DOCSLIB.ORG

Contribution of Adipose-Derived Factor D/Adipsin to Complement

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Contribution of Adipose-Derived Factor D/Adipsin to Complement Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy This information is current as of September 25, 2021. Xiaobo Wu, Irina Hutson, Antonina M. Akk, Smita Mascharak, Christine T. N. Pham, Dennis E. Hourcade, Rebecca Brown, John P. Atkinson and Charles A. Harris J Immunol 2018; 200:2786-2797; Prepublished online 12 March 2018; Downloaded from doi: 10.4049/jimmunol.1701668 http://www.jimmunol.org/content/200/8/2786 http://www.jimmunol.org/ References This article cites 51 articles, 25 of which you can access for free at: http://www.jimmunol.org/content/200/8/2786.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists by guest on September 25, 2021 • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Contribution of Adipose-Derived Factor D/Adipsin to Complement Alternative Pathway Activation: Lessons from Lipodystrophy Xiaobo Wu,* Irina Hutson,† Antonina M. Akk,* Smita Mascharak,‡ Christine T. N. Pham,*,x Dennis E. Hourcade,* Rebecca Brown,{ John P. Atkinson,* and Charles A. Harris†,‖ Factor D (FD) is an essential component of the complement alternative pathway (AP). It is an attractive pharmaceutical target because it is an AP-specific protease circulating in blood. Most components of the complement activation pathways are produced by the liver, but FD is highly expressed by adipose tissue. Two critical questions are: 1) to what degree does adipose tissue contribute to circulating FD levels and 2) what quantity of FD is sufficient to maintain a functional AP? To address these issues, we studied a novel mouse strain with complete lipodystrophy (LD), the fld mouse with partial LD, an FD-deficient mouse, and samples from lipodystrophic patients. FD Downloaded from was undetectable in the serum of LD mice, which also showed minimal AP function. Reconstitution with purified FD, serum mixing experiments, and studies of partial LD mice all demonstrated that a low level of serum FD is sufficient for normal AP activity in the mouse system. This conclusion was further supported by experiments in which wild-type adipose precursors were transplanted into LD mice. Our results indicate that almost all FD in mouse serum is derived from adipose tissue. In contrast, FD levels were reduced ∼50% in the sera of patients with congenital generalized LD. Our studies further demonstrate that a relatively small amount of serum FD is sufficient to facilitate significant time-dependent AP activity in humans and in mice. Furthermore, this observation highlights the http://www.jimmunol.org/ potential importance of obtaining nearly complete inhibition of FD in treating alternative complement activation in various auto- immune and inflammatory human diseases. The Journal of Immunology, 2018, 200: 2786–2797. omplement is an important arm of innate immunity binding to a microbial surface, it engages the protease precursor against bacteria and viruses and its activated products also (zymogen) factor B (FB) to form C3bB. This bimolecular complex C serve as a bridge between innate and adaptive immunity. is cleaved by factor D (FD), a serine protease unique to AP. The Three distinct but related pathways are responsible for complement cleavage results in C3bBb, known as the AP C3 convertase, which activation: the classical pathway (CP), the alternative pathway is stabilized by properdin (P), an AP-specific positive regulator. FD (AP), and the lectin pathway. All three enzymatic pathways itself is cleaved from a pro-FD zymogen to a mature FD. This by guest on September 25, 2021 converge on the cleavage of C3. This results in the generation of cleavage is mediated by members of the mannose-binding protein- proinflammatory complement fragment C3a and a major opsonin associated serine protease (MASP) family. Mice deficient in both C3b. The latter also serves as gateway to the membrane attack MASP1 and MASP3 only have pro-FD in the serum and no AP complex and a substrate to engage the AP’s amplification loop. In activity, suggesting that MASP1/3 serve as proteases to cleave pro- the CP, C1, via its C1q subcomponent, binds Ab–Ag complexes, FD into FD (1). MASP3 is thought to be the major pro-FD con- thus attacking foreign agents. In the lectin pathway, a plasma vertase whereas MASP1 is the minor convertase (2–4). lectin, such as Abs ficolins, collectins, or mannose-binding lectin, Owing to its low concentration in human serum [2–4 mg/ml (5, 6) binds to the microbial surface. In the AP, upon C3b’s covalent and our data in this study] and highly selective function, FD is a *Division of Rheumatology, Department of Medicine, Washington University School analyzed and interpreted data; and C.T.N.P., D.E.H., R.B., and J.P.A. provided re- of Medicine, St. Louis, MO 63110; †Division of Endocrinology, Metabolism and sources, interpreted data, and revised the manuscript. Lipid Research, Department of Medicine, Washington University School of Medi- The contents do not represent the views of the U.S. Department of Veterans Affairs or cine, St. Louis, MO 63110; ‡Department of Medicine, David Geffen School of x the U.S. Government. Medicine at University of California, Los Angeles, Los Angeles, CA 90095; Section of Rheumatology, Department of Medicine, St. Louis Veterans Affairs Medical Cen- Address correspondence and reprint requests to Dr. Charles A. Harris or Dr. Xiaobo ter, St. Louis, MO 63106; {Diabetes, Endocrinology, and Obesity Branch, National Wu, Division of Endocrinology, Metabolism and Lipid Research, Department of Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Health, Bethesda, MD 20814; and ‖Section of Endocrinology, Department of Med- Box 8127, Saint Louis, MO 63110 (C.A.H.) or Division of Rheumatology, Depart- icine, St. Louis Veterans Affairs Medical Center, St. Louis, MO 63106 ment of Medicine, Washington University School of Medicine, 660 South Euclid Avenue, Box 8045, St. Louis, MO 63110 (X.W.). E-mail addresses: harrisc@wustl. ORCIDs: 0000-0002-6703-2272 (X.W.); 0000-0003-1127-3699 (C.T.N.P.); 0000- edu (C.A.H.) or [email protected] (X.W.) 0002-2589-7382 (R.B.); 0000-0002-2514-3441 (J.P.A.); 0000-0003-1815- 5046 (C.A.H.). Abbreviations used in this article: AGL, acquired generalized LD; AMD, age-related macular degeneration; AP, alternative pathway; BAT, brown adipose tissue; BSCL, Received for publication December 1, 2017. Accepted for publication February 15, Berardinelli–Seip congenital LD; CGL, congenital generalized LD; CP, classical 2018. pathway; CVF, cobra venom factor; DIX, dexamethasone, insulin, and 3-isobutyl- This work was supported by National Institutes of Health Grants R01 DK106083 1-methylxanthine; E, embryonic day; FB, factor B; FD, factor D; fld, fatty liver (to C.A.H.), 5 R01 AI041592, U54 HL112303, and 1 P30AR048335 (to J.P.A. and dystrophy; FPL, familial partial LD; hFD, human FD; LD, lipodystrophy; LMNA, X.W.), R01 AR067491 (to C.T.N.P.), and R01 AI051436 (to D.E.H. and C.T.N.P.), lamin A; MASP, mannose-binding protein-associated serine protease; MEF, mouse and by the Intramural Research Program of the National Institute of Diabetes and embryonic fibroblast; P, properdin; PNGase, peptide-N-glycosidase; PPAR, peroxi- Digestive and Kidney Diseases (to R.B.). some proliferator-activated receptor; RT, room temperature; WAT, white adipose tissue; WT, wild-type. X.W. and C.A.H. performed experiments, analyzed and interpreted data, and wrote and revised the manuscript; I.H., A.M.A., and S.M. performed experiments and Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$35.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701668 The Journal of Immunology 2787 strong candidate for pharmaceutical approaches to block the pow- erful AP and its feedback loop for the treatment of numerous in- flammatory diseases such as atypical hemolytic uremic syndrome (7, 8), paroxysmal nocturnal hemoglobinuria (8), and age-related macular degeneration (AMD) (9–13). Abs to FD can be used to neutralize AP activity in mice (14) and more recently have been developed for the treatment of patients with AMD (15, 16). An mAb to FD was shown to block AP in primates without affecting the CP. AP components FB and C3 in blood are largely produced by the liver but also locally by bone marrow–derived and many other cell types (17). FD is also known as adipsin because it was inde- pendently identified as an abundant transcript in 3T3-L1 adipocytes (18), but it was soon identified as identical to FD (19, 20). In ad- dition to the high level of mRNA expression of adipsin/FD in ad- ipose tissue, adipsin/FD expression has been described in other tissues, including muscle and lung in humans (19) and the sciatic nerve (21) as well as by the adrenal gland and ovary in mice (22). Spiegelman and colleagues (23–26) went on to demonstrate that paradoxically adipsin mRNA is decreased in genetic and chemical Downloaded from models of obesity. More recently, they demonstrated that adipsin plays a role in pancreatic b cell function (27).
Load more

Recommended publications
  • TOPOLOGY and ITS APPLICATIONS the Number of Complements in The
    TOPOLOGY AND ITS APPLICATIONS ELSEVIER Topology and its Applications 55 (1994) 101-125 The number of complements in the lattice of topologies on a fixed set Stephen Watson Department of Mathematics, York Uniuersity, 4700 Keele Street, North York, Ont., Canada M3J IP3 (Received 3 May 1989) (Revised 14 November 1989 and 2 June 1992) Abstract In 1936, Birkhoff ordered the family of all topologies on a set by inclusion and obtained a lattice with 1 and 0. The study of this lattice ought to be a basic pursuit both in combinatorial set theory and in general topology. In this paper, we study the nature of complementation in this lattice. We say that topologies 7 and (T are complementary if and only if 7 A c = 0 and 7 V (T = 1. For simplicity, we call any topology other than the discrete and the indiscrete a proper topology. Hartmanis showed in 1958 that any proper topology on a finite set of size at least 3 has at least two complements. Gaifman showed in 1961 that any proper topology on a countable set has at least two complements. In 1965, Steiner showed that any topology has a complement. The question of the number of distinct complements a topology on a set must possess was first raised by Berri in 1964 who asked if every proper topology on an infinite set must have at least two complements. In 1969, Schnare showed that any proper topology on a set of infinite cardinality K has at least K distinct complements and at most 2” many distinct complements.
    [Show full text]
  • Determinacy in Linear Rational Expectations Models
    Journal of Mathematical Economics 40 (2004) 815–830 Determinacy in linear rational expectations models Stéphane Gauthier∗ CREST, Laboratoire de Macroéconomie (Timbre J-360), 15 bd Gabriel Péri, 92245 Malakoff Cedex, France Received 15 February 2002; received in revised form 5 June 2003; accepted 17 July 2003 Available online 21 January 2004 Abstract The purpose of this paper is to assess the relevance of rational expectations solutions to the class of linear univariate models where both the number of leads in expectations and the number of lags in predetermined variables are arbitrary. It recommends to rule out all the solutions that would fail to be locally unique, or equivalently, locally determinate. So far, this determinacy criterion has been applied to particular solutions, in general some steady state or periodic cycle. However solutions to linear models with rational expectations typically do not conform to such simple dynamic patterns but express instead the current state of the economic system as a linear difference equation of lagged states. The innovation of this paper is to apply the determinacy criterion to the sets of coefficients of these linear difference equations. Its main result shows that only one set of such coefficients, or the corresponding solution, is locally determinate. This solution is commonly referred to as the fundamental one in the literature. In particular, in the saddle point configuration, it coincides with the saddle stable (pure forward) equilibrium trajectory. © 2004 Published by Elsevier B.V. JEL classification: C32; E32 Keywords: Rational expectations; Selection; Determinacy; Saddle point property 1. Introduction The rational expectations hypothesis is commonly justified by the fact that individual forecasts are based on the relevant theory of the economic system.
    [Show full text]
  • 180: Counting Techniques
    180: Counting Techniques In the following exercise we demonstrate the use of a few fundamental counting principles, namely the addition, multiplication, complementary, and inclusion-exclusion principles. While none of the principles are particular complicated in their own right, it does take some practice to become familiar with them, and recognise when they are applicable. I have attempted to indicate where alternate approaches are possible (and reasonable). Problem: Assume n ≥ 2 and m ≥ 1. Count the number of functions f :[n] ! [m] (i) in total. (ii) such that f(1) = 1 or f(2) = 1. (iii) with minx2[n] f(x) ≤ 5. (iv) such that f(1) ≥ f(2). (v) that are strictly increasing; that is, whenever x < y, f(x) < f(y). (vi) that are one-to-one (injective). (vii) that are onto (surjective). (viii) that are bijections. (ix) such that f(x) + f(y) is even for every x; y 2 [n]. (x) with maxx2[n] f(x) = minx2[n] f(x) + 1. Solution: (i) A function f :[n] ! [m] assigns for every integer 1 ≤ x ≤ n an integer 1 ≤ f(x) ≤ m. For each integer x, we have m options. As we make n such choices (independently), the total number of functions is m × m × : : : m = mn. (ii) (We assume n ≥ 2.) Let A1 be the set of functions with f(1) = 1, and A2 the set of functions with f(2) = 1. Then A1 [ A2 represents those functions with f(1) = 1 or f(2) = 1, which is precisely what we need to count. We have jA1 [ A2j = jA1j + jA2j − jA1 \ A2j.
    [Show full text]
  • Properdin Factor D: Effects on Thrombin-Induced Platelet Aggregation
    Properdin factor D: effects on thrombin-induced platelet aggregation. A E Davis 3rd, D M Kenney J Clin Invest. 1979;64(3):721-728. https://doi.org/10.1172/JCI109515. Research Article Factor D, when preincubated with platelet suspensions, at concentrations as low as 1.2 micrograms/ml, inhibited thrombin-induced platelet aggregation. No inhibition of collagen or arachidonic acid-induced platelet aggregation was found. Inhibition occurred, but to a lesser extent, when thrombin and factor D were added to platelets at the same time. No inhibition occurred when factor D was added after thrombin. Thrombin was able to overcome inhibition by factor D by increasing its concentration. Diisopropyl-phosphorofluoridate-inactivated factor D also inhibited thrombin-induced platelet aggregation so that enzymatic activity of factor D was not required for inhibition. Factor D absorbed with hirudin coupled to Sepharose 6B showed no decrease in inhibitory capacity. 125I-Factor D bound to platelets in a manner suggesting an equilibrium reaction similar to thrombin. At low factor D input, binding was linear, whereas at higher input, binding began to approach saturation. Binding of 125I-labeled thrombin to platelets was inhibited by factor D. Analysis of these data show that factor D does not alter the total number of thrombin molecules which bind to the platelet surface at saturation. However, the dissociation constant for thrombin is altered from 2.78 to 6.90 nM in the presence of factor D (20 micrograms/ml). Factor D is thus a competitive inhibitor of thrombin binding, although the affinity of factor D for the platelet thrombin receptor is much less […] Find the latest version: https://jci.me/109515/pdf Properdin Factor D EFFECTS ON THROMBIN-INDUCED PLATELET AGGREGATION ALVIN E.
    [Show full text]
  • Set Difference and Symmetric Difference of Fuzzy Sets
    Preliminaries Symmetric Dierence Set Dierence and Symmetric Dierence of Fuzzy Sets N.R. Vemuri A.S. Hareesh M.S. Srinath Department of Mathematics Indian Institute of Technology, Hyderabad and Department of Mathematics and Computer Science Sri Sathya Sai Institute of Higher Learning, India Fuzzy Sets Theory and Applications 2014, Liptovský Ján, Slovak Republic Vemuri, Sai Hareesh & Srinath Symmetric Dierence Preliminaries Introduction Symmetric Dierence Earlier work Outline 1 Preliminaries Introduction Earlier work 2 Symmetric Dierence Denition Examples Properties Applications Future Work References Vemuri, Sai Hareesh & Srinath Symmetric Dierence Preliminaries Introduction Symmetric Dierence Earlier work Classical set theory Set operations Union- [ Intersection - \ Complement - c Dierence -n Symmetric dierence - ∆ .... Vemuri, Sai Hareesh & Srinath Symmetric Dierence Preliminaries Introduction Symmetric Dierence Earlier work Classical set theory Set operations Union- [ Intersection - \ Complement - c Dierence -n Symmetric dierence - ∆ .... Vemuri, Sai Hareesh & Srinath Symmetric Dierence Preliminaries Introduction Symmetric Dierence Earlier work Classical set theory Set operations Union- [ Intersection - \ Complement - c Dierence -n Symmetric dierence - ∆ .... Vemuri, Sai Hareesh & Srinath Symmetric Dierence Preliminaries Introduction Symmetric Dierence Earlier work Classical set theory Set operations Union- [ Intersection - \ Complement - c Dierence -n Symmetric dierence - ∆ .... Vemuri, Sai Hareesh & Srinath Symmetric Dierence Preliminaries
    [Show full text]
  • E. A. Emerson and C. S. Jutla, Tree Automata, Mu-Calculus, And
    Tree Automata MuCalculus and Determinacy Extended Abstract EA Emerson and CS Jutla The University of Texas at Austin IBM TJ Watson Research Center Abstract that tree automata are closed under disjunction pro jection and complementation While the rst two We show that the prop ositional MuCalculus is eq are rather easy the pro of of Rabins Complemen uivalent in expressivepower to nite automata on in tation Lemma is extraordinarily complex and di nite trees Since complementation is trivial in the Mu cult Because of the imp ortance of the Complemen Calculus our equivalence provides a radically sim tation Lemma a numb er of authors have endeavored plied alternative pro of of Rabins complementation and continue to endeavor to simplify the argument lemma for tree automata which is the heart of one HR GH MS Mu Perhaps the b est of the deep est decidability results We also showhow known of these is the imp ortant work of Gurevich MuCalculus can b e used to establish determinacy of and Harrington GH which attacks the problem innite games used in earlier pro ofs of complementa from the standp oint of determinacy of innite games tion lemma and certain games used in the theory of While the presentation is brief the argument is still online algorithms extremely dicult and is probably b est appreciated Intro duction y the page supplementofMonk when accompanied b Mon We prop ose the prop ositional Mucalculus as a uniform framework for understanding and simplify In this pap er we present a new enormously sim ing the imp ortant and technically challenging
    [Show full text]
  • Naïve Set Theory Basic Definitions Naïve Set Theory Is the Non-Axiomatic Treatment of Set Theory
    Naïve Set Theory Basic Definitions Naïve set theory is the non-axiomatic treatment of set theory. In the axiomatic treatment, which we will only allude to at times, a set is an undefined term. For us however, a set will be thought of as a collection of some (possibly none) objects. These objects are called the members (or elements) of the set. We use the symbol "∈" to indicate membership in a set. Thus, if A is a set and x is one of its members, we write x ∈ A and say "x is an element of A" or "x is in A" or "x is a member of A". Note that "∈" is not the same as the Greek letter "ε" epsilon. Basic Definitions Sets can be described notationally in many ways, but always using the set brackets "{" and "}". If possible, one can just list the elements of the set: A = {1,3, oranges, lions, an old wad of gum} or give an indication of the elements: ℕ = {1,2,3, ... } ℤ = {..., -2,-1,0,1,2, ...} or (most frequently in mathematics) using set-builder notation: S = {x ∈ ℝ | 1 < x ≤ 7 } or {x ∈ ℝ : 1 < x ≤ 7 } which is read as "S is the set of real numbers x, such that x is greater than 1 and less than or equal to 7". In some areas of mathematics sets may be denoted by special notations. For instance, in analysis S would be written (1,7]. Basic Definitions Note that sets do not contain repeated elements. An element is either in or not in a set, never "in the set 5 times" for instance.
    [Show full text]
  • Complement Activation in Factor D-Deficient Mice
    Complement activation in factor D-deficient mice Yuanyuan Xu*†, Minghe Ma‡, Gregory C. Ippolito*, Harry W. Schroeder, Jr.*, Michael C. Carroll‡, and John E. Volanakis*§ *Department of Medicine, University of Alabama, Birmingham, AL 35294; ‡Department of Pathology, Harvard Medical School, Boston, MA 02138; and §Biomedical Sciences Research Center ‘‘A. Fleming,’’ Vari 166 72, Greece Edited by Douglas T. Fearon, University of Cambridge, Cambridge, United Kingdom, and approved October 18, 2001 (received for review August 15, 2001) To assess the contribution of the alternative pathway in comple- mice. The results indicate that factor D is indispensable for ment activation and host defense and its possible role in the complement activation through the AP and that it plays a regulation of systemic energy balance in vivo, factor D-deficient significant role in opsonization of bacteria by ‘‘natural’’ IgM mice were generated by gene targeting. The mutant mice have no antibody. It is also shown that factor D does not play a major role apparent abnormality in development and their body weights are in fat metabolism. Interestingly, the data revealed a unique mode similar to those of factor D-sufficient littermates. Complement of factor B activation, which provides valuable insights into the activation could not be initiated in the serum of deficient mice by mechanism of AP activation. the alternative pathway activators rabbit erythrocytes and zymo- san. Surprisingly, injection of cobra venom factor (CVF) caused a Materials and Methods profound and reproducible reduction in serum C3 levels, whereas, Generation of Factor D-Deficient Mice. A gene targeting vector, as expected, there was no C3 reduction in factor B-deficient mice Adn͞TK, was constructed (9) on the backbone of pBluescript treated similarly.
    [Show full text]
  • Regularity Properties and Determinacy
    Regularity Properties and Determinacy MSc Thesis (Afstudeerscriptie) written by Yurii Khomskii (born September 5, 1980 in Moscow, Russia) under the supervision of Dr. Benedikt L¨owe, and submitted to the Board of Examiners in partial fulfillment of the requirements for the degree of MSc in Logic at the Universiteit van Amsterdam. Date of the public defense: Members of the Thesis Committee: August 14, 2007 Dr. Benedikt L¨owe Prof. Dr. Jouko V¨a¨an¨anen Prof. Dr. Joel David Hamkins Prof. Dr. Peter van Emde Boas Brian Semmes i Contents 0. Introduction............................ 1 1. Preliminaries ........................... 4 1.1 Notation. ........................... 4 1.2 The Real Numbers. ...................... 5 1.3 Trees. ............................. 6 1.4 The Forcing Notions. ..................... 7 2. ClasswiseConsequencesofDeterminacy . 11 2.1 Regularity Properties. .................... 11 2.2 Infinite Games. ........................ 14 2.3 Classwise Implications. .................... 16 3. The Marczewski-Burstin Algebra and the Baire Property . 20 3.1 MB and BP. ......................... 20 3.2 Fusion Sequences. ...................... 23 3.3 Counter-examples. ...................... 26 4. DeterminacyandtheBaireProperty.. 29 4.1 Generalized MB-algebras. .................. 29 4.2 Determinacy and BP(P). ................... 31 4.3 Determinacy and wBP(P). .................. 34 5. Determinacy andAsymmetric Properties. 39 5.1 The Asymmetric Properties. ................. 39 5.2 The General Definition of Asym(P). ............. 43 5.3 Determinacy and Asym(P). ................. 46 ii iii 0. Introduction One of the most intriguing developments of modern set theory is the investi- gation of two-player infinite games of perfect information. Of course, it is clear that applied game theory, as any other branch of mathematics, can be modeled in set theory. But we are talking about the converse: the use of infinite games as a tool to study fundamental set theoretic questions.
    [Show full text]
  • Innate Immunity: the Inside Story on Complement Activation
    RESEARCH HIGHLIGHTS Nature Reviews Immunology | AOP, published online 31 December 2013; doi:10.1038/nri3603 INNATE IMMUNITY The inside story on complement activation The evolutionarily ancient comple- inconsistent with de novo protein — the production of interferon-γ ment system might have started life production, so the authors looked (IFNγ) and interleukin-17 was sig- as an intracellular activation pathway for a potential role of endogenous nificantly decreased but could be par- rather than as a liver-derived serum proteases. They showed that rest- tially rescued by the addition of C3a. effector cascade. Other recent studies ing human T cells express mRNA Cytokine production was not affected have suggested the importance of encoding cathepsin L (CTSL), and in serum-free medium or in the T cell-derived local complement acti- that CTSL cleaves C3 into biologi- presence of a C3 convertase inhibitor, vation in the autocrine stimulation of cally active C3a and C3b fragments which shows that the CTSL-mediated T helper 1 (T 1) cell responses, but in vitro. C3 and CTSL were found to C3 activation pathway is sufficient H intracellular Claudia Kemper, John Atkinson and be colocalized in resting T cells in for autocrine C3aR-induced T cell colleagues are the first to show that C3a the endoplasmic reticulum (ER) and effector function in humans. the C3 activation products C3a and generation ER-derived secretory vesicles. The in vivo relevance of this C3b can be generated intracellularly … is both Intracellular C3a was detected in pathway was shown in synovial fluid in human CD4+ T cells. resting T cells, and the increase in CD4+ T cells from patients with juve- Activation of mouse T cells is upregulated intracellular C3a levels observed after nile idiopathic arthritis.
    [Show full text]
  • A Family with Complement Factor D Deficiency
    A family with complement factor D deficiency Douwe H. Biesma,1 André J. Hannema,2 Heleen van Velzen-Blad,3 Leontine Mulder,3 Rob van Zwieten,2 Irma Kluijt,4 and Dirk Roos2,5 1Department of Internal Medicine, St. Antonius Hospital, Nieuwegein, The Netherlands 2Central Laboratory of the Netherlands Blood Transfusion Service, Amsterdam, The Netherlands 3Department of Medical Microbiology and Immunology, St. Antonius Hospital, Nieuwegein, The Netherlands 4Department of Clinical Genetics, and 5Laboratory for Experimental and Clinical Immunology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands Address correspondence to: Douwe H. Biesma, Department of Internal Medicine, St. Antonius Hospital, PO Box 2500, 3430 EM Nieuwegein, The Netherlands. Phone: 31-30-6099111; Fax: 31-30-6056357; E-mail: [email protected]. Received for publication December 15, 2000, and accepted in revised form June 11, 2001. A complement factor D deficiency was found in a young woman who had experienced a serious Neis- seria meningitidis infection, in a deceased family member with a history of meningitis, and in three rel- atives without a history of serious infections. The patient and these three relatives showed a normal activity of the classical complement pathway, but a very low activity of the alternative complement pathway and a very low capacity to opsonize Escherichia coli and N. meningitidis (isolated from the patient) for phagocytosis by normal human neutrophils. The alternative pathway-dependent hemolytic activity and the opsonizing capacity of these sera were restored by addition of purified fac- tor D. The family had a high degree of consanguinity, and several other family members exhibited decreased levels of factor D.
    [Show full text]
  • Targeting of Mannan-Binding Lectin-Associated Serine Protease-2 Confers Protection from Myocardial and Gastrointestinal Ischemia/Reperfusion Injury
    Targeting of mannan-binding lectin-associated serine protease-2 confers protection from myocardial and gastrointestinal ischemia/reperfusion injury Wilhelm J. Schwaeblea,1, Nicholas J. Lyncha, James E. Clarkb, Michael Marberb, Nilesh J. Samanic, Youssif Mohammed Alia,d, Thomas Dudlere, Brian Parente, Karl Lhottaf, Russell Wallisa, Conrad A. Farrarg, Steven Sacksg, Haekyung Leeh, Ming Zhangh, Daisuke Iwakii, Minoru Takahashii, Teizo Fujitai, Clark E. Tedforde, and Cordula M. Stovera Departments of aInfection, Immunity, and Inflammation and cCardiovascular Sciences, University of Leicester, Leicester LE1 9HN, United Kingdom; bBritish Heart Foundation Centre and gMedical Research Council Centre for Transplantation and National Institute for Health Research Biomedical Research Centre at Guy’s and St. Thomas’ National Health Service Foundation Trust, King’s College London, London SE1 9RT, United Kingdom; dFaculty of Pharmacy, Department of Microbiology, University of Mansoura, Mansoura 35516, Egypt; eOmeros Corporation, Seattle, WA 98101; fLandeskrankenhaus Feldkirch, 6807 Feldkirch, Austria; hDepartment of Anesthesiology, State University of New York-Downstate Medical Center, New York, NY 11203; and iDepartment of Immunology, Fukushima Medical University, Fukushima 960-1295, Japan Edited* by Douglas T. Fearon, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom, and approved March 16, 2011 (received for review February 1, 2011) Complement research experienced a renaissance with the discovery aberrant glycosylation
    [Show full text]