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Chia-Lin Hsu,
Weiyu Lin, Dhaya Seshasayee,
Yung-Hsiang Chen,
Xiao Ding,
Zhonghua Lin,
Eric Suto,
Zhiyu Huang,
Wyne P Lee,
Hyunjoo Park, [......],
Jeff L Lutman,
Sheila Ulufatu,
Eric Stefanich,
Cecile Chalouni,
Meredith Sagolla,
Lauri Diehl,
Paul Fielder,
Brian Dean,
Mercedesz Balazs,
Flavius Martin
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ABSTRACT: Lysosomal storage diseases (LSDs) are a group of heterogeneous disorders caused by defects in lysosomal enzymes or transporters, resulting in accumulation of undegraded macromolecules or metabolites. Macrophage numbers are expanded in several LSDs, leading to histiocytosis of unknown pathophysiology. Here, we found that mice lacking the equilibrative nucleoside transporter 3 (ENT3) developed a spontaneous and progressive macrophage-dominated histiocytosis. In the absence of ENT3, defective apoptotic cell clearance led to lysosomal nucleoside buildup, elevated intralysosomal pH, and altered macrophage function. The macrophage accumulation was partly due to increased macrophage colony-stimulating factor and receptor expression and signaling secondary to the lysosomal defects. These studies suggest a cellular and molecular basis for the development of histiocytosis in several human syndromes associated with ENT3 mutations and potentially other LSDs.
Science 12/2011; 335(6064):89-92. · 31.20 Impact Factor
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ABSTRACT: Sh2d3c is an adaptor protein that has been implicated in T cell activation and shown to associate with different components of the integrin signaling pathway ex vivo. However, the in vivo significance of Sh2d3c expression in the regulation of the immune response and/or hematopoietic cell lineage development is not known. In this study, we show that expression of Sh2d3c is more critical for development and function of marginal zone B (MZB) cells than for T cell maturation. Mice deficient in Sh2d3c expression (Sh2d3c(-/-)) had a reduced number of MZB cells, and the residual MZB cells failed to properly capture polysaccharide Ags. Activation-induced proliferation, cytokine production, and migration of Sh2d3c(-)(/)(-) splenic B cells were also significantly reduced in vitro compared with wild-type (Sh2d3c(+/+)) cells. In contrast, T cell development and function were largely normal in Sh2d3c(-/-) mice. The thymi of Sh2d3c(-/-) mice showed no maturational abnormalities, the number of splenic T cells was only modestly reduced, and the T cells responded normally to in vitro polyclonal activation. The observed B cell deficiency in the Sh2d3c(-/-) mice led to diminished humoral immune response against thymus-independent type 2, but not thymus-dependent Ags, which highlights the primary in vivo role of Sh2d3c in regulating B cell development and function.
The Journal of Immunology 07/2010; 185(1):327-34. · 5.79 Impact Factor
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Dhaya Seshasayee,
Wyne P Lee,
Meijuan Zhou,
Jean Shu,
Eric Suto,
Juan Zhang,
Laurie Diehl,
Cary D Austin,
Y Gloria Meng,
Martha Tan, [......],
Stefan Seeber,
Maria E Fuentes,
Aran F Labrijn,
Yvo M F Graus,
Lisa A Miller,
Edward S Schelegle,
Dallas M Hyde,
Lawren C Wu,
Sarah G Hymowitz,
Flavius Martin
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ABSTRACT: Thymic stromal lymphopoietin (TSLP) potently induces deregulation of Th2 responses, a hallmark feature of allergic inflammatory diseases such as asthma, atopic dermatitis, and allergic rhinitis. However, direct downstream in vivo mediators in the TSLP-induced atopic immune cascade have not been identified. In our current study, we have shown that OX40 ligand (OX40L) is a critical in vivo mediator of TSLP-mediated Th2 responses. Treating mice with OX40L-blocking antibodies substantially inhibited immune responses induced by TSLP in the lung and skin, including Th2 inflammatory cell infiltration, cytokine secretion, and IgE production. OX40L-blocking antibodies also inhibited antigen-driven Th2 inflammation in mouse and nonhuman primate models of asthma. This treatment resulted in both blockade of the OX40-OX40L receptor-ligand interaction and depletion of OX40L-positive cells. The use of a blocking, OX40L-specific mAb thus presents a promising strategy for the treatment of allergic diseases associated with pathologic Th2 immune responses.
Journal of Clinical Investigation 01/2008; 117(12):3868-78. · 15.39 Impact Factor
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Wei Yu Lin,
Qian Gong, Dhaya Seshasayee,
Zhonghua Lin,
Qinglin Ou,
Shiming Ye,
Eric Suto,
Jean Shu,
Wyne Pun Lee,
Ching-Wei V Lee, [......],
Joseph Beyer,
Dimitry Danilenko,
Sherry Yeh,
Laura E DeForge,
Allen Ebens,
Jeffrey S Thompson,
Christine Ambrose,
Mercedesz Balazs,
Melissa A Starovasnik,
Flavius Martin
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ABSTRACT: Removal of pathogenic B lymphocytes by depletion of monoclonal antibodies (mAbs) or deprivation of B-cell survival factors has demonstrated clinical benefit in both oncologic and immunologic diseases. Partial clinical responses and emerging data demonstrating incomplete B-cell depletion after immunotherapy fuels the need for improved therapeutic modalities. Lessons from the first generation of therapeutics directed against B-cell-specific antigens (CD20, CD22) are being applied to develop novel antibodies with additional functional attributes. We describe the generation of a novel class of B-cell-directed therapy (anti-BR3 mAbs) that combines the depleting capacity of a therapeutic mAb and blockade of B-cell-activating factor (BAFF)-BR3 B-cell survival. In mice, treatment with antagonistic anti-BR3 antibodies results in quantitatively greater reduction in some B-cell subsets and qualitatively different effects on bone marrow plasma cells compared with BR3-Fc BAFF blockade or with anti-CD20 treatment. Comparative analysis of BR3-Fc and anti-BR3 mAb reveals a lower B-cell dependence for BAFF-mediated survival in nonhuman primates than in mice. This novel class of B-cell-targeted therapies shows species characteristics in mice and primates that will guide translation to treatment of human disease.
Blood 01/2008; 110(12):3959-67. · 9.90 Impact Factor
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Yulia Vugmeyster, Dhaya Seshasayee,
Wesley Chang,
Anahid Storn,
Kathy Howell,
Susan Sa,
Tenea Nelson,
Flavius Martin,
Iqbal Grewal,
Ellen Gilkerson,
Ben Wu,
Jeff Thompson,
Barbara N Ehrenfels,
Song Ren,
An Song,
Thomas R Gelzleichter,
Dimitry M Danilenko
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ABSTRACT: BAFF (also known as BLyS), a member of the tumor necrosis factor superfamily, plays a critical role in the maturation and development of B cells. BAFF has three receptors on B cells, the most crucial of which is BR3. In this study, we demonstrate the biological outcome of BAFF blockade in cynomolgus monkeys using a soluble fusion protein consisting of human BR3 and human IgG1 Fc. In vitro, BR3-Fc blocked BAFF-mediated survival and proliferation of cynomolgus monkey B cells. Weekly treatment of cynomolgus monkeys with BR3-Fc for 13 to 18 weeks resulted in significant B-cell reduction in the peripheral blood and in lymphoid organs. CD21(high) B cells in lymphoid tissues, a subset analogous to human marginal zone B cells, expressed nearly twofold higher BR3 levels than did CD21(med) B cells. Lymphoid tissue flow cytometric analysis showed that BR3-Fc reduced this CD21(high) B-cell subset to a greater extent than it reduced CD21(med) B cells. Dual-label immunohistochemistry and morphometric image analysis supported these results by demonstrating that BR3-Fc reduced a significant proportion of the B cells within the splenic inner and outer marginal zones. These findings should prove very useful in guiding the desired therapeutic use of BR3-Fc for autoimmune diseases in the clinic.
American Journal Of Pathology 03/2006; 168(2):476-89. · 4.89 Impact Factor
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ABSTRACT: Osteoprotegerin Ligand (OPGL) is a member of the tumor necrosis factor ligand superfamily and has been shown to be involved in interactions between T cells and dendritic cells. Its role in monocyte effector function, however, has not been defined. In the present study a role for OPGL in activating monocytes/macrophages has been characterized. OPGL was found to up-regulate receptor activator of NF-kappaB (RANK) receptor expression on monocytes, regulate their effector function by inducing cytokine and chemokine secretion, activate antigen presentation through up-regulation of co-stimulatory molecule expression, and promote survival. This activation is mediated through the MAPK pathway as evidenced by activation of p38 and p42/44 MAPK and up-regulation of BCL-XL protein levels. A physiological role for OPGL in monocyte activation and effector function was tested in a model of lipopolysaccharide-induced endotoxic shock. Administration of receptor activator of NF-kappaB (RANK)-Fc to block OPGL activity in vivo was able to protect mice from death induced by sepsis, indicating a hitherto undescribed role for OPGL in monocyte function and in mediating inflammatory response. This was further tested in an animal model of inflammation-mediated arthritis. Treatment with RANK-Fc significantly ameliorated disease development and attenuated bone destruction. Thus, our study strongly suggests that administration of receptor fusion proteins to specifically block OPGL activity in vivo may result in blocking development of monocyte/macrophage-mediated diseases.
Journal of Biological Chemistry 08/2004; 279(29):30202-9. · 4.77 Impact Factor
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ABSTRACT: The CD28 co-stimulatory pathway is well established for T cell activation; however, results from CD28 -/- mice suggest the existence of additional co-stimulatory pathways. Here we report the further characterization of a new member of the CD2 superfamily, NTB-A, important in T cell co-stimulation. NTB-A is expressed on T cells, and its expression is up-regulated on activated cells. Triggering of NTB-A with monoclonal antibodies in the absence of CD28 signals leads to T cell proliferation and interferon-gamma secretion but not interleukin-4. Cross-linking of NTB-A also induces phosphorylation of NTB-A and the association of SAP (SLAM-associated protein), the protein absent in X-linked lymphoproliferative disease. T helper cells differentiated by cross-linking NTB-A and CD3 developed predominantly into Th1 cells not Th2 cells. In vivo blocking of NTB-A interactions with its ligands by using soluble NTB-A-Fc fusion protein inhibits B cell isotype switching to IgG2a and IgG3, commonly induced by Th1-type cytokines. Most important, treatment of mice with NTB-A-Fc delays the onset of antigen-induced experimental allergic encephalomyelitis in myelin basic protein-T cell receptor transgenic mice, suggesting a role in T cell-mediated autoimmune disease. Regulation of interferon-gamma secretion, and not interleukin-4 in vitro, as well as inhibition of Th1 cell-induced isotype switching and attenuation of experimental allergic encephalomyelitis indicate that NTB-A is important for Th1 responses. The observation that cross-linking of NTB-A induces T cell activation, expansion, and Th1-type cytokine production suggests NTB-A is a novel co-stimulatory receptor. The identification of NTB-A as a regulator of T cell response paves the way to provide novel therapeutic approaches for modulation of the immune response.
Journal of Biological Chemistry 05/2004; 279(18):18662-9. · 4.77 Impact Factor
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Eugene Varfolomeev,
Frank Kischkel,
Flavius Martin, Dhaya Seshasayee,
Hua Wang,
David Lawrence,
Christine Olsson,
Lucrece Tom,
Sharon Erickson,
Dorothy French,
Peter Schow,
Iqbal S Grewal,
Avi Ashkenazi
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ABSTRACT: APRIL (a proliferation-inducing ligand) is a member of the tumor necrosis factor (TNF) superfamily. APRIL mRNA shows high levels of expression in tumors of different origin and a low level of expression in normal cells. APRIL shares two TNF receptor family members, TACI and BCMA, with another TNF homolog, BLyS/BAFF. BLyS is involved in regulation of B-cell activation and survival and also binds to a third receptor, BR3/BAFF-R, which is not shared with APRIL. Recombinant APRIL and BLyS induce accumulation of B cells in mice, while BLyS deficiency results in severe B-cell dysfunction. To investigate the physiological role of APRIL, we generated mice that are deficient in its encoding gene. APRIL(-/-) mice were viable and fertile and lacked any gross abnormality. Detailed histological analysis did not reveal any defects in major tissues and organs, including the primary and secondary immune organs. T- and B-cell development and in vitro function were normal as well, as were T-cell-dependent and -independent in vivo humoral responses to antigenic challenge. These data indicate that APRIL is dispensable in the mouse for proper development. Thus, BLyS may be capable of fulfilling APRIL's main functions.
Molecular and Cellular Biology 03/2004; 24(3):997-1006. · 5.53 Impact Factor
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ABSTRACT: BLys , a key cytokine that sustains B cell maturation and tolerance, binds three receptors: BR3, BCMA, and TACI. Results from knockout mice implicate a major functional role for BR3 and a redundant one for BCMA in B cell function. TACI's role is controversial based on defects in TI antibody responses accompanied by B cell hyperplasia in knockout mice. We have presently characterized a precise role for TACI in vivo. TACI(-/-) mice develop fatal autoimmune glomerulonephritis, proteinurea, and elevated levels of circulating autoantibodies. Treatment of B cells with TACI agonistic antibodies inhibits proliferation in vitro and activation of a chimeric receptor containing the TACI intracellular domain induces apoptosis. These results demonstrate the critical requirement for TACI in regulating B cell homeostasis.
Immunity 03/2003; 18(2):279-88. · 21.64 Impact Factor
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Nobuhiko Kayagaki,
Minhong Yan, Dhaya Seshasayee,
Hua Wang,
Wyne Lee,
Dorothy M French,
Iqbal S Grewal,
Andrea G Cochran,
Nathaniel C Gordon,
JianPing Yin,
Melissa A Starovasnik,
Vishva M Dixit
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ABSTRACT: The TNF-like ligand BAFF/BLyS is a potent survival factor for B cells. It binds three receptors: TACI, BCMA, and BR3. We show that BR3 signaling promotes processing of the transcription factor NF-kappaB2/p100 to p52. NF-kappaB2/p100 cleavage was abrogated in B cells from A/WySnJ mice possessing a mutant BR3 gene, but not in TACI or BCMA null B cells. Furthermore, wild-type mice injected with BAFF-neutralizing BR3-Fc protein showed reduced basal NF-kappaB2 activation. BR3-Fc treatment of NZB/WF1 mice, which develop a fatal lupus-like syndrome, inhibited NF-kappaB2 processing and attenuated the disease process. Since inhibiting the BR3-BAFF interaction has therapeutic ramifications, the ligand binding interface of BR3 was investigated and found to reside within a 26 residue core domain. When stabilized within a structured beta-hairpin peptide, six of these residues were sufficient to confer binding to BAFF.
Immunity 11/2002; 17(4):515-24. · 21.64 Impact Factor
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ABSTRACT: The identification of BAFF as a fundamental B cell survival factor in mouse and man, its over-expression in certain autoimmune
disease patient populations, and the discovery of three cognate receptors, stimulated interest in understanding the role of
BAFF in the pathogenesis of autoimmunity, and designing novel therapeutics to blunt B cell participation in disease pathogenesis
via blockade of this pathway. Positive clinical trial results with B cell depletion have demonstrated beyond doubt the pathogenic
B cell component in human rheumatoid arthritis [1, 2]. This current chapter focuses on data obtained in mice (both normal
and disease models), non-human primates and human clinical trials with several large molecule inhibitors of the BAFF B cell
survival pathway. The focus is on normal, non-diseased animals as well as rheumatology diseases and disease models although
implications are clear for all other diseases with a B cell pathogenic component. Three strategies for blocking BAFF/receptor
interactions have been used in mice and primates, 1) blocking antibodies directed specifically against BAFF, 2) receptor/
receptor fragment- Fc fusion proteins (receptor:Fc) to act as decoys, and 3) depleting mAb directed against BR3, the BAFF
receptor responsible for transducing a survival signal and which is expressed on all mature B cells. The first two strategies
target B cells indirectly by depriving them of a survival signal, while the third option utilizes an additional direct approach
through antibody mediated cell killing. We described the experience with each of these types of molecules first in mice, then
monkeys and human. Finally, we discuss the differences observed between species regarding in vivo blockade of this pathway
and potential implications for human disease therapy.
KeywordsBAFF-BAFF-R-BR3-TACI-Belimumab-LymphoStat- B-Atacicept-Rheumatoid arthritis-Systemic lupus erythematosus-Sjögren syndrome
01/1970: pages 221-243;
