype and results from genome scans point to multiple molecular defects. Contrary to this expectation, our analysis of ENU-mutagenized mice indicates that homozygous mutations frequently cause anti-nuclear antibodies (ANAs), and can account for a full blown lupus phenotype. The best characterized example is the sanroque strain, which develops high-affinity dsDNA autoantibodies and fails to censor self-reactive germinal centre T cells. Mapping the underlying mutation identified not only a novel gene, Roquin, but also a novel pathogenic pathway for SLE. Identification of such rare variants with strong effects is likely to identify pathogenic pathways that underlie pathology in many patients, lead to interacting molecular partners that also cause pathology, and identify the most effective therapeutic targets.
  Novartis Foundation symposium 02/2007; 281:103-20; discussion 120-8, 208-9.