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Unformatted text preview: CJASN CJASN’s Renal Immunology for the Clinician Review the fundamentals of renal immunology in this comprehensive 8-part series available now in a user-friendly compiled pdf file. Leading investigators will provide a focused update for practicing nephrologists and trainees on immunology and its relationship to kidney disease. Series Editor: Fadi G. Lakkis, MD Deputy Editor: Paul M. Palevsky, MD, FASN Editor-in-Chief: Gary C. Curhan, MD, ScD, FASN ASN LEADING THE FIGHT AGAINST KIDNEY DISEASE CJASN Clinical Journal of the American Society of Nephrology Renal Immunology for the Clinician Article 1 A New CJASN Series: Renal Immunology for the Clinician Fadi G. Lakkis and Paul M. Palevsky Article 2 A Brief Journey through the Immune System Karim M. Yatim and Fadi G. Lakkis Article 3 How the Innate Immune System Senses Trouble and Causes Trouble Takashi Hato and Pierre C. Dagher Article 4 Molecules Great and Small: The Complement System Douglas R. Mathern and Peter S. Heeger Article 5 Dendritic Cells and Macrophages: Sentinels in the Kidney Christina K. Weisheit, Daniel R. Engel, and Christian Kurts Article 6 T Cells: Soldiers and Spies—The Surveillance and Control of Effector T Cells by Regulatory T Cells Bruce M. Hall Article 7 Cytokines: Names and Numbers You Should Care About Stephen R. Holdsworth and Poh-Yi Gan Article 8 B Cells, Antibodies, and More William Hoffman, Fadi G. Lakkis, and Geetha Chalasani Article 9 Immunosuppressive Medications Alexander C. Wiseman CJASN Clinical Journal of the American Society of Nephrology Editors Editor-in-Chief Gary C. Curhan, MD, ScD, FASN Boston, MA Deputy Editors Kirsten L. Johansen, MD San Francisco, CA Paul M. Palevsky, MD, FASN Pittsburgh, PA Associate Editors Michael Allon, MD Birmingham, AL Ann M. O’Hare, MD Seattle, WA Jeffrey C. Fink, MD, MS, FASN Baltimore, MD Mark A. Perazella, MD, FASN New Haven, CT Linda F. Fried, MD, MPH, FASN Pittsburgh, PA Vlado Perkovic, MBBS, PhD, FASN, FRACP Sydney, Australia David S. Goldfarb, MD, FASN New York, NY Katherine R. Tuttle, MD, FACP, FASN Spokane, WA Donald E. Hricik, MD Cleveland, OH Sushrut S. Waikar, MD Boston, MA Mark M. Mitsnefes, MD Cincinnati, OH Section Editors Attending Rounds Series Editor Education Series Editor Ethics Series Editor Public Policy Series Editor Renal Immunology Series Editor Mitchell H. Rosner, MD, FASN Charlottesville, VA Suzanne Watnick, MD Portland, OR Alvin H. Moss, MD, FACP Morgantown, WV Alan S. Kliger, MD New Haven, CT Fadi G. Lakkis, MD Pittsburgh, PA Statistical Editors Ronit Katz, DPhil Seattle, WA Editor-in-Chief, Emeritus William M. Bennett, MD, FASN Portland, OR Managing Editor Shari Leventhal Washington, DC Robert A. Short, PhD Spokane, WA CJASN Clinical Journal of the American Society of Nephrology Editorial Board Rajiv Agarwal Indianapolis, Indiana Lance Dworkin Providence, Rhode Island T. Alp Ikizler Nashville, Tennessee Nader Najafian Boston, Massachusetts Edward Siew Nashville, Tennessee Ziyad Al-Aly Saint Louis, Missouri Jeffrey Fadrowski Baltimore, Maryland Tamara Isakova Chicago, Illinois Andrew Narva Bethesda, Maryland Theodore Steinman Boston, Massachusetts Charles Alpers Seattle, Washington Derek Fine Baltimore, Maryland Meg Jardine Sydney, Australia Sankar Navaneethan Cleveland, Ohio Peter Stenvinkel Stockholm, Sweden Sandra Amaral Philadelphia, Pennsylvania Kevin Finkel Houston, Texas Michelle Josephson Chicago, Illinois Alicia Neu Baltimore, Maryland Bryce Kiberd Halifax, BC, Canada Thomas Nickolas New York, New York Greg Knoll Ottawa, ON, Canada Toshiharu Ninomiya Fukuoka, Japan Jay Koyner Chicago, Illinois Rainer Oberbauer Vienna, Austria Holly Kramer Maywood, Illinois Gregorio Obrador Mexico Manjula Kurella Tamura Palo Alto, California Runolfur Palsson Reykjavik, Iceland Hiddo Lambers Heerspink Groningen, Netherlands Mandip Panesar Buffalo, New York Craig Langman Chicago, Illinois Neesh Pannu Edmonton, Canada James Lash Chicago, Illinois Rulan Parekh Baltimore, Maryland Eleanor Lederer Louisville, Kentucky Uptal Patel Durham, North Carolina Michael Walsh Hamilton, ON, Canada Andrew Lewington Leeds, United Kingdom Aldo Peixoto West Haven, Connecticut Matthew Weir Baltimore, Maryland Orfeas Liangos Coburg, Germany Anthony Portale San Francisco, California Steven Weisbord Pittsburgh, Pennsylvania Fernando Lian˜o Madrid, Spain Jai Radhakrishnan New York, New York Jessica Weiss Portland, Oregon Jerry Appel New York, New York Arif Asif Miami, Florida Mohamed Atta Baltimore, Maryland Joanne Bargman Toronto, ON, Canada Brendan Barrett St. John’s, NL, Canada Srinivasan Beddhu Salt Lake City, Utah Jeffrey Berns Philadelphia, PA Geoffrey Block Denver, Colorado W. Kline Bolton Charlottesville, Virginia Andrew Bomback New York, New York Ursula Brewster New Haven, Connecticut Patrick Brophy Iowa City, Iowa Steven Fishbane Mineola, New York John Forman Boston, Massachusetts Lui Forni Worthing, United Kingdom Barry Freedman Winston Salem, North Carolina Masafumi Fukagawa Kanagawa, Japan Susan Furth Philadelphia, PA Martin Gallagher Sydney, Australia Maurizio Gallieni Milan, Italy Ronald Gansevoort Groningen, Netherlands Amit Garg London, ON, Canada Michael Germain Springfield, Massachusetts Eric Gibney Atlanta, Georgia John Gill Vancouver, BC, Canada Harold Szerlip Augusta, Georgia Eric Taylor Boston, Massachusetts Ashita Tolwani Birmingham, Alabama James Tumlin Chattanooga, Tennessee Mark Unruh Albuquerque, New Mexico Raymond Vanholder Gent, Belgium Anitha Vijayan St. Louis, Missouri Ron Wald Toronto, ON, Canada Emmanuel Burdmann Sa˜o Paulo, Brazil David Goldsmith London, United Kingdom John Lieske Rochester, Minnesota Mahboob Rahman Cleveland, Ohio Kerri Cavanaugh Nashville, Tennessee Stuart Goldstein Cincinnati, Ohio Kathleen Liu San Francisco, California Dominic Raj Washington, District of Columbia Micah Chan Madison, Wisconsin Barbara Greco Springfield, Massachusetts Randy Luciano New Haven, Connecticut Peter Reese Philadelphia, Pennsylvania Anil Chandraker Boston, Massachusetts Orlando Gutierrez Birmingham, Alabama Jicheng Lv Beijing, China Giuseppe Remuzzi Bergamo, Italy David Charytan Boston, Massachusetts Yoshio Hall Seattle, Washington Mark Marshall Auckland, New Zealand Mark Rosenberg Minneapolis, Minnesota Michael Choi Baltimore, Maryland Lee Hamm New Orleans, Louisiana William McClellan Atlanta, Georgia Andrew Rule Rochester, Minnesota Michel Chonchol Denver, Colorado Ita Heilberg Sa˜o Paulo, Brazil Anita Mehrotra New York, New York Jeffrey Saland New York, New York Steven Coca New Haven, Connecticut Brenda Hemmelgarn Calgary, AB, Canada Rajnish Mehrotra Seattle, Washington Jane Schell Pittsburgh, Pennsylvania Andrew Davenport London, United Kingdom Jonathan Himmelfarb Seattle, Washington Michal Melamed Bronx, New York Bernd Schro¨ppel Ulm, Germany Ian de Boer Seattle, Washington Eric Hoste Gent, Belgium Sharon Moe Indianapolis, Indiana Stephen Seliger Baltimore, Maryland Eric Young Ann Arbor, Michigan Bradley Dixon Iowa City, Iowa Chi-yuan Hsu San Francisco, California Barbara Murphy New York, New York Michael Shlipak San Francisco, California Carmine Zoccali Reggio Calabria, Italy Adam Whaley-Connell Columbia, Missouri Colin White Vancouver, BC, Canada Mark Williams Boston, Massachusetts Alexander Wiseman Aurora, Colorado Jay Wish Indianapolis, IN Myles Wolf Chicago, Illinois Jerry Yee Detroit, Michigan Bessie Young Seattle, Washington CJASN Executive Director Tod Ibrahim Director of Communications Robert Henkel Managing Editor Shari Leventhal The American Society of Nephrology (ASN) marks 50 years of leading the fight against kidney diseases in2016.Throughouttheyear, ASN willrecognize kidney health advances from the past half century and look forward to new innovations in kidney care. Celebrations will culminate at ASN Kidney Week 2016, November 15–20, 2016, at McCormick Place in Chicago, IL. Submit your manuscript online through Manuscript Central at . Contacting CJASN Correspondence regarding editorial matters should be addressed to the Editorial Office. Editorial Office Clinical Journal of the American Society of Nephrology 1510 H Street, NW, Suite 800 Washington, DC 20005 Phone: 202-503-7804; Fax: 202-478-5078 E-mail: [email protected] Contacting ASN Correspondence concerning business matters should be addressed to the Publishing Office. Indexing Services The Journal is indexed by NIH NLM’s PubMed MEDLINE; Elsevier’s Scopus; and Thomson Reuters’ Science Citation Index Expanded (Web of Science), Journal Citation Reports - Science Edition, Research Alert, and Current Contents/Clinical Medicine. Display Advertising The Walchli Tauber Group 2225 Old Emmorton Road, Suite 201 Bel Air, MD 21015 Mobile: 443-252-0571 Phone: 443-512-8899 *104 E-mail: [email protected] Publishing Office American Society of Nephrology 1510 H Street, NW, Suite 800 Washington, DC 20005 Phone: 202-640-4660; Fax: 202-637-9793 E-mail: [email protected] Classified Advertising The Walchli Tauber Group 2225 Old Emmorton Road, Suite 201 Bel Air, MD 21015 Phone: 443-512-8899 *106 E-mail: [email protected] Membership Queries For information on American Society of Nephrology membership, contact Pamela Gordon at 202-640-4668; E-mail: [email protected] Change of Address The publisher must be notified 60 days in advance. Journals undeliverable because of incorrect address will be destroyed. Duplicate copies may be obtained, if available, from the Publisher at the regular price of a single issue. Subscription Services ASN Journal Subscriptions 1510 H Street NW, Suite 800 Washington, DC 20005 Phone: 202-557-8360; Fax: 202-403-3615 E-mail: [email protected] Commercial Reprints/ePrints Hope Robinson Sheridan Content Services The Sheridan Press 450 Fame Avenue Hanover, Pennsylvania 17331 Phone: 800-635-7181, ext. 8065 Fax: 717-633-8929 E-mail: [email protected] Disclaimer The statements and opinions contained in the articles of The Clinical Journal of the American Society of Nephrology are solely those of the authors and not of the American Society of Nephrology or the editorial policy of the editors. The appearance of advertisements in the Journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality, or safety. The American Society of Nephrology disclaims responsibility for any injury to persons or property resulting from any ideas or products referred to in the articles or advertisements. The Editor-in-Chief, Deputy, Associate, and Series Editors, as well as the Editorial Board disclose potential conflicts on an annual basis. This information is available on the CJASN website at . POSTMASTER: Send changes of address to Customer Service, CJASN Clinical Journal of the American Society of Nephrology, 1510 H Street, NW, Suite 800, Washington, DC 20005. CJASN Clinical Journal of the American Society of Nephrology, ISSN 1555-9041 (Online: 1555-905X), is an official journal of the American Society of Nephrology and is published monthly by the American Society of Nephrology. Periodicals postage at Washington, DC, and at additional mailing offices. Subscription rates: domestic individual $438; international individual, $588; domestic institutional, $970; international institutional, $1120; single copy, $75. To order, call 504-942-0902. Subscription prices subject to change. Annual dues include $33 for journal subscription. Publications mail agreement No. 40624074. Return undeliverable Canadian addresses to PO Box 503 RPO West Beaver Creek Richmond Hill ON L4B 4R6. Copyright Ó 2016 by the American Society of Nephrology. ∞ This paper meets the requirements of ANSI/NISO Z39.48-1992 (Permanence of Paper), effective with January 2006, Vol. 1, No. 1. A New CJASN Series: Renal Immunology for the Clinician Fadi G. Lakkis* and Paul M. Palevsky† Clin J Am Soc Nephrol 10: 1273, 2015. doi: 10.2215/CJN.03870415 With this issue, CJASN begins a new series of review articles covering immunology for the clinical nephrologist. There has been explosive growth in our understanding of immune mechanisms and the relationship between these integral defense systems within the body and the function of the kidney in health and disease. The role of the immune system as a barrier to transplantation has been long recognized and has been a primary impetus for our drive to better understand immunologic detection of nonself and mechanisms of tolerance and the development of medications to modulate the body’s normal response to reject foreign organs. Immunologic dysregulation leads to the development of autoimmune kidney diseases both limited to the kidney or as part of systemic illness. These include primary glomerular diseases and interstitial nephritis as well as systemic vasculitides, collagen vascular disorders, such as SLE, and a widening array of diseases understood to be mediated by complement activation, including thrombotic microangiopathies and the spectrum of C3 nephropathy. Increasing evidence over the past decade has also shown a central role for the immune system in the pathogenesis of AKI resulting from ischemia reperfusion injury or nephrotoxin exposure, and in sepsis, even when the kidney is not the focus of infection. An additional important connection between the kidney and immune Vol 10 July, 2015 system is the influence of CKD on immunity; paradoxically weakening defenses against infection while increasing systemic inflammation, which contributes to the excessive burden of cardiovascular disease in our patients. The role of immunologic processes in the progression of CKD is an area of growing interest. This series, which will run over eight issues, begins this month with an overview of the immune system from an evolutionary/teleologic standpoint. In succeeding issues, the series will cover the mechanisms of the innate immune system, the normal regulation of the complement system and the role of its dysregulation in disease, the roles of dendritic cells and macrophages as both sensors and effectors in the kidney, the biology of T cells in mediating and regulating the immune response, the role of B cells, and the role of the increasing number of known soluble cytokines that allow the components of the immune system to communicate and function harmoniously. Finally, the series will end with a review of the enlarging armamentarium of pharmacologic agents at our service to control the immune response. It is the editors’ hope that these reviews will serve as a primer for understanding this important and rapidly advancing field and be helpful to both seasoned practitioners and new trainees in nephrology. *Thomas E. Starzl Transplantation Institute and Departments of Surgery, Immunology, and Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania; and † Renal Section, Veterans Affairs Pittsburgh Healthcare System and RenalElectrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Correspondence: Dr. Paul M. Palevsky, Veterans Affairs Pittsburgh Healthcare System, Mail Stop: 111F-U, University Drive, Pittsburgh, PA 15240. Email: [email protected] Copyright © 2015 by the American Society of Nephrology 1273 A Brief Journey through the Immune System Karim M. Yatim and Fadi G. Lakkis Abstract This review serves as an introduction to an Immunology Series for the Nephrologist published in CJASN. It provides a brief overview of the immune system, how it works, and why it matters to kidneys. This review describes in broad terms the main divisions of the immune system (innate and adaptive), their cellular and tissue components, and the ways by which they function and are regulated. The story is told through the prism of evolution in order to relay to the reader why the immune system does what it does and why imperfections in the system can lead to renal disease. Detailed descriptions of cell types, molecules, and other immunologic curiosities are avoided as much as possible in an effort to not detract from the importance of the broader concepts that define the immune system and its relationship to the kidney. Clin J Am Soc Nephrol 10: 1274–1281, 2015. doi: 10.2215/CJN.10031014 The Beginning of the Journey Imagine that you are a primitive animal, perhaps a distant predecessor of all mammals. You have lived a long life, thus far relying solely on a basic defense system. If you are invaded by a microbe or parasite, you quickly expel or kill it by releasing chemicals, producing a barrage of defensive protein molecules or unleashing phagocytic cells (1). If all fails, you wall the invader off or regenerate that part of your body reduced to rot by infection. Even if infection proves fatal, your extreme fecundity, which started at a very early age, has already ensured the continuity of your species. This seemingly imaginary scenario is in fact how the more ancient of our ancestors attain near immortality (2). Now imagine that evolution has something grander in store for you. You are destined to become the progenitor of more sophisticated beings. Your descendants will grow complex organs—robust kidneys that empower them to roam the earth and mighty brains that enable them to rule it. To do so, they will carry their embryos and nurture their young for an extended period of time. Reproduction becomes a later and infrequent event in life, and life itself becomes a much shorter journey. The capacity to regenerate tissues, limbs, and organs dwindles as tissue architecture and function grow increasingly differentiated and complex. Although less abundant, life for your descendants becomes more valuable as failure to survive until a reproductive age spells doom for the species. Faced with these burdens, you quickly realize that you have to devise a more intelligent defense system: one that protects against virtually all pathogens that your successors may encounter during their forays into known and unknown realms, one that provides long-lasting security against infection, and one that is carefully regulated so that it does not attack its own tissues or endanger beneficial cohabitants. You will call this defense system immunity (Figure 1). Defense, after all, is a primitive term that is equally associated with defeat and victory, whereas immunity exudes strength and confidence. So 1274 Copyright © 2015 by the American Society of Nephrology how would you (with the guiding hand of evolution, of course) go about devising such a system, what would it look like, and why will it eventually matter to our kidneys? Innate and Adaptive Immunity Devising a sophisticated biologic system, as evolution teaches us, does not require the destruction of preexisting, primitive tools, but instead depends on preserving and building on the best of them (3). Heeding this advice, you take your time, spending hundreds of millions of years, choosing the best and discarding the least useful of your primitive defense mechanisms. You call what is left innate immunity: innate because the defense mechanisms you have chosen are encoded in your germline, having been selected over evolutionary time and passed down from generation to generation with only minor refinements (4). In other words, they have stood the test of time. They include household names such as the complement system, Toll-like receptors (TLRs), and phagocytic cells. Modern-day genome sequencing has established that much of these defense systems are conserved across animal phyla, a true reflection of not only their remarkable effectiveness but also their versatility (3). A complement molecule, a TLR, or a phagocyte is not only essential for detecting and eliminating harmful nonself but is also key to maintaining normal tissue homeostasis, be it sensing and repairing damaged tissues or quietly eliminating senescent or apoptotic cells. Obviously, you have chosen prudently. However, that is clearly not sufficient. An innate immune system provides immediate al...
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