Publications by authors named "Rajita Pappu"

20 Publications

  • Page 1 of 1

Astegolimab (anti-ST2) efficacy and safety in adults with severe asthma: a randomized clinical trial.

J Allergy Clin Immunol 2021 Apr 16. Epub 2021 Apr 16.

Department of Respiratory Sciences, University of Leicester, Leicestershire, United Kingdom. Electronic address:

Background: The interleukin (IL)-33/ST2 pathway is linked with asthma susceptibility. Inhaled allergens, pollutants, and respiratory viruses, which trigger asthma exacerbations, induce release of IL-33, an epithelial-derived "alarmin." Astegolimab, a human IgG2 monoclonal antibody, selectively inhibits the IL-33 receptor, ST2. Approved biologic therapies for severe asthma mainly benefit patients with elevated blood eosinophils (Type 2-high), but limited options are available for patients with low blood eosinophils (Type 2-low). Inhibiting IL-33 signaling may target pathogenic pathways in a wider spectrum of asthmatics.

Objective: This study evaluated astegolimab efficacy and safety in patients with severe asthma.

Methods: This double-blind, placebo-controlled, dose-ranging study (ZENYATTA) randomized 502 adults with severe asthma to subcutaneous placebo or 70-mg, 210-mg, or 490-mg astegolimab every 4 weeks. The primary endpoint was the annualized asthma exacerbation rate (AER) at Week 54. Enrollment caps ensured ∼30 eosinophil-high (≥300 cells/μL) and ∼95 eosinophil-low (<300 cells/μL) patients per arm.

Results: Overall, adjusted AER reductions relative to placebo were 43% (p=0.005), 22% (p=0.18), and 37% (p=0.01) for 490-mg, 210-mg, and 70-mg astegolimab, respectively. Adjusted AER reductions for eosinophil-low patients were comparable to reductions in the overall population: 54% (p=0.002), 14% (p=0.48), and 35% (p=0.05) for 490-mg, 210-mg, and 70-mg astegolimab. Adverse events were similar in astegolimab and placebo-treated groups.

Conclusion: Astegolimab reduced AER in a broad population of patients, including eosinophil-low patients, with inadequately controlled, severe asthma. Astegolimab was safe and well tolerated.

Trial Registration: EudraCT 2016-001549-13; ClinicalTrials.gov, NCT02918019 CLINICAL IMPLICATIONS: Inhibiting IL-33/ST2-mediated inflammation with astegolimab reduces asthma exacerbations in a broad population of patients with severe, uncontrolled asthma, including those with low blood eosinophils who have limited treatment options.
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http://dx.doi.org/10.1016/j.jaci.2021.03.044DOI Listing
April 2021

The kinase IRAK4 promotes endosomal TLR and immune complex signaling in B cells and plasmacytoid dendritic cells.

Sci Signal 2020 06 2;13(634). Epub 2020 Jun 2.

Research, Genentech, 1 DNA Way, South San Francisco, CA 94080, USA.

The dysregulation of multiple signaling pathways, including those through endosomal Toll-like receptors (TLRs), Fc gamma receptors (FcγR), and antigen receptors in B cells (BCR), promote an autoinflammatory loop in systemic lupus erythematosus (SLE). Here, we used selective small-molecule inhibitors to assess the regulatory roles of interleukin-1 receptor (IL-1R)-associated kinase 4 (IRAK4) and Bruton's tyrosine kinase (BTK) in these pathways. The inhibition of IRAK4 repressed SLE immune complex- and TLR7-mediated activation of human plasmacytoid dendritic cells (pDCs). Correspondingly, the expression of interferon (IFN)-responsive genes (IRGs) in cells and in mice was positively regulated by the kinase activity of IRAK4. Both IRAK4 and BTK inhibition reduced the TLR7-mediated differentiation of human memory B cells into plasmablasts. TLR7-dependent inflammatory responses were differentially regulated by IRAK4 and BTK by cell type: In pDCs, IRAK4 positively regulated NF-κB and MAPK signaling, whereas in B cells, NF-κB and MAPK pathways were regulated by both BTK and IRAK4. In the pristane-induced lupus mouse model, inhibition of IRAK4 reduced the expression of IRGs during disease onset. Mice engineered to express kinase-deficient IRAK4 were protected from both chemical (pristane-induced) and genetic (NZB/W_F1 hybrid) models of lupus development. Our findings suggest that kinase inhibitors of IRAK4 might be a therapeutic in patients with SLE.
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http://dx.doi.org/10.1126/scisignal.aaz1053DOI Listing
June 2020

30 Years of Biotherapeutics Development-What Have We Learned?

Annu Rev Immunol 2020 04;38:249-287

Research-Biology, Genentech, South San Francisco, California 94080, USA; email:

Since the birth of biotechnology, hundreds of biotherapeutics have been developed and approved by the US Food and Drug Administration (FDA) for human use. These novel medicines not only bring significant benefit to patients but also represent precision tools to interrogate human disease biology. Accordingly, much has been learned from the successes and failures of hundreds of high-quality clinical trials. In this review, we discuss general and broadly applicable themes that have emerged from this collective experience. We base our discussion on insights gained from exploring some of the most important target classes, including interleukin-1 (IL-1), tumor necrosis factor α (TNF-α), IL-6, IL-12/23, IL-17, IL-4/13, IL-5, immunoglobulin E (IgE), integrins and B cells. We also describe current challenges and speculate about how emerging technological capabilities may enable the discovery and development of the next generation of biotherapeutics.
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http://dx.doi.org/10.1146/annurev-immunol-101619-031510DOI Listing
April 2020

Design and Evaluation of Highly Selective Human Immunoproteasome Inhibitors Reveal a Compensatory Process That Preserves Immune Cell Viability.

J Med Chem 2019 08 29;62(15):7032-7041. Epub 2019 Jul 29.

Proteros Biostructures GmbH , Bunsenstrasse 7a , Planegg-Martinsried 82152 , Germany.

The pan-proteasome inhibitor bortezomib demonstrated clinical efficacy in off-label trials of Systemic Lupus Erythematosus. One potential mechanism of this clinical benefit is from the depletion of pathogenic immune cells (plasmablasts and plasmacytoid dendritic cells). However, bortezomib is cytotoxic against nonimmune cells, which limits its use for autoimmune diseases. An attractive alternative is to selectively inhibit the immune cell-specific immunoproteasome to deplete pathogenic immune cells and spare nonhematopoietic cells. Here, we disclose the development of highly subunit-selective immunoproteasome inhibitors using insights obtained from the first bona fide human immunoproteasome cocrystal structures. Evaluation of these inhibitors revealed that immunoproteasome-specific inhibition does not lead to immune cell death as anticipated and that targeting viability requires inhibition of both immuno- and constitutive proteasomes. CRISPR/Cas9-mediated knockout experiments confirmed upregulation of the constitutive proteasome upon disruption of the immunoproteasome, protecting cells from death. Thus, immunoproteasome inhibition alone is not a suitable approach to deplete immune cells.
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http://dx.doi.org/10.1021/acs.jmedchem.9b00509DOI Listing
August 2019

Cutting Edge: IL-17B Uses IL-17RA and IL-17RB to Induce Type 2 Inflammation from Human Lymphocytes.

J Immunol 2019 04 15;202(7):1935-1941. Epub 2019 Feb 15.

Department of Immunology Discovery, Genentech, South San Francisco, CA 94080;

IL-17 family cytokines are critical to host defense responses at cutaneous and mucosal surfaces. Whereas IL-17A, IL-17F, and IL-17C induce overlapping inflammatory cascades to promote neutrophil-mediated immunity, IL-17E/IL-25 drives type 2 immune pathways and eosinophil activity. Genetic and pharmacological studies reveal the significant contribution these cytokines play in antimicrobial and autoimmune mechanisms. However, little is known about the related family member, IL-17B, with contrasting reports of both pro- and anti-inflammatory function in rodents. We demonstrate that in the human immune system, IL-17B is functionally similar to IL-25 and elicits type 2 cytokine secretion from innate type 2 lymphocytes, NKT, and CD4 CRTH2 Th2 cells. Like IL-25, this activity is dependent on the IL-17RA and IL-17RB receptor subunits. Furthermore, IL-17B can augment IL-33-driven type 2 responses. These data position IL-17B as a novel component in the regulation of human type 2 immunity.
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http://dx.doi.org/10.4049/jimmunol.1800696DOI Listing
April 2019

Mice deficient in NRROS show abnormal microglial development and neurological disorders.

Nat Immunol 2017 06 1;18(6):633-641. Epub 2017 May 1.

Department of Immunology, Genentech, South San Francisco, California, USA.

Microglia and other tissue-resident macrophages within the central nervous system (CNS) have essential roles in neural development, inflammation and homeostasis. However, the molecular pathways underlying their development and function remain poorly understood. Here we report that mice deficient in NRROS, a myeloid-expressed transmembrane protein in the endoplasmic reticulum, develop spontaneous neurological disorders. NRROS-deficient (Nrros) mice show defects in motor functions and die before 6 months of age. Nrros mice display astrogliosis and lack normal CD11bCD45 microglia, but they show no detectable demyelination or neuronal loss. Instead, perivascular macrophage-like myeloid cells populate the Nrros CNS. Cx3cr1-driven deletion of Nrros shows its crucial role in microglial establishment during early embryonic stages. NRROS is required for normal expression of Sall1 and other microglial genes that are important for microglial development and function. Our study reveals a NRROS-mediated pathway that controls CNS-resident macrophage development and affects neurological function.
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http://dx.doi.org/10.1038/ni.3743DOI Listing
June 2017

Functional analysis of protective IL1RL1 variants associated with asthma risk.

J Allergy Clin Immunol 2015 Apr 4;135(4):1080-1083.e3. Epub 2014 Dec 4.

Department of Immunology Discovery, Genentech, South San Francisco, Calif. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2014.10.028DOI Listing
April 2015

Endogenously expressed IL-13Rα2 attenuates IL-13-mediated responses but does not activate signaling in human lung fibroblasts.

J Immunol 2014 Jul 30;193(1):111-9. Epub 2014 May 30.

Genentech Research and Early Development, Genentech, Inc., South San Francisco, CA 94080; and

IL-13 can bind to two distinct receptors: a heterodimer of IL-13Rα1/IL-4Rα and IL-13Rα2. Whereas IL-13Rα1/IL-4Rα engagement by IL-13 leads to the activation of STAT6, the molecular events triggered by IL-13 binding to IL-13Rα2 remain incompletely understood. IL-4 can bind to and signal through the IL-13Rα1/IL-4Rα complex but does not interact with IL-13Rα2. Idiopathic pulmonary fibrosis is a progressive and generally fatal parenchymal lung disease of unknown etiology with no current pharmacologic treatment options that substantially prolong survival. Preclinical models of fibrotic diseases have implicated IL-13 activity on multiple cell types, including macrophages and fibroblasts, in initiating and perpetuating pathological fibrosis. In this study, we show that IL-13, IL-4, IL-13Rα2, and IL-13-inducible target genes are expressed at significantly elevated levels in lung tissue from patients with idiopathic pulmonary fibrosis compared with control lung tissue. IL-4 and IL-13 induce virtually identical transcriptional responses in human monocytes, macrophages, and lung fibroblasts. IL-13Rα2 expression can be induced in lung fibroblasts by IL-4 or IL-13 via a STAT6-dependent mechanism, or by TNF-α via a STAT6-independent mechanism. Endogenously expressed IL-13Rα2 decreases, but does not abolish, sensitivity of lung fibroblasts to IL-13 and does not affect sensitivity to IL-4. Genome-wide transcriptional analyses of lung fibroblasts stimulated with IL-13 in the presence of Abs that selectively block interactions of IL-13 with IL-13Rα1/IL-4Rα or IL-13Rα2 show that endogenously expressed IL-13Rα2 does not activate any unique IL-13-mediated gene expression patterns, confirming its role as a decoy receptor for IL-13 signaling.
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http://dx.doi.org/10.4049/jimmunol.1301761DOI Listing
July 2014

Specification of type 2 innate lymphocytes by the transcriptional determinant Gfi1.

Nat Immunol 2013 Dec 20;14(12):1229-36. Epub 2013 Oct 20.

Department of Discovery Immunology, Genentech, South San Francisco, California, USA.

Type 2 innate lymphoid cells (ILC2 cells) participate in host defense against helminth parasites and in allergic inflammation. Given their functional relatedness to type 2 helper T cells (T(H)2 cells), we explored whether Gfi1 acts as a shared transcriptional determinant in ILC2 cells. Gfi1 promoted the development of ILC2 cells and controlled their responsiveness during infection with Nippostrongylus brasiliensis and protease allergen-induced lung inflammation. Gfi1 'preferentially' regulated the responsiveness of ILC2 cells to interleukin 33 (IL-33) by directly activating Il1rl1, which encodes the IL-33 receptor (ST2). Loss of Gfi1 in activated ILC2 cells resulted in impaired expression of the transcription factor GATA-3 and a dysregulated genome-wide effector state characterized by coexpression of IL-13 and IL-17. Our findings establish Gfi1 as a shared determinant that reciprocally regulates the type 2 and IL-17 effector states in cells of the innate and adaptive immune systems.
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http://dx.doi.org/10.1038/ni.2743DOI Listing
December 2013

Regulation of epithelial immunity by IL-17 family cytokines.

Trends Immunol 2012 Jul 2;33(7):343-9. Epub 2012 Apr 2.

Department of Immunology, Genentech Inc., 1 DNA Way, MS 34, South San Francisco, CA 94080, USA.

Cutaneous and mucosal epithelial cells function as both a physical barrier and as immune sentinels against environmental challenges, such as microbial pathogens, allergens and stress. The crosstalk between epithelial cells and leukocytes is essential for orchestrating proper immune responses during host defense. Interleukin (IL)-17 family cytokines are important players in regulating innate epithelial immune responses. Although IL-17A and IL-17F promote antibacterial and antifungal responses, IL-17E is essential for defense against parasitic infections. Emerging data indicate that another member of this family, IL-17C, specifically regulates epithelial immunity. IL-17C production serves as an immediate defense mechanism by epithelial cells, utilizing an autocrine mechanism to promote antibacterial responses at barrier surfaces.
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http://dx.doi.org/10.1016/j.it.2012.02.008DOI Listing
July 2012

IL-17C regulates the innate immune function of epithelial cells in an autocrine manner.

Nat Immunol 2011 Oct 12;12(12):1159-66. Epub 2011 Oct 12.

Department of Immunology, Genentech, South San Francisco, California, USA.

Interleukin 17C (IL-17C) is a member of the IL-17 family that is selectively induced in epithelia by bacterial challenge and inflammatory stimuli. Here we show that IL-17C functioned in a unique autocrine manner, binding to a receptor complex consisting of the receptors IL-17RA and IL-17RE, which was preferentially expressed on tissue epithelial cells. IL-17C stimulated epithelial inflammatory responses, including the expression of proinflammatory cytokines, chemokines and antimicrobial peptides, which were similar to those induced by IL-17A and IL-17F. However, IL-17C was produced by distinct cellular sources, such as epithelial cells, in contrast to IL-17A, which was produced mainly by leukocytes, especially those of the T(H)17 subset of helper T cells. Whereas IL-17C promoted inflammation in an imiquimod-induced skin-inflammation model, it exerted protective functions in dextran sodium sulfate-induced colitis. Thus, IL-17C is an essential autocrine cytokine that regulates innate epithelial immune responses.
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http://dx.doi.org/10.1038/ni.2156DOI Listing
October 2011

The interleukin-17 cytokine family: critical players in host defence and inflammatory diseases.

Immunology 2011 Sep 4;134(1):8-16. Epub 2011 Jul 4.

Department of Immunology, Genentech Inc., South San Francisco, CA, USA.

The interleukin-17 (IL-17) cytokines, IL-17A to IL-17F, are emerging as critical players in host defence responses and inflammatory diseases. Substantial data support the role of these proteins in innate and adaptive immunity. Of these family members, IL-17A, IL-17F and IL-17E have been the best studied. Both IL-17A and IL-17F contribute to the host response to extracellular bacteria and fungi, and IL-17E has been shown to play a role in parasitic infections. In addition, numerous pre-clinical and clinical studies link these proteins to the pathogenesis of inflammatory diseases, and a number of therapeutic programmes targeting these family members are in clinical development. This review will highlight the cellular sources, receptors/target cells, and role in inflammation of these and the less-characterized family members, IL-17B, IL-17C and IL-17D.
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http://dx.doi.org/10.1111/j.1365-2567.2011.03465.xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3173690PMC
September 2011

The IL-17 family cytokines in immunity and disease.

J Clin Immunol 2010 Mar 23;30(2):185-95. Epub 2010 Feb 23.

Department of Immunology, Genentech, Inc., South San Francisco, CA 94080, USA.

Introduction: Accumulating evidence suggests that the interleukin (IL)-17 cytokines are major players in the immune response to foreign pathogens. In addition, the pathogeneses of a number of inflammatory diseases have been linked to uncontrolled expression of these cytokine pathways.

Discussion: Genetic and biochemical analyses have elucidated the cellular and molecular events triggered by these proteins during an inflammatory response. While significant efforts have been placed on understanding the functions of IL-17A, IL-17F, and IL-17E, the significance of the other family members, IL-17B-D, in inflammation remains to be determined.

Conclusion: This review will focus on the cellular sources, target cell/receptors that are utilized by these cytokines to control pathogenesis, and the therapeutic potential of targeting these pathways to treat inflammatory disorders.
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http://dx.doi.org/10.1007/s10875-010-9369-6DOI Listing
March 2010

Lymphatic endothelial cell sphingosine kinase activity is required for lymphocyte egress and lymphatic patterning.

J Exp Med 2010 Jan 21;207(1):17-27. Epub 2009 Dec 21.

Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143, USA.

Lymphocyte egress from lymph nodes (LNs) is dependent on sphingosine-1-phosphate (S1P), but the cellular source of this S1P is not defined. We generated mice that expressed Cre from the lymphatic vessel endothelial hyaluronan receptor 1 (Lyve-1) locus and that showed efficient recombination of loxP-flanked genes in lymphatic endothelium. We report that mice with Lyve-1 CRE-mediated ablation of sphingosine kinase (Sphk) 1 and lacking Sphk2 have a loss of S1P in lymph while maintaining normal plasma S1P. In Lyve-1 Cre+ Sphk-deficient mice, lymphocyte egress from LNs and Peyer's patches is blocked. Treatment with pertussis toxin to overcome Galphai-mediated retention signals restores lymphocyte egress. Furthermore, in the absence of lymphatic Sphks, the initial lymphatic vessels in nonlymphoid tissues show an irregular morphology and a less organized vascular endothelial cadherin distribution at cell-cell junctions. Our data provide evidence that lymphatic endothelial cells are an in vivo source of S1P required for lymphocyte egress from LNs and Peyer's patches, and suggest a role for S1P in lymphatic vessel maturation.
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http://dx.doi.org/10.1084/jem.20091619DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2812554PMC
January 2010

Sphingosine-1-phosphate in the plasma compartment regulates basal and inflammation-induced vascular leak in mice.

J Clin Invest 2009 Jul;119(7):1871-9

Cardiovascular Research Institute, UCSF, San Francisco, California 94158-2517, USA.

Maintenance of vascular integrity is critical for homeostasis, and temporally and spatially regulated vascular leak is a central feature of inflammation. Sphingosine-1-phosphate (S1P) can regulate endothelial barrier function, but the sources of the S1P that provide this activity in vivo and its importance in modulating different inflammatory responses are unknown. We report here that mutant mice engineered to selectively lack S1P in plasma displayed increased vascular leak and impaired survival after anaphylaxis, administration of platelet-activating factor (PAF) or histamine, and exposure to related inflammatory challenges. Increased leak was associated with increased interendothelial cell gaps in venules and was reversed by transfusion with wild-type erythrocytes (which restored plasma S1P levels) and by acute treatment with an agonist for the S1P receptor 1 (S1pr1). S1pr1 agonist did not protect wild-type mice from PAF-induced leak, consistent with plasma S1P levels being sufficient for S1pr1 activation in wild-type mice. However, an agonist for another endothelial cell Gi-coupled receptor, Par2, did protect wild-type mice from PAF-induced vascular leak, and systemic treatment with pertussis toxin prevented rescue by Par2 agonist and sensitized wild-type mice to leak-inducing stimuli in a manner that resembled the loss of plasma S1P. Our results suggest that the blood communicates with blood vessels via plasma S1P to maintain vascular integrity and regulate vascular leak. This pathway prevents lethal responses to leak-inducing mediators in mouse models.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2701879PMC
http://dx.doi.org/10.1172/jci38575DOI Listing
July 2009

Contribution of bone marrow-derived cells associated with brain angiogenesis is primarily through leukocytes and macrophages.

Arterioscler Thromb Vasc Biol 2008 Dec 18;28(12):2151-7. Epub 2008 Sep 18.

Center for Cerebrovascular Research, Department of Anesthesia and Perioperative Care, University of California, San Francisco, CA, USA.

Objective: We investigated the role of bone marrow-derived cells (BMDCs) in an angiogenic focus, induced by VEGF stimulation.

Methods And Results: BM from GFP donor mice was isolated and transplanted into lethally irradiated recipients. Four weeks after transplantation, groups of mice received adeno-associated viral vector (AAV)-VEGF or AAV-lacZ gene (control) injection and were euthanized at 1 to 24 weeks. BMDCs were characterized by double-labeled immunostaining. The function of BMDCs was further examined through matrix metalloproteinase (MMP)-2 and -9 activity. We found that capillary density increased after 2 weeks, peaked at 4 weeks (P<0.01), and sustained up to 24 weeks after gene transfer. GFP-positive BMDCs infiltration in the angiogenic focus began at 1 week, peaked at 2 weeks, and decreased thereafter. The GFP-positive BMDCs were colocalized with CD45 (94%), CD68 (71%), 5% Vimentin (5%), CD31/von Willebrand factor (vWF) (1%), and alpha-smooth muscle actin (alpha -SMA, 0.5%). Infiltrated BMDCs expressed MMP-9. MMP-9 KO mice confirmed the dependence of the angiogenic response on MMP-9 availability.

Conclusions: Nearly all BMDCs in the angiogenic focus showed expression for leukocytes/macrophages, indicating that BMDCs minimally incorporated into the neovasculature. Colocalization of MMPs with GFP suggests that BMDCs play a critical role in VEGF-induced angiogenic response through up-regulation of MMPs.
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http://dx.doi.org/10.1161/ATVBAHA.108.176297DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2610019PMC
December 2008

Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate.

Science 2007 Apr 15;316(5822):295-8. Epub 2007 Mar 15.

Cardiovascular Research Institute, University of California, San Francisco, 600 16th Street S472D, San Francisco, CA 94143-2240, USA.

Lymphocytes require sphingosine-1-phosphate (S1P) receptor-1 to exit lymphoid organs, but the source(s) of extracellular S1P and whether S1P directly promotes egress are unknown. By using mice in which the two kinases that generate S1P were conditionally ablated, we find that plasma S1P is mainly hematopoietic in origin, with erythrocytes a major contributor, whereas lymph S1P is from a distinct radiation-resistant source. Lymphocyte egress from thymus and secondary lymphoid organs was markedly reduced in kinase-deficient mice. Restoration of S1P to plasma rescued egress to blood but not lymph, and the rescue required lymphocyte expression of S1P-receptor-1. Thus, separate sources provide S1P to plasma and lymph to help lymphocytes exit the low-S1P environment of lymphoid organs. Disruption of compartmentalized S1P signaling is a plausible mechanism by which S1P-receptor-1 agonists function as immunosuppressives.
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http://dx.doi.org/10.1126/science.1139221DOI Listing
April 2007

Haploinsufficiency of B cell linker protein enhances B cell signaling defects in mice expressing a limiting dosage of Bruton's tyrosine kinase.

Int Immunol 2003 Mar;15(3):383-92

Simmons Arthritis Research Center, Department of Internal Medicine and Center for Immunology, UT Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.

Current models of lymphocyte activation suggest that formation of a signaling complex, or "signalosome", composed of Syk, Bruton's tyrosine kinase (Btk), phospholipase gamma2 and the adaptor protein B cell linker protein (BLNK) is critical for transmission of signals from the BCR. However, impaired B cell development in mice lacking each individual signalosome component has made it difficult to study the functional consequences of the formation of this complex in mature B cells. Sensitized genetic systems, commonly used in Drosophila, define signaling pathways by combining partial loss of function mutations in the components of interest. This allows genetic interactions to be observed in the absence of pleiotropic or lethal effects of complete deficiency of either gene. We used this approach to demonstrate that Btk and BLNK are limiting components of a common signaling pathway that mediates the mitogenic response of mature B cells to antigen. B cells from transgenic mice expressing a limiting dosage of Btk (Btk(lo)) have normal numbers of mature B cells that have reduced, but measurable, responses to BCR cross-linking. Haploinsufficiency of BLNK did not affect the development of Btk(lo) B cells. However, it exacerbated their defects in BCR-induced Ca(2+) flux, IkappaB degradation, and up-regulation of cyclin D2, bcl-x(L) and A1 leading to dramatic impairment of B cell mitogenic responses. In contrast, no effect of reduced Btk and BLNK dosage was observed on extracellular signal-regulated kinase activation. These results suggest that the signals regulating the maintenance and activation of mature B cells are differentially sensitive to the strength of the signal emanating from the signalosome.
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http://dx.doi.org/10.1093/intimm/dxg034DOI Listing
March 2003