Apoptosis and Its Relevance to Autoimmunity - K. Elkon (Karger, 2006) WW

219 Pages·2006·3.58 MB·English

Apoptosis and Its Relevance to Autoimmunity

Current Directions in
Autoimmunity

Vol. 9

Series Editor

A.N. Theofilopoulos
La Jolla, Calif.

Apoptosis and Its
Relevance to
Autoimmunity

Basel · Freiburg · Paris · London · New York ·
Bangalore · Bangkok · Singapore · Tokyo · Sydney

Volume Editor

Keith B. Elkon
Seattle, Wash.

40 figures, 4 in color, and 2 tables, 2006

Keith B. Elkon
Division of Rheumatology
University of Washington
Seattle, Wash. (USA)

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© Copyright 2006 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland)
www.karger.com
Printed in Switzerland on acid-free paper by Reinhardt Druck, Basel
ISSN 1422–2132
ISBN 3–8055–8036–3

Library of Congress Cataloging-in-Publication Data

Apoptosis and its relevance to autoimmunity / volume editor, Keith B.
Elkon.
p. ; cm. – (Current directions in autoimmunity, ISSN 1422-2132
; v. 9)
Includes bibliographical references and indexes.
ISBN 3-8055-8036-3 (hard cover : alk. paper)
1. Apoptosis. 2. Autoimmunity. 3. Autoimmune diseases.
I. Elkon, Keith B. II. Series.
[DNLM: 1. Apoptosis–immunology. 2. Autoimmune Diseases
–physiopathology. 3. Autoimmunity–physiology. 4. Receptors,
Immunologic–physiology. QU 375 A652 2006]
QH671.A6544 2006
616.97�8–dc22

2005027202

V

Contents

VII Preface
Elkon, K.B. (Seattle, Wash.)

Extrinsic Death Receptor Pathways

1 Death Receptor Signaling and Its Function in the Immune System
Fas, S.C.; Fritzsching, B.; Suri-Payer, E.; Krammer, P.H. (Heidelberg)

18 Inherited and Acquired Death Receptor Defects in
Human Autoimmune Lymphoproliferative Syndrome
Rieux-Laucat, F. (Paris)

37 Tumor Necrosis Factor Ligand-Receptor Superfamily and Arthritis
Hsu, H.-C.; Wu, Y.; Mountz, J.D. (Birmingham, Ala.)

Intrinsic Death Pathways

55 Mitochondria, Apoptosis and Autoimmunity
Pinkoski, M.J. (Leicester); Waterhouse, N.J. (Melbourne, Vic.);
Green, D.R. (Memphis, Tenn.)

74 Role of Bim and other Bcl-2 Family Members in Autoimmune and
Degenerative Diseases
Hughes, P.; Bouillet, P.; Strasser, A. (Parkville, Vic.)

95 Mitochondria, Cell Death, and B Cell Tolerance
Deming, P.B. (Burlington, Vt.); Rathmell, J.C. (Durham, N.C.)

Apoptotic Cell Clearance

120 Role of Complement and Other Innate Immune Mechanisms
in the Removal of Apoptotic Cells
Ogden, C.A.; Elkon, K.B. (Seattle, Wash.)

143 Collectins: Opsonins for Apoptotic Cells and Regulators
of Inflammation
Stuart, L.M. (Boston, Mass./Edinburgh); Henson, P.M.;
Vandivier, R.W. (Denver, Colo.)

162 MFG-E8-Dependent Clearance of Apoptotic Cells, and
Autoimmunity Caused by Its Failure
Hanayama, R.; Miyasaka, K.; Nakaya, M.; Nagata, S. (Osaka)

173 Clearance of Apoptotic Cells in Human SLE
Gaipl, U.S. (Erlangen); Kuhn, A. (Düsseldorf); Sheriff, A.; Munoz, L.E.; Franz, S.;
Voll, R.E.; Kalden, J.R.; Herrmann, M. (Erlangen)

188 Apoptosis and Glomerulonephritis
Watson, S.; Cailhier, J.-F.; Hughes, J.; Savill, J. (Edinburgh)

205 Author Index

206 Subject Index

Contents
VI

Preface

Over the last 15 years, apoptosis has moved from a peripheral circum-
scribed interest amongst a small group of scientists to the mainstream of mod-
ern biology and a highly prominent and, in some cases, dominant focus of
medical research. This is particularly true in the field of immunology where
more than 10 billion cells are turned over each day and cell death is a necessary
part of immune tolerance and contraction following immune activation.
In this volume of Current Directions in Autoimmunity on Apoptosis, con-
tributors discuss the three major areas of apoptosis research: Extrinsic Death
Receptor Pathways, Intrinsic Death Pathways, and the mechanisms responsible
for Apoptotic Cell Clearance. In each of these sections, the proteins and signal
transduction pathways are delineated and genetic alterations that lead to
autoimmune diseases are described. Although most cell death abnormalities
have been associated with systemic autoimmune disorders such as lupus, it is
evident that regulation of cell death is pertinent to disease expression in many
organ-specific diseases as well.
The precise understanding of how molecular defects in apoptotic pathways
lead to different diseases provides innovative directions in autoimmunity
research that will ultimately facilitate the development of new classes of dis-
ease-modifying agents.
Sincere thanks is given to the outstanding contributors of this volume for
their time and effort.

Keith B. Elkon
Seattle, Wash.

VII

Elkon K (ed): Apoptosis and Its Relevance to Autoimmunity.
Curr Dir Autoimmun. Basel, Karger, 2006, vol 9, pp 1–17

Death Receptor Signaling and Its
Function in the Immune System

Stefanie C. Fas, Benedikt Fritzsching, Elisabeth Suri-Payer,
Peter H. Krammer

Tumor Immunology Program, Division of Immunogenetics,
German Cancer Research Center, Heidelberg, Germany

Abstract
Death receptors belong to the TNF (tumor necrosis factor)/NGF (nerve growth factor)
receptor superfamily. Signaling via death receptors plays a distinct role, e.g. in the immune
system, where it contributes to regulation of the adaptive immune response in various ways,
most notably by triggering activation-induced cell death (AICD) of T cells. Thus, dysregula-
tion of death receptor signaling, either allowing too much or too little apoptosis, can lead to
autoimmune disorders and also impacts on tumorigenesis or other diseases. In this chapter
we address components, molecular mechanisms and regulation of death receptor signaling
with particular focus on CD95 (APO-1, Fas). We discuss the role of death receptor-mediated
AICD in regulation of the adaptive immune response against foreign and self antigens in
comparison to cytokine deprivation-mediated death by neglect. Finally, the contribution of
dysregulated death receptor/ligand systems to autoimmune diseases such as diabetes, mul-
tiple sclerosis and Hashimoto’s thyroiditis is discussed.

Copyright © 2006 S. Karger AG, Basel

Death Receptors

Death receptor signaling plays a distinct role, e.g. in the immune system,
where it contributes to the regulation of the adaptive immune response but also
in other physiological and pathophysiological states such as development, dif-
ferentiation and tumorigenesis. Death receptors belong to the TNF (tumor
necrosis factor)/NGF (nerve growth factor) receptor superfamily. Members of
this family are type I transmembrane receptors, contain 1–5 cysteine-rich
domains in their extracellular domain and an 80 amino acid death domain (DD)
in the cytoplasmic tail which is essential for transduction of the death signal.
Six members of this death receptor subfamily are known so far (fig. 1),
namely TNF-R1 (tumor necrosis factor receptor 1; also known as CD120a), CD95

Extrinsic Death Receptor Pathways