DOCSLIB.ORG

Role of Mast Cells in Progressive Renal Diseases

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Role of Mast Cells in Progressive Renal Diseases BRIEF REVIEW www.jasn.org Role of Mast Cells in Progressive Renal Diseases Stephen R. Holdsworth and Shaun A. Summers Centre for Inflammatory Diseases, Department of Medicine, Monash Medical Center, Melbourne, Australia ABSTRACT Advances in understanding mast cell biology reveal their diverse functional capac- nerves in connective tissues, allowing ity well beyond already established roles in host defense against parasites and their participation in homeostatic func- allergic disease. Mast cells can initiate, amplify, and direct innate and adaptive tions as well as being strategic sentinels at immune responses. They also modulate inflammation and regulate immunity. Mast primary immune barriers where their cells potentially induce tissue repair and direct fibrosis; however, they also play density is increased. Their anatomic dis- other roles in tissue remodeling and repair. Various activation and differentiating tribution and structural relationships al- signals result in a diverse range of functional phenotypes called “mast cell heter- low mast cells to modulate innate im- ogeneity.” Mast cells are significant participants in chronic progressive kidney mune and adaptive effector responses; disease, and their presence is associated with function loss and fibrosis. This however, this role requires mast cell acti- suggests a potential role in the fibrotic process, which may involve mast cell vation to stimulate cell degranulation to- activation of local renin-angiotensin systems. Experimental animal studies suggest, gether with synthetic molecule release. however, they do not directly cause renal fibrosis but rather spark inflammation. The best known, classical pathway of Evidence for both pro- and anti-inflammatory roles in nephritis is emerging. mast cell activation is through IgE-Fc␧ cross-linking.5 The role mast cells serve J Am Soc Nephrol 19: 2254–2261, 2008. doi: 10.1681/ASN.2008010015 in expulsion of parasites from their host is well known.2 More recent studies rec- ognized additional, alternative, activat- The mast cell, originally named “fattened inflammation and autoimmunity. Their ing pathways including complement and or well-fed cell” (Mastzellen) by Ehr- participation in a diverse range of human signaling through microbial pattern rec- lich,1 is a sentinel for host defense.2 After kidney diseases is also now clear, and their ognition receptors, toll-like receptors recent discoveries demonstrated an ex- phenotypic characterization; mechanism (TLR). This work has expanded our un- panded role for mast cells in both sys- of recruitment and proliferation; and pos- derstanding of a role for mast cells in host temic and local host immune responses, sible roles in inflammation, fibrosis, re- defense in other diseases. Galli3 suggested the name “master” cell modeling, and repair are now open to ex- In animal models of bacterial infec- would be more appropriate. Mast cells ploration. This review focuses on the tion, including bacterial peritonitis, mast are present in low numbers in all vascular biology of mast cells, mast cells in fibrosis, cells are required for optimal innate im- organs, including the kidney. In chronic the renin-angiotensin system (RAS) in mune responses conferring survival ben- progressive kidney diseases, mast cell mast cell fibrosis, and the role of mast cells efit.6,7 Complement also activates mast proliferation in tubulointerstitial injury in autoimmune kidney diseases. cells, and complement-dependant mi- is prominent regardless of the initiating crobial killing is at least partially depen- disease and correlates with progressive dent on mast cell function for full expres- loss of function and poor outcome. MAST CELL BIOLOGY sion.8 The pattern recognition receptors, Outside the kidney, mast cell biology TLR, serve as an important link between is a rapidly advancing field. Mast cells Mast cells derive from hematopoietic have diverse functional capacities well progenitor cells. They migrate through Published online ahead of print. Publication date beyond those associated with allergy and vascularized tissue to complete their available at www.jasn.org. IgE. Rodents genetically deficient in mast maturation.4 Mast cells are tissue-spe- Correspondence: Prof. Stephen R. Holdsworth, cells have been extensively studied to de- cific multifunctional cells, with diverse Monash Medical Centre, Monash University, Level 5/Block E, 246 Clayton Road, Clayton, Victoria, 3168, termine whether these cells play a role in phenotypes in different anatomic sites in Australia. Phone: 61-3-9594-5525; Fax: 61-3-9594-6437; models of human disease, and, as it turns various species, collectively referred to as E-mail: [email protected] 2,4 out, mast cells have functional roles in “mast cell heterogeneity.” They locate Copyright ᮊ 2008 by the American Society of vivo in chronic diseases associated with close to blood vessels, epithelia, and Nephrology 2254 ISSN : 1046-6673/1912-2254 J Am Soc Nephrol 19: 2254–2261, 2008 www.jasn.org BRIEF REVIEW innate and adaptive immunity. Both MAST CELLS IN RENAL Early events in this process involve leu- mouse9,10 and human mast cells11 express INFLAMMATION AND FIBROSIS kocyte (including mast cell) recruitment TLR. In animal models, the important syn- and epithelial-mesenchymal transition ergistic interaction between TLR in mast Although mast cells are found infre- forming fibroblasts. Profibrotic stimuli cells demonstrates upregulated cytokine quently in normal kidney tissue, their include key growth factors, TGF-␤45 and production12 and increased survival from numbers increase significantly in the set- fibroblast growth factor, as well as inflam- bacterial infection.13 In addition to com- ting of renal disease. Mast cells are prom- matory cytokines and chemokines facili- plement and TLR activation, stress hor- inent in tubulointerstitial nephritis asso- tating leukocyte recruitment and activa- mones, in particular corticotrophin-re- ciated with progressive fibrosis and renal tion. Tubular epithelial cells play an leasing hormone, enhances mast cell failure. These include almost all of the important role in these processes, and the activation and degranulation, facilitating primary and secondary forms of glomer- release of proteolytic enzymes, including further mediator release.14 ulonephritis,19–30 diabetic nephropa- matrix metalloproteases (MMP), mediates As well as these novel pathways, sev- thy,31,32 and allograft rejection,33–38 as fibrogenic injury. The balance of overall eral other molecules can initiate mast cell well as amyloid,39 renovascular isch- activators and inhibitors is altered in a activation. These include growth factors emia,40 reflux nephropathy,41 polycystic manner favoring net matrix deposition such as stem cell factor, co-stimulatory kidney disease,42 and drug-induced ne- and scarification. molecules CD28 (and ligands CD80/86), phropathy.19 Mast cell presence is corre- Mast cells have the potential to sup- the integrins, and CCR1.15 The close lated semiquantitatively with fibrosis, port this process actively. They elaborate proximity of mast cells to neurons facili- progressive decline in glomerular filtra- cytokines,46 chemokines,47 and leukotri- tates neuropeptide activation of mast tion, and poor outcome.20–22,24,25,27,29 enes48 recruiting and activating leuko- cells.16 Mast cells are also important in The intensity and extent of tubulointer- cytes. They also indirectly support leuko- chronic inflammation with the capacity stitial damage is one of the strongest de- cyte recruitment by affecting vascular to produce a range of bioactive amines, terminants of progressive functional de- endothelial expression of selectins and proteoglycans, growth hormones, che- cline.43,44 adhesion molecules.49,50 Mast cell de- mokines, and cytokines, which mediate a Interstitial inflammation and fibrosis granulation leads to the release of hista- diverse range of mast cell function (Fig- involve a common sequence of events re- mine, heparin, and cytokines, in particu- ure 1). This breadth of activity has been quiring the interaction of tubular and in- lar IL-451 and TNF-␣,52 which can reviewed extensively.2,17,18 terstitial cells with infiltrating leukocytes. influence fibroblast function. Further- more, the release of TGF-␤,53 MMP-9,54 and a variety of proteases, principally MEDIATOR RELEASE AND PHYSIOLOGICAL tryptase and chymase, contributes to REACTIONS OF MAST CELL DEGRANULATION progressive fibrogenesis.55,56 In addition to direct injury, some proteases are capa- Mast cell ble of activating latent MMP and other proteases. They also serve as chemoat- Growth factors Cytokines and tractants and mitogens for fibroblasts. • Stem cell factor chemokines • Granulocyte macrophage • Interferon γ Growth factors are mediators of mast • Colony stimulating factor • Tumour necrosis factor cell–associated histologic and functional • Gonadotrophin • Macrophage inhibitory factor kidney injury,57 although their mecha- releasing hormone • Transforming growth factor • Fibroblast growth factor • Interleukin 1, 3-6, 9, 10, 13, 16 nism of action is complex. • Vascular endothelial • CCL 2-5 growth factor Proteases Leukotrienes • CXCL ligand 8-11 • Nerve growth factor • Tryptase • LeukotrieneC4 Action • Chymase • LeukotrieneB4 • Pro and anti-inflammatory RAS IN MAST CELL–INDUCED • Carboxypeptidase • Platelet activating factor responses FIBROSIS • Histamine • Prostaglandin D2 • Immune regulation • Proteoglycan (heparin) • Prostaglandin E2 Action Action Current understanding of the
Load more

Recommended publications
  • Serine Proteases with Altered Sensitivity to Activity-Modulating
    (19) & (11) EP 2 045 321 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 08.04.2009 Bulletin 2009/15 C12N 9/00 (2006.01) C12N 15/00 (2006.01) C12Q 1/37 (2006.01) (21) Application number: 09150549.5 (22) Date of filing: 26.05.2006 (84) Designated Contracting States: • Haupts, Ulrich AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 51519 Odenthal (DE) HU IE IS IT LI LT LU LV MC NL PL PT RO SE SI • Coco, Wayne SK TR 50737 Köln (DE) •Tebbe, Jan (30) Priority: 27.05.2005 EP 05104543 50733 Köln (DE) • Votsmeier, Christian (62) Document number(s) of the earlier application(s) in 50259 Pulheim (DE) accordance with Art. 76 EPC: • Scheidig, Andreas 06763303.2 / 1 883 696 50823 Köln (DE) (71) Applicant: Direvo Biotech AG (74) Representative: von Kreisler Selting Werner 50829 Köln (DE) Patentanwälte P.O. Box 10 22 41 (72) Inventors: 50462 Köln (DE) • Koltermann, André 82057 Icking (DE) Remarks: • Kettling, Ulrich This application was filed on 14-01-2009 as a 81477 München (DE) divisional application to the application mentioned under INID code 62. (54) Serine proteases with altered sensitivity to activity-modulating substances (57) The present invention provides variants of ser- screening of the library in the presence of one or several ine proteases of the S1 class with altered sensitivity to activity-modulating substances, selection of variants with one or more activity-modulating substances. A method altered sensitivity to one or several activity-modulating for the generation of such proteases is disclosed, com- substances and isolation of those polynucleotide se- prising the provision of a protease library encoding poly- quences that encode for the selected variants.
    [Show full text]
  • For Serine Proteas
    Ribeiro et al. BMC Structural Biology 2010, 10:36 http://www.biomedcentral.com/1472-6807/10/36 METHODOLOGY ARTICLE Open Access Analysis of binding properties and specificity through identification of the interface forming residues (IFR) for serine proteases in silico docked to different inhibitors Cristina Ribeiro1†, Roberto C Togawa2†, Izabella AP Neshich3, Ivan Mazoni3, Adauto L Mancini3, Raquel C de Melo Minardi5, Carlos H da Silveira4, José G Jardine3, Marcelo M Santoro1, Goran Neshich3* Abstract Background: Enzymes belonging to the same super family of proteins in general operate on variety of substrates and are inhibited by wide selection of inhibitors. In this work our main objective was to expand the scope of studies that consider only the catalytic and binding pocket amino acids while analyzing enzyme specificity and instead, include a wider category which we have named the Interface Forming Residues (IFR). We were motivated to identify those amino acids with decreased accessibility to solvent after docking of different types of inhibitors to sub classes of serine proteases and then create a table (matrix) of all amino acid positions at the interface as well as their respective occupancies. Our goal is to establish a platform for analysis of the relationship between IFR characteristics and binding properties/specificity for bi-molecular complexes. Results: We propose a novel method for describing binding properties and delineating serine proteases specificity by compiling an exhaustive table of interface forming residues (IFR) for serine proteases and their inhibitors. Currently, the Protein Data Bank (PDB) does not contain all the data that our analysis would require. Therefore, an in silico approach was designed for building corresponding complexes The IFRs are obtained by “rigid body docking” among 70 structurally aligned, sequence wise non-redundant, serine protease structures with 3 inhibitors: bovine pancreatic trypsin inhibitor (BPTI), ecotine and ovomucoid third domain inhibitor.
    [Show full text]
  • Proteolytic Enzymes in Grass Pollen and Their Relationship to Allergenic Proteins
    Proteolytic Enzymes in Grass Pollen and their Relationship to Allergenic Proteins By Rohit G. Saldanha A thesis submitted in fulfilment of the requirements for the degree of Masters by Research Faculty of Medicine The University of New South Wales March 2005 TABLE OF CONTENTS TABLE OF CONTENTS 1 LIST OF FIGURES 6 LIST OF TABLES 8 LIST OF TABLES 8 ABBREVIATIONS 8 ACKNOWLEDGEMENTS 11 PUBLISHED WORK FROM THIS THESIS 12 ABSTRACT 13 1. ASTHMA AND SENSITISATION IN ALLERGIC DISEASES 14 1.1 Defining Asthma and its Clinical Presentation 14 1.2 Inflammatory Responses in Asthma 15 1.2.1 The Early Phase Response 15 1.2.2 The Late Phase Reaction 16 1.3 Effects of Airway Inflammation 16 1.3.1 Respiratory Epithelium 16 1.3.2 Airway Remodelling 17 1.4 Classification of Asthma 18 1.4.1 Extrinsic Asthma 19 1.4.2 Intrinsic Asthma 19 1.5 Prevalence of Asthma 20 1.6 Immunological Sensitisation 22 1.7 Antigen Presentation and development of T cell Responses. 22 1.8 Factors Influencing T cell Activation Responses 25 1.8.1 Co-Stimulatory Interactions 25 1.8.2 Cognate Cellular Interactions 26 1.8.3 Soluble Pro-inflammatory Factors 26 1.9 Intracellular Signalling Mechanisms Regulating T cell Differentiation 30 2 POLLEN ALLERGENS AND THEIR RELATIONSHIP TO PROTEOLYTIC ENZYMES 33 1 2.1 The Role of Pollen Allergens in Asthma 33 2.2 Environmental Factors influencing Pollen Exposure 33 2.3 Classification of Pollen Sources 35 2.3.1 Taxonomy of Pollen Sources 35 2.3.2 Cross-Reactivity between different Pollen Allergens 40 2.4 Classification of Pollen Allergens 41 2.4.1
    [Show full text]
  • Associations Between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration
    International Journal of Molecular Sciences Review Associations between the Complement System and Choroidal Neovascularization in Wet Age-Related Macular Degeneration 1 2 1 1, Emilie Grarup Jensen , Thomas Stax Jakobsen , Steffen Thiel , Anne Louise Askou y 1,2, , and Thomas J. Corydon * y 1 Department of Biomedicine, Aarhus University, 8000 Aarhus C, Denmark; [email protected] (E.G.J.); [email protected] (S.T.); [email protected] (A.L.A.) 2 Department of Ophthalmology, Aarhus University Hospital, 8200 Aarhus N, Denmark; [email protected] * Correspondence: [email protected]; Tel.: +45-28-99-21-79 These authors contributed equally to this work. y Received: 18 November 2020; Accepted: 17 December 2020; Published: 21 December 2020 Abstract: Age-related macular degeneration (AMD) is the leading cause of blindness affecting the elderly in the Western world. The most severe form of AMD, wet AMD (wAMD), is characterized by choroidal neovascularization (CNV) and acute vision loss. The current treatment for these patients comprises monthly intravitreal injections of anti-vascular endothelial growth factor (VEGF) antibodies, but this treatment is expensive, uncomfortable for the patient, and only effective in some individuals. AMD is a complex disease that has strong associations with the complement system. All three initiating complement pathways may be relevant in CNV formation, but most evidence indicates a major role for the alternative pathway (AP) and for the terminal complement complex, as well as certain complement peptides generated upon complement activation. Since the complement system is associated with AMD and CNV, a complement inhibitor may be a therapeutic option for patients with wAMD.
    [Show full text]
  • Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases
    International Journal of Molecular Sciences Review Trypsin-Like Proteases and Their Role in Muco-Obstructive Lung Diseases Emma L. Carroll 1,†, Mariarca Bailo 2,†, James A. Reihill 1 , Anne Crilly 2 , John C. Lockhart 2, Gary J. Litherland 2, Fionnuala T. Lundy 3 , Lorcan P. McGarvey 3, Mark A. Hollywood 4 and S. Lorraine Martin 1,* 1 School of Pharmacy, Queen’s University, Belfast BT9 7BL, UK; [email protected] (E.L.C.); [email protected] (J.A.R.) 2 Institute for Biomedical and Environmental Health Research, School of Health and Life Sciences, University of the West of Scotland, Paisley PA1 2BE, UK; [email protected] (M.B.); [email protected] (A.C.); [email protected] (J.C.L.); [email protected] (G.J.L.) 3 Wellcome-Wolfson Institute for Experimental Medicine, School of Medicine, Dentistry and Biomedical Sciences, Queen’s University, Belfast BT9 7BL, UK; [email protected] (F.T.L.); [email protected] (L.P.M.) 4 Smooth Muscle Research Centre, Dundalk Institute of Technology, A91 HRK2 Dundalk, Ireland; [email protected] * Correspondence: [email protected] † These authors contributed equally to this work. Abstract: Trypsin-like proteases (TLPs) belong to a family of serine enzymes with primary substrate specificities for the basic residues, lysine and arginine, in the P1 position. Whilst initially perceived as soluble enzymes that are extracellularly secreted, a number of novel TLPs that are anchored in the cell membrane have since been discovered. Muco-obstructive lung diseases (MucOLDs) are Citation: Carroll, E.L.; Bailo, M.; characterised by the accumulation of hyper-concentrated mucus in the small airways, leading to Reihill, J.A.; Crilly, A.; Lockhart, J.C.; Litherland, G.J.; Lundy, F.T.; persistent inflammation, infection and dysregulated protease activity.
    [Show full text]
  • 31 Antiphospholipid Antibody–Induced Pregnancy Loss and Thrombosis Guillermina Girardi and Jane E
    31 Antiphospholipid Antibody–Induced Pregnancy Loss and Thrombosis Guillermina Girardi and Jane E. Salmon Antiphospholipid (aPL) antibodies are a family of autoantibodies that exhibit a broad range of target specificities and affinities, all recognizing various combina- tions of phospholipids, phospholipid binding proteins, or both. The first aPL anti- body, a complement fixing antibody that reacted with extracts from bovine hearts, was detected in patients with syphilis in 1906 [1]. The relevant antigen was later identified as cardiolipin, a mitochondrial phospholipid [2]. The presence of aPL antibodies in serum has been associated with arterial and venous thrombosis and recurrent pregnancy loss [3–7], but the pathogenic mechanisms mediating these events are unknown. Several hypotheses have been proposed to explain the cellular and molecular mechanisms by which aPL antibodies induce thrombosis and fetal loss. There are reports that aPL antibodies activate endothelial cells, monocytes, and platelets [8–10]. In vivo and in vitro studies have shown that exposure to aPL antibodies induces activation of endothelial cells and a prothrombotic phenotype, as assessed by upregulation of the expression of adhesion molecules, secretion of cytokines, and the metabolism of prostacyclins [8, 10, 11]. aPL antibodies recognize β 2-glycoprotein I bound to resting endothelial cells, although the basis for the inter- β action of 2-glycoprotein I with viable endothelial cells remains unclear [12, 13]. As β 2-glycoprotein I is considered a natural anticoagulant [14], some authors propose that aPL antibodies interfere with or modulate the function of phospholipid binding proteins involved in the regulation of coagulation, activate platelets, or induce monocytes to express tissue factor [9].
    [Show full text]
  • Hereditary Alpha Tryptasemia, Mastocytosis and Beyond
    International Journal of Molecular Sciences Review Genetic Regulation of Tryptase Production and Clinical Impact: Hereditary Alpha Tryptasemia, Mastocytosis and Beyond Bettina Sprinzl 1,2, Georg Greiner 3,4,5 , Goekhan Uyanik 1,2,6, Michel Arock 7,8 , Torsten Haferlach 9, Wolfgang R. Sperr 4,10, Peter Valent 4,10 and Gregor Hoermann 4,9,* 1 Ludwig Boltzmann Institute for Hematology and Oncology at the Hanusch Hospital, Center for Medical Genetics, Hanusch Hospital, 1140 Vienna, Austria; [email protected] (B.S.); [email protected] (G.U.) 2 Center for Medical Genetics, Hanusch Hospital, 1140 Vienna, Austria 3 Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria; [email protected] 4 Ludwig Boltzmann Institute for Hematology and Oncology, Medical University of Vienna, 1090 Vienna, Austria; [email protected] (W.R.S.); [email protected] (P.V.) 5 Ihr Labor, Medical Diagnostic Laboratories, 1220 Vienna, Austria 6 Medical School, Sigmund Freud Private University, 1020 Vienna, Austria 7 Department of Hematology, APHP, Pitié-Salpêtrière-Charles Foix University Hospital and Sorbonne University, 75013 Paris, France; [email protected] 8 Centre de Recherche des Cordeliers, INSERM, Sorbonne University, Cell Death and Drug Resistance in Hematological Disorders Team, 75006 Paris, France 9 MLL Munich Leukemia Laboratory, 81377 Munich, Germany; [email protected] 10 Department of Internal Medicine I, Division of Hematology and Hemostaseology, Medical University of Vienna, 1090 Vienna, Austria * Correspondence: [email protected]; Tel.: +49-89-99017-315 Citation: Sprinzl, B.; Greiner, G.; Uyanik, G.; Arock, M.; Haferlach, T.; Abstract: Tryptase is a serine protease that is predominantly produced by tissue mast cells (MCs) and Sperr, W.R.; Valent, P.; Hoermann, G.
    [Show full text]
  • 12) United States Patent (10
    US007635572B2 (12) UnitedO States Patent (10) Patent No.: US 7,635,572 B2 Zhou et al. (45) Date of Patent: Dec. 22, 2009 (54) METHODS FOR CONDUCTING ASSAYS FOR 5,506,121 A 4/1996 Skerra et al. ENZYME ACTIVITY ON PROTEIN 5,510,270 A 4/1996 Fodor et al. MICROARRAYS 5,512,492 A 4/1996 Herron et al. 5,516,635 A 5/1996 Ekins et al. (75) Inventors: Fang X. Zhou, New Haven, CT (US); 5,532,128 A 7/1996 Eggers Barry Schweitzer, Cheshire, CT (US) 5,538,897 A 7/1996 Yates, III et al. s s 5,541,070 A 7/1996 Kauvar (73) Assignee: Life Technologies Corporation, .. S.E. al Carlsbad, CA (US) 5,585,069 A 12/1996 Zanzucchi et al. 5,585,639 A 12/1996 Dorsel et al. (*) Notice: Subject to any disclaimer, the term of this 5,593,838 A 1/1997 Zanzucchi et al. patent is extended or adjusted under 35 5,605,662 A 2f1997 Heller et al. U.S.C. 154(b) by 0 days. 5,620,850 A 4/1997 Bamdad et al. 5,624,711 A 4/1997 Sundberg et al. (21) Appl. No.: 10/865,431 5,627,369 A 5/1997 Vestal et al. 5,629,213 A 5/1997 Kornguth et al. (22) Filed: Jun. 9, 2004 (Continued) (65) Prior Publication Data FOREIGN PATENT DOCUMENTS US 2005/O118665 A1 Jun. 2, 2005 EP 596421 10, 1993 EP 0619321 12/1994 (51) Int. Cl. EP O664452 7, 1995 CI2O 1/50 (2006.01) EP O818467 1, 1998 (52) U.S.
    [Show full text]
  • Β-Tryptase and Complement Fractions C3-C4 Are the Indispensable Working Tools
    Int. J. Mol. Sci. 2015, 16, 6557-6570; doi:10.3390/ijms16036557 OPEN ACCESS International Journal of Molecular Sciences ISSN 1422-0067 www.mdpi.com/journal/ijms Review Amniotic Fluid Embolism Pathophysiology Suggests the New Diagnostic Armamentarium: β-Tryptase and Complement Fractions C3-C4 Are the Indispensable Working Tools Francesco Paolo Busardò 1, Paola Frati 1,2, Simona Zaami 1 and Vittorio Fineschi 1,* 1 Department of Anatomical, Histological, Forensic and Orthopaedic Sciences, Sapienza University of Rome, Viale Regina Elena 336, 00161 Rome, Italy; E-Mails: [email protected] (F.P.B.); [email protected] (S.Z.) 2 Neuromed, Istituto Mediterraneo Neurologico (IRCCS), Via Atinense 18, Pozzilli, 86077 Isernia, Italy; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]; Tel.: +39-06-49912722; Fax: +39-06-445535. Academic Editor: Robert J. Norman Received: 26 December 2014 / Accepted: 10 March 2015 / Published: 23 March 2015 Abstract: Amniotic fluid embolism (AFE) is an uncommon obstetric condition involving pregnant women during labor or in the initial stages after delivery. Its incidence is estimated to be around 5.5 cases per 100,000 deliveries. Therefore, this paper investigated the pathophysiological mechanism, which underlies AFE, in order to evaluate the role of immune response in the development of this still enigmatic clinical entity. The following databases (from 1956 to September 2014) Medline, Cochrane Central, Scopus, Web of Science and Science Direct were used, searching the following key words: AFE, pathophysiology, immune/inflammatory response, complement and anaphylaxis. The main key word “AFE” was searched singularly and associated individually to each of the other keywords.
    [Show full text]
  • Cleavage Specificity and Biochemical Characterization of Mast Cell Serine Proteases
    Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology 870 Cutting Edge – Cleavage Specificity and Biochemical Characterization of Mast Cell Serine Proteases BY ULRIKA KARLSON ACTA UNIVERSITATIS UPSALIENSIS UPPSALA 2003 !" # $ $ % & " ' & & (" ") !" * + '") , ) $) ' +' - ' . & " " / & 0 . ( ) 1 ) 23) ) ) 4.5 %6768%%6 4 * " " 90: * " ' " ' " " * " & ') 0 " ; & ' ' & 0 & ) !* ; ' & 0 " < " *"" ' & & *"" & & " ' ) " " / & " & * ' " 0 & ) # & " " " " ' & & * 0 " 90(:67 0(6) !" & * / ' " ' " = *"" ' & ' ) !" " 0(67 ' & * " ' & & * = 56 & " ' ) !" " "& " ' & & " " ) " ' " ' = & ' ' & 0(67 " " >?@444 " !A>B ) !" " ' " = * / " & & 0(6) 0(6 " " = " " ) 4 ' 0(6 " " * " * " / & " & ) 0(6 " " '" "& " && ' & ) !" & ' & & " " && & & * & * ' ' & ) !" 0 " 6 & & " 0) ! " = & & 0(68 0(68 * ) 1 * C 9D8): * ' " ' ' )') " * " * " ) E " " " ' * & " " 0(68 " ) 4 " " ' * " * "'" && " ) !" " ' '" ' & " ' " ) " & " ' ! " # ! #$ %&'! #"! ! ()*%+,- ! F , $ 4..5 76$$G 4.5 %6768%%6
    [Show full text]
  • Granzyme a in the Pathogenesis of Type 1 Diabetes: the Yes and the No
    Diabetes Volume 66, December 2017 2937 Granzyme A in the Pathogenesis of Type 1 Diabetes: The Yes and the No Thomas Mandrup-Poulsen Diabetes 2017;66:2937–2939 | https://doi.org/10.2337/dbi17-0037 Two major unanswered questions related to the pathogen- GrzmA, discovered by Tschopp and colleagues (9) in esis of type 1 diabetes (T1D) prevent progress in our ability 1986, belongs to the granzyme family of serine proteases to intervene in disease development: What breaks immune encompassing 10 members in the mouse and 5 members in tolerance to the pancreatic b-cells? And what kills the the human (10,11). They have trypsin-, chymotrypsin-, and b-cells? elastase-like proteolytic activities, but in contrast to these By the surprising demonstration that knockout of the broad serine proteases, granzymes have higher substrate tryptase granzyme A (GrzmA), conventionally considered to specificity conferred by a substrate binding pocket. Gran- be a key proapoptotic mediator of immune killer cell cyto- zymes are expressed mainly in cytotoxic T cells and natural toxicity, does not protect but markedly accelerates and in- killer (NK) cells in response to interleukin (IL)-2 in synergy creases incidence of T1D in the nonobese diabetic (NOD) with IL-12 (12,13), with GrzmA being the most abundantly mouse, Mollah et al. (1) add to answering both of these expressed but also having lower cytotoxic activity than questions. On one hand, they show that GrzmA does not GrzmB. GrzmA and GrzmB are also expressed in gdT cells, COMMENTARY contribute to b-cell killing. On the other hand, their striking a subset of the intraepithelial lymphocytes abundant in the finding that diabetes resistance in the proinsulin II trans- intestinal mucosa, and in thymocytes, suggesting roles in genic mouse is broken by GrzmA knockout provides evi- both central tolerance and gut immunity.
    [Show full text]
  • A Role of a Lymphocyte Tryptase, Granzyme A, in Experimental Ulcerative Colitis
    Biosci. Biotechnol. Biochem., 71 (1), 234–237, 2007 Note A Role of a Lymphocyte Tryptase, Granzyme A, in Experimental Ulcerative Colitis y Hirofumi HIRAYASU,* Yumiko YOSHIKAWA,* Satoshi TSUZUKI, and Tohru FUSHIKI Laboratory of Nutrition Chemistry, Division of Food Science and Biotechnology, Graduate School of Agriculture, Kyoto University, Kyoto 606-8502, Japan Received June 23, 2006; Accepted October 4, 2006; Online Publication, January 7, 2007 [doi:10.1271/bbb.60354] In the large-intestinal mucosae of rats orally admin- site, and the mucosae from at least two rats (about 2 ng istered dextran sulfate sodium, which induces an enter- of GzmA) were required for detection by binding assay. itis resembling ulcerative colitis (UC), the activity for On the other hand, the activity of GzmA can be granzyme A, a lymphocyte tryptase, increased at an determined sensitively by hydrolysis of N -benzyloxy- earlier stage than that at which UC markers (growth- L-lysine thiobenzyl ester (BLT), a synthetic substrate for regulated gene product/cytokine-induced neutrophil the enzyme,6,8) which is completely inhibited in the chemoattractant-1 and caspase-3) increased. This sug- presence of a recombinant rat PSTI6) (more than 2 mM) gests involvement of the enzyme in the exacerbation and (Fig. 1A). Therefore, of the hydrolysis of BLT by perpetuation of enteritis. samples from large-intestinal mucosae, hydrolysis in which hydrolysis in the absence of PSTI is subtracted Key words: granzyme A; cytotoxic T-lymphocytes; ul- from hydrolysis in the presence of PSTI should cor- cerative colitis; dextran sulfate sodium; respond to that catalyzed by GzmA. In addition, neither pancreatic secretory trypsin inhibitor the binding between GzmA and 125I-labeled PSTI7) nor BLT hydrolysis by a recombinant rat GzmA was A family of serine proteases termed granzymes are inhibited by soybean trypsin inhibitor (SBTI, type I-S, stored in granules of cytotoxic T-lymphocytes (CTLs) Sigma, St.
    [Show full text]