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Handbook of Systemic Autoimmune Diseases

Series Editor: F. Atzeni and P. Sarzi-Puttini

Volume 1 The Heart in Systemic Autoimmune Diseases

Edited by: Andrea Doria and Paolo Pauletto
Volume 2 Pulmonary Involvement in Systemic Autoimmune Diseases
Edited by: Athol U. Wells and Christopher P. Denton
Volume 3 Neurologic Involvement in Systemic Autoimmune Diseases
Edited by: Doruk Erkan and Steven R. Levine
Volume 4 Reproductive and Hormonal Aspects of Systemic Autoimmune Diseases
Edited by: Michael Lockshin and Ware Branch
Volume 5 The Skin in Systemic Autoimmune Diseases
Edited by: Piercarlo Sarzi-Puttini, Andrea Doria, Giampiero Girolomoni
and Annegret Kuhn
Volume 6 Pediatrics in Systemic Autoimmune Diseases
Edited by: Rolando Cimaz and Thomas Lehman
Volume 7 The Kidney in Systemic Autoimmune Diseases
Edited by: Justin C. Mason and Charles D. Pusey
Volume 8 Digestive Involvement in Systemic Autoimmune Diseases
Edited by: Josep Font, Manuel Ramos-Casals and Juan Rode´s
Volume 9 Endocrine Manifestations of Systemic Autoimmune Diseases
Edited by: Sara E. Walker and Luis J. Jara
Volume 10 Antiphospholipid Syndrome in Systemic Autoimmune Diseases
Edited by: Ricard Cervera, Joan Carles Reverter and Munther
Khamashta
Volume 11 Pediatrics in Systemic Autoimmune Diseases, Second Edition
Edited by: Rolando Cimaz and Thomas Lehman
Volume 12 Antiphospholipid Syndrome in Systemic Autoimmune
Diseases, Second Edition
Edited by: Ricard Cervera, Gerard Espinosa, and Munther Khamashta
Volume 13 The Digestive Involvement in Systemic Autoimmune Diseases, Second
Edition
Edited by: Manuel Ramos-Casals, Munther Khamashta, Pilar Brito-
Zerón, Fabiola Atzeni, and Joan Rode´s Teixidor
Volume 14 The Heart in Systemic Autoimmune Diseases, Second Edition
Edited by: Fabiola Atzeni, Andrea Doria, Michael Nurmohamed, and
Paolo Pauletto
Handbook of Systemic Autoimmune Diseases, Volume 13

The Digestive Involvement

in Systemic Autoimmune
Diseases
SECOND EDITION

Edited by

Manuel Ramos-Casals
Sjögren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases
Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD,
University of Barcelona, Hospital Clı́nic, Barcelona, Spain
Munther Khamashta
Graham Hughes Lupus Research Laboratory, Division of Women’s Health,
King’s College London; The Rayne Institute, St Thomas’ Hospital, London,
United Kingdom
Pilar Brito-Zerón
Autoimmune Diseases Unit, Department of Internal Medicine, Hospital
CIMA-Sanitas, Barcelona, and Laboratory of Autoimmune Diseases Josep Font,
CELLEX-IDIBAPS, Department of Autoimmune Diseases, ICMiD, Hospital Clı́nic,
Barcelona, Spain
Fabiola Atzeni
Rheumatology Unit, L. Sacco University Hospital, Milan, Italy
Joan Rodés Teixidor
Liver Unit, ICMD, Ciberehd, Instituto de Investigaciones Biomédicas August Pi I
Sunyer (IDIBAPS), Hospital Clinic, Barcelona, Spain

AMSTERDAM l BOSTON l HEIDELBERG l LONDON l NEW YORK l OXFORD

PARIS l SAN DIEGO l SAN FRANCISCO l SINGAPORE l SYDNEY l TOKYO
Elsevier
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Dedication

The first edition of this book was one of the last projects led by Dr. Josep
Font (Barcelona, 1953e2006) before his unexpected death, and the
remaining editors wish to dedicate these lines as a means of paying a deeply
felt homage. Dr. Font devoted his professional career to the care of patients
with systemic autoimmune diseases (SAD). He trained in Internal Medicine
at the Hospital Clinic of Barcelona from 1978 to 1982 and obtained his PhD
in 1984 for his thesis on systemic lupus erythematosus (SLE). His post-
doctoral experience was closely linked with the Lupus Research Unit at St.
Thomas’ Hospital, London. His research output was prodigious, with a total
of over 500 scientific articles published over 25 years. In addition, he
designed and coordinated many international projects including the Euro-
lupus, Europhospholipid, Catastrophic Antiphospholipid Syndrome (CAPS)
Registry, Sjögren syndrome-HCV Registry, and Hispanoamerican Registry
of Extrahepatic Manifestations of HCV (HISPAMEC) and was an active
member of some of the most prestigious international research groups, such
as the Eurolupus Nephritis Trial and SLICC.
In 1995, Dr. Font established the Department of Autoimmune Diseases at
the Hospital Clinic, a pioneering unit in Europe specifically dedicated to the
clinical management of patients with SAD. He played a leading role in
creating a network of different specialists at the Hospital Clinic dedicated to
the care of these patients. A key characteristic of his clinical research was its
multidisciplinary design and the close collaboration between different medical
specialties, of which this book is an excellent example. He was working
actively until the last days of his life, and died like a soldier “with his boots
on’.” His integrity, intelligence, and loyalty made him a formidable physician
and a wonderful colleague and friend. He was undoubtedly one of the foremost
figures in the field of autoimmune diseases in recent decades, and the immense
human and professional legacy that he left must be maintained and continued
by all who had the great fortune to know and work with him.
For this second edition, we would also like to honor two of the main in-
ternational experts in the field of autoimmunity and liver diseases who recently
retired, professors Jenny Heathcote and Joan Rodés.
In June 2013 and after authoring 350 papers, conducting 800 lectures,
mentoring 64 residents, and training 31 fellows in hepatology, Prof. Jenny
Heathcote, a world-renowned liver specialist based at Toronto Western
vi Dedication

Hospital, fully retired from her position as Senior Scientist in the Toronto
Western. In 2009 she received the Chair in Hepatology at the University and
was awarded the EASL International Recognition Award (2010) for her sus-
tained contribution to the knowledge and understanding of liver diseases. In
the last decade, Prof. Heathcote has built up a world renowned liver unit and
fostered many new initiatives. We have decided to maintain the original
chapter written by Prof. Heathcote for the first edition of this book (including a
brief update for the past 5 years) as a tribute from the editors to their
outstanding work in liver diseases.
Prof. Joan Rodés, born in 1938 in Barcelona, is considered one of the
most prestigious international hepatologists and his career is also closely
linked to the Hospital Clinic of Barcelona; he was the Medical Director of the
Hospital Clinic between 1984 and 1986 and General Director between 2003
and 2008. The recognition of his research work has led Prof. Rodés to occupy
positions in international organizations (President of the European Association
for the Study of the Liver in 1991, President of the International Association
for the Study of the Liver in 1992). He has authored or coauthored more than
500 papers in major medical journals internationally, and was also founder and
Director of the Institute of Biomedical Research August Pi i Sunyer (IDI-
BAPS). The accumulation of merits and distinctions received by Prof. Rodés is
more than an expression of an exceptional personality; a tireless worker with
extraordinary leadership qualities, able to create, enhance, and hold together a
group of leading researchers and a proverbial modesty.
Finally, we wish to thank Linda Versteeg-Buschman, Halima Williams
and their staff at Elsevier for their hard work. It has been a great pleasure
working together on this second edition.

The Editors
List of Contributors

R. Abdalian, University Health Network, Toronto, ON, Canada

N. Acar-Denizli, Mimar Sinan Fine Arts University, Istanbul, Turkey
G.S. Alarcón, The University of Alabama at Birmingham, Birmingham, AL, United
States
J. Al Saleh, Dubai Hospital, Dubai, United Arab Emirates
F. Atzeni, IRCCS Galeazzi Orthopedic Institute, Milan, Italy
C. Ayuso, Hospital Clinic, University of Barcelona, Spain
K. Bari, University of Cincinnati Medical Center, Cincinnati, OH, United States
R.P. Baughman, University of Cincinnati Medical Center, Cincinnati, OH, United
States
D. Ben-Ami Shor, Tel-Aviv University, Israel
X. Bosch, Hospital Clı́nic, Barcelona, Spain
P. Brito-Zerón, Hospital CIMA-Sanitas, Barcelona, Spain; Laboratory of Autoimmune
Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune Diseases,
ICMiD, Hospital Clı́nic, Barcelona, Spain
P. Cacoub, Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-
Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM,
UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe
Hospitalier Pitié-Salpêtrière, Paris, France
R. Cervera, Hospital Clı́nic, Barcelona, Spain
R.W. Chapman, University of Oxford, Oxford, United Kingdom; John Radcliffe
Hospital, Oxford, United Kingdom
C. Commarmond, Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and
Inflammation-Immunopathology-Biotherapy Department (DHU i2B), Paris,
France; INSERM, UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France;
AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
A.J. Czaja, Mayo Clinic College of Medicine, Rochester, MN, United States
A.C. Desbois, Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-
Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM,
UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hos-
pitalier Pitié-Salpêtrière, Paris, France
S. De Vita, University of Udine, Udine, Italy

xix
xx List of Contributors

H. Direskeneli, Marmara University, Istanbul, Turkey

F. Domont, Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-
Immunopathology-Biotherapy Department (DHU i2B), Paris, France; AP-HP, Groupe
Hospitalier Pitié-Salpêtrière, Paris, France
L. Donoso, Hospital Clinic, University of Barcelona, Spain
G. Espinosa, Hospital Clı́nic, Barcelona, Spain
J.J. Fernández-Martı́n, Hospital Álvaro Cunqueiro, Vigo, Spain
R.A. Ferrandiz, Hospital Nacional Cayetano Heredia and Universidad Peruana
Cayetano Heredia, Lima, Perú
X. Forns, Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS),
Hospital Clinic, Barcelona, Spain
M. Gandı́a, Hospital Punta Europa, Algeciras (Cádiz), Spain; Hospital Jerez Puerta del
Sur-ASISA, Jerez de la Frontera (Cádiz), Spain
L. Guillevin, Université Paris 5 e René Descartes, Paris, France
R. Hamad, Dubai Hospital, Dubai, United Arab Emirates
J. Heathcote, University Health Network, Toronto, ON, Canada
I.R.L. Kean, University of WisconsineMadison, Madison, WI, United States
W.F. Kean, McMaster University Faculty of Health Sciences, Hamilton, ON, Canada
M. Khamashta, Dubai Hospital, Dubai, United Arab Emirates; King’s College
London, London, United Kingdom
D. Khanna, University of Michigan Medical School, Ann Arbor, MI, United States
B. Kostov, Institut d’Investigacions Biomèdiques August Pi i Sunyer, Barcelona and
University of Barcelona
M.P. Manns, Hannover Medical School, Hannover, Germany
I.F. Masala, Santissima Trinità Hospital, Cagliari, Italy
G. Mieli-Vergani, King’s College London Faculty of Life Sciences & Medicine at
King’s College Hospital, London, United Kingdom
H. Mix, Hannover Medical School, Hannover, Germany
C. Morcillo, Hospital CIMA-Sanitas, Barcelona
J. Ordi-Ros, Vall D’Hebron General Hospital, Barcelona, Spain
M. Pagés, Hospital Clinic, University of Barcelona, Spain
C. Pagnoux, University of Toronto, Toronto, ON, Canada
L. Pallarés-Ferreres, Hospital de Son Espases, Palma de Mallorca, Spain
N.P. Papageorgiou, American Medical Center, Nicosia, Cyprus
R. Pérez-Álvarez, Hospital Álvaro Cunqueiro, Vigo, Spain
M. Pérez-de-Lis Novo, Hospital Álvaro Cunqueiro, Vigo, Spain
L. Quartuccio, University of Udine, Udine, Italy
 List of Contributors xxi

K.D. Rainsford, Sheffield Hallam University, Sheffield, England, United Kingdom

M. Ramos-Casals, Sjögren Syndrome Research Group (AGAUR), Laboratory of
Autoimmune Diseases Josep Font, CELLEX-IDIBAPS, Department of Autoimmune
Diseases, ICMiD, University of Barcelona, Hospital Clı́nic, Barcelona, Spain
S. Retamozo, Hospital Privado Universitario de Córdoba, Institute University of
Biomedical Sciences, University of Córdoba (IUCBC), Córdoba, Argentina
I. Rodrı́guez-Pintó, Hospital Clı́nic, Barcelona, Spain
J. Romero-Dı́az, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán,
México City, México
D. Saadoun, Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-
Immunopathology-Biotherapy Department (DHU i2B), Paris, France; INSERM,
UMR_S 959, Paris, France; CNRS, FRE3632, Paris, France; AP-HP, Groupe Hos-
pitalier Pitié-Salpêtrière, Paris, France
J. Sánchez-Guerrero, Instituto Nacional de Ciencias Médicas y Nutrición Salvador
Zubirán, México City, México
J.-M. Sanchez-Tapias, Instituto de Investigaciones Biomédicas August Pi I Sunyer
(IDIBAPS), Hospital Clinic, Barcelona, Spain
P. Sarzi-Puttini, University Hospital L. Sacco, Milan, Italy
L. Savey, Sorbonne Universités, UPMC Univ Paris 06, UMR 7211, and Inflammation-
Immunopathology-Biotherapy Department (DHU i2B), Paris, France; AP-HP,
Groupe Hospitalier Pitié-Salpêtrière, Paris, France
A. Selva-O’Callaghan, Universitat Autònoma de Barcelona, Barcelona, Spain; Vall
D’Hebron General Hospital, Barcelona, Spain
Y. Shoenfeld, Tel-Aviv University, Israel
A.B. Shreiner, University of Michigan Medical School, Ann Arbor, MI, United States
M.-J. Soto Cárdenas, University of Cádiz, Hospital Puerta del Mar, Cádiz, Spain
J.H. Stone, Massachusetts General Hospital, Boston, MA 02114, United States
R. Talotta, University Hospital L. Sacco, Milan, Italy
J.R. Teixidor, Instituto de Investigaciones Biomédicas August Pi I Sunyer (IDIBAPS),
Hospital Clinic, Barcelona, Spain
M. Vauthier, AP-HP, Groupe Hospitalier Pitié-Salpêtrière, Paris, France
D. Vergani, King’s College London Faculty of Life Sciences & Medicine at King’s
College Hospital, London, United Kingdom
M. Vilardell-Tarrés, Vall D’Hebron General Hospital, Barcelona, Spain
K.D. Williamson, University of Oxford, Oxford, United Kingdom; John Radcliffe
Hospital, Oxford, United Kingdom
Preface

The second edition of The Digestive System in Systemic Autoimmune Diseases

represents the state of the art in the field of digestive disorders for the most
common systemic and organ-specific autoimmune diseases.
This volume consists of an introductory section including chapters
focusing on etiopathogenic aspects along with a specific chapter on imaging
techniques in digestive diseases, followed by two chapters on organ-specific
autoimmune diseases and autoimmune manifestations of viral hepatitis
(including a new chapter on new anti-HCV agents).
The final section deals with the digestive manifestations of patients with
systemic and rheumatic autoimmune diseases, with the aim of being a prac-
tical guide to the identification, diagnosis, and treatment of digestive
involvement in these patients that will be useful for all medical specialties. For
this second edition, we have also included new chapters (spondyloar-
thropathies, Behçet disease, sarcoidosis and IgG4-related disease), expanding
to other rheumatic diseases and rare systemic diseases.
The final chapter is devoted to update the gastrointestinal and liver com-
plications of the rheumatologic medications used in daily practice.
We hope you will enjoy and learn from the second edition of this book.

The Editors

xxiii
Chapter 1

Digestive System and

Autoimmunity
H. Mix and M.P. Manns
Hannover Medical School, Hannover, Germany

1. THE DIGESTIVE SYSTEM AND GUT-ASSOCIATED

IMMUNITY
Mammals depend on feeding and digestion. While single-celled organisms can
directly take in nutrients from their outside environment, multicellular or-
ganisms, with most of their cells removed from direct contact with the outside
environment, have developed specialized structures for obtaining and breaking
down their food. Large, complex molecules must be broken down into
monomers that can then be distributed throughout the body to every cell. This
vital function is accomplished by a series of specialized organs that comprise
the digestive system. The human digestive system is a coiled, muscular tube
about 6e9 m in length when fully extended, stretching from the mouth to the
anus. Several specialized compartments occur along this length: the mouth,
pharynx, esophagus, stomach, small intestine, large intestine, and anus.
Accessory digestive organs are connected to the main system by a series of
ducts, including salivary glands, the pancreas, and the liver with the biliary
system. Like the skin, the digestive tract is situated at the interface between
external and internal milieus. To maintain homeostasis, physical and chemical
mechanisms as elements of the innate immune response are used to protect
against exogenous, potentially noxious agents. The membranes of the diges-
tive tract provide a physical barrier against invading pathogens. A huge
number of chemical factors, including low pH in the stomach, pepsin, lyso-
zyme, antimicrobial substances such as cryptidins and defensins, limit the
growth and invasion of microorganisms [1] (Table 1.1).
In addition to innate defense mechanisms, the digestive system is lined by
mucosal lymphatic tissues [2]. It consists of diffuse lymphocytic infiltrates
throughout the epithelium and lamina propria of the mucosa or nonencapsu-

The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00001-5

Copyright © 2017 Elsevier B.V. All rights reserved. 3
4 SECTION j I Introduction

TABLE 1.1 Mechanisms to Minimize Self-Reactive Lymphocyte

Differentiation and Activation
Clonal deletion
Receptor editing
Clonal anergy and tuning
Extrinsic regulation
Induction of apoptosis by inhibition of prosurvival
pathways (BIM induction) or by activation of death
receptors (FAS activation)
Receptor editing through V(D)J recombination in
primary lymphatic tissues (in T cells and B cells) or
by somatic hypermutation in secondary lymphatic
tissues (in B cells)
Intrinsic regulation by B or T cell receptor
downregulation
Induction of inhibitory receptors (CD5, CTLA4)
Induction of phosphatases (SHP1, SHIP)
Induction of ubiquitin ligases (cbl, GRAIL, Itch,
Roquin)
Limitation of survival factors (BAFF, IL-7)
Limitation of costimulation (CD40L,
TLR ligands, B7 molecules)
Active suppression (regulatory T cells)

lated lymphoid nodules in the submucosa of the intestinal tract. Peyer patches
are the prototypical mucosal lymphatic tissue, specialized to sample envi-
ronmental antigens. The Peyer patches contain lymphoid compartments that
are analogous to the cortex and follicles of lymph nodes. Each follicle is
covered by a single-layered follicle-associated epithelium, and a more diffuse
area immediately below, called subepithelial dome. The follicle-associated
epithelium is interrupted by specialized membranous cells (M cells) that
have luminal microfolds instead of microvilli and lack the normal thick layer
of mucus. The M cells differentiate from enterocytes under the influence of
membrane-bound lymphotoxin-a1b2 present on local lymphoid cells [3e5].
These cells endocytose and transport various materials [6]. Antigen is deliv-
ered to lymphocytes, mononuclear phagocytes, and dendritic cells immedi-
ately beneath M cells. The germinal centers contain B cell blasts, follicular
dendritic cells, macrophages, and unique T cells. B cells undergo immuno-
globulin class switching from expression of IgM to IgA under the influence of
several local factors, including transforming growth factor-b (TGF-b),
interleukin-10 (IL-10), and other cellular signals that are delivered by dendritic
cells and T cells [7]. Lymphocytes exit the Peyer patches through the draining
lymphatics to the mesenteric lymph nodes, from where they migrate into the
 Digestive System and Autoimmunity Chapter j 1 5

bloodstream and finally home to the mucosa. The exit of lymphocytes from the
bloodstream into the mucosa is mediated by loss of L-selectin expression and
selective upregulation of a4b7 integrin. The ligand for a4b7 integrin mucosal
addressin cell-adhesion molecule 1 (MADCAM1) is highly expressed by the
vasculature of mucosal surfaces and mediates the emigration from the
bloodstream [8]. In addition, expression of the chemokine receptor CCR9 is
induced in gut-derived T cells, allowing them to respond to the chemokine
CCL25, which is exclusively expressed by small-bowel epithelial cells [9,10].
In contrast, T cells primed in peripheral lymphoid organs acquire the a4b1
integrin very late antigen 4 (VLA4) and the chemokine receptor CCR4 and do
not migrate to mucosal surfaces [10,11].
Lymphocytes that home into the mucosa of the gut redistribute into distinct
compartments. IgA-producing plasma cells remain in the lamina propria.
CD4þ T cells are distributed more evenly throughout the villusecrypt unit
within the lamina propria. CD8þ T cells preferentially reside in the epithelium.
A memory phenotype of CD4þ and CD8þ T cells predominates in both the
epithelium and the lamina propria, indicating that the cells have been exposed
to antigen. CD4þ T cells in the lamina propria are of particular importance to
local immune regulation. They produce large amounts of cytokines, particu-
larly interferon-g (IFN-g), but also IL-4 and IL-10 [12e14]. Lamina propria
CD8þ T cells can have potent cytotoxic T lymphocyte (CTL) activity [15].
Many of the properties of the lamina propria CD4þ T cells are similar to those
of regulatory T cells in other systems [16e18]. The unresponsiveness of
lamina propria T cells to commensal bacteria can be reversed by the depletion
of IL-10 or TGF-b [19].
Mesenteric lymph nodes have a crucial role in the induction of mucosal
immunity and tolerance. Antigen recognition in the mesenteric lymph nodes
occurs within a few hours of feeding protein antigen [20e23]. More impor-
tantly, induction of oral tolerance is not possible in lymphotoxin-aedeficient
or lymphotoxin-aedeficient tumor necrosis factor (TNF)-deficient mice,
which lack mesenteric lymph nodes [24]. Furthermore, total and specific
IgA-antibody responses are absent in mice lacking mesenteric lymph nodes,
while responses to parenterally administered antigens are preserved in these
mice [25,26].
Generally, immune responses to most tissue antigens are initiated in the
draining lymph nodes. Recent evidence has suggested that na€ıve intestinal
T cells first encounter antigen in the mesenteric lymph nodes and not in Peyer
patches [27,28]. While priming of T cells selectively in Peyer patches would
lead to efficient local immune responses or tolerance, priming of T cells in the
mesenteric lymph nodes could explain that intestinal antigens are able to
induce systemic immunity or tolerance.
Peyer patches harbor distinctive subsets of dendritic cells, which have
unusual phenotypic and functional characteristics [29]. Conventional subsets
of CD8aCD11bþ (myeloid) and CD8aþCD11b (lymphoid) dendritic cells are
6 SECTION j I Introduction

present next to a large number of CD8aCD11b dendritic cells. Currently, little

information is available about this subset of dendritic cells. They can be found
outside the organized lymphoid areas, especially in the dome region, which is
immediately beneath the follicle-associated epithelium, together with
CD8aCD11bþ dendritic cells. Their presence depends on the production of
macrophage inflammatory protein 3a (MIP3a), or CCL20, by local epithelial
cells [30,31]. The predominant CD8aCD11bþ dendritic cell subset is
distinctive in that it secretes IL-10. Interestingly, after ligation of the cos-
timulator molecule receptor activator of NF-kB (RANK), the dendritic cells of
Peyer patches respond by secretion of IL-10. Outside Peyer patches, i.e., in the
spleen, the same conditions result in the production of IL-12 [32]. Dendritic
cells in Peyer patches are also able to stimulate antigen-specific T cells to
produce T-helper type 2 (TH2) cytokines and IL-10. Collectively, these ob-
servations underscore an important role of Peyer patch dendritic cells in
maintaining a state of tolerance against food antigens and commensal bacteria
in the digestive system [33].
In addition, intestinal epithelial cells have recently been identified as key
elements in the development and regulation of mucosal immunity [34]. These
cells have been implicated in the regulation of innate immunity and chronic
inflammation before [35,36]; however, supporting data from in vivo experi-
ments were lacking. The authors could show that mice, deficient in IkB kinase-
b (IKK-b), produce reduced levels of the epithelial cellerestricted cytokine
thymic stromal lymphopoietin. The mice were unable to mount an efficient
CD4þ Th2 response against the parasite Trichuris. Severe intestinal inflam-
mation was the result of exacerbated dendritic cellederived IL-12/23p40 and
TNF-a production, as well as increased levels of CD4þ T cellederived IFN-g
and IL-17. The results were proof that the balance of IKK-bedependent gene
expression in the intestinal epithelium is crucial in intestinal immune ho-
meostasis in addition to the established pathways involved in pathogen
recognition and initiation of immune responses in the gastrointestinal tract,
which include M cells and specialized dendritic cell subsets that directly
sample the luminal environment.
The nervous innervation of the gastrointestinal tract is extensive, including
Peyer patches, and the diversity of adrenergic, cholinergic, and peptidergic
nerve endings in patches is greater than for any other peripheral lymphatic
tissue. Noradrenergic fibers form interfollicular plexuses that ramify through
the diffuse T-dependent areas near high endothelial venules. It is likely that the
extensive innervation of Peyer patches is involved in regulating traffic and
reactivity of mucosal immune cells. The nervous system, through the vagus
nerve, was shown to significantly and rapidly inhibit the release of
macrophage-derived TNF-a, thereby attenuating systemic inflammatory re-
sponses [37e39]. It could be demonstrated that this cholinergic antiin-
flammatory pathway of acetylcholine-mediated vagus nerve signals was
mediated via the nicotinic acetylcholine receptor a7 subunit [40].
 Digestive System and Autoimmunity Chapter j 1 7

The liver as a member of the accessory digestive organs plays an important

role in systemic immunity [41]. It contains large amounts of professional
antigen-presenting cell, including liver sinusoidal endothelial cells, Kupffer
cells, and dendritic cells. Potential antigen-rich blood is filtered, and pathogens
are quickly eliminated by phagocytes or by the huge population of natural
killer cells or natural killer T cells present in the liver. The liver has a high
capacity to induce antigen-specific tolerance. It acts as a central regulator in
systemic immune responses by synthesizing and secreting acute-phase pro-
teins and other mediators.

2. SELF-TOLERANCE AND AUTOIMMUNITY

Adaptive immune responses are essential for normal health. In some
cases, adaptive immune responses are elicited by antigens not associated
with infectious agents. The responses are essentially identical to adaptive
immune responses to infectious agents; however, the antigens are
different. Autoimmunity is the response to self-antigens in the absence of
infection.
The mammalian immune system is able to mount a response to any
chemical structure imaginable. B cells and T cells express receptors with
huge receptor diversity able to achieve specificity that differentiates mol-
ecules at the atomic level. This huge receptor diversity is encoded in the
mammalian genome and is possible through two processes of somatic
genome modification that occurs selectively in lymphocytes. In central
lymphoid organs, i.e., bone marrow for B cells and the thymus for T cells,
V(D)J recombination assembles unique receptor genes for B and T cells. In
peripheral lymphoid tissues, B cell receptor genes can further be modified
by single-nucleotide substitutions through somatic hypermutation. The
random processes of V(D)J recombination and somatic hypermutation
generate huge amounts, i.e., between 20% and 50%, of self-reactive B cells
and T cells [42e45]. Remarkably, only 3e8% of the population develops
an autoimmune disease [46].
Four mechanisms have been identified that limit the number of self-
reactive lymphocytes. First, clonal deletion is used to trigger apoptosis of
cells with self-reactive receptors. Second, cells with self-reactive receptors can
edit their specificity by further V(D)J recombination or somatic hypermutation
until the receptor does not bind to self-antigens [47]. Third, clonal anergy or
tuning is the unresponsiveness of cells to signals from self-reactive receptors
by changes in intrinsic biochemical processes and gene expression [48e50].
Collectively, these first three mechanisms are called immunologic ignorance.
When cells have evaded all the three mechanisms, extrinsic controls can limit
the potential of an autoimmune response by limiting the supply of growth
factors, costimuli, proinflammatory mediators, and other factors, or through
active suppression by regulatory T cells.
8 SECTION j I Introduction

3. TOLERANCE MECHANISMS FOR AUTOREACTIVE B CELLS

IN THE BONE MARROW
A series of events have been identified that occur if an immature B cell dis-
plays a self-reactive receptor in the bone marrow. The immature B cell in-
ternalizes the self-reactive receptor when the strength of receptor cross-linking
and intracellular signaling exceeds a certain threshold [51,52]. As a result,
homing receptors such as CD62 ligand, required to enter the lymph nodes, are
not expressed [52]. In addition, B celleactivating factor (BAFF) receptors are
only poorly induced [53]. BAFF is required to sustain peripheral B cell sur-
vival. Furthermore, recombination-activating gene 1 (RAG1) and RAG2,
which encode the core enzymes for V(D)J recombination, continue to be
expressed, allowing further editing of B cell receptors by rearranging a
replacement B cell receptor light chain [54]. If the receptor cannot be edited to
be less self-reactive, cell death is induced, either by withdrawal of growth
factors and/or through increasing levels of BCL-2einteracting mediator of cell
death (BIM), a proapoptotic factor that inhibits essential B cell survival pro-
teins of the BCL-2 family [55]. Interestingly, BIM-deficient mice spontane-
ously produce anti-DNA autoantibodies [55].

4. TOLERANCE MECHANISMS FOR AUTOREACTIVE T CELLS

IN THE THYMUS
While B cells are designed to recognize native antigen, T cell receptors bind to
peptide fragments of antigen displayed on MHC molecules. An array of self-
peptides are displayed on cortical thymic epithelial cells, and T cells that
weakly bind to these ligands receive maturation signals that inhibit further
RAG gene expression. They increase the level of surface receptor expression
and upregulate homing receptors for chemokines found in the thymic medulla
and the peripheral lymphoid tissues. This so-called positive selection is unique
to the thymic cortical epithelium. Self-reactive T cells are further edited by
downregulating the self-reactive receptor, and RAG expression continues until
the self-reactive T cell receptor a-chain is replaced with another, less self-
reactive chain.
In the thymic medulla, the process of testing for self-reactivity continues
with the help of medullary thymic epithelial cells and dendritic cells. The cells
in the medulla express costimulatory molecules, including CD80 (B7.1) and
CD86 (B7.2), the ligands for CD28. Here, T cell receptors that bind strongly to
self-peptideeMHC complexes are triggered to induce cell death (negative
selection). In animals, deficient in this process either through lack of medul-
lary MHC expression or through B7 expression, huge amounts of self-reactive
T cells reach the periphery, causing pathologies resembling graft-versus-host
disease [56]. It can be speculated that the well-established association
between particular MHC molecules and susceptibility to specific autoimmune
 Digestive System and Autoimmunity Chapter j 1 9

diseases may stem from inefficient presentation of particular self-peptides

during this phase of T cell receptor deletion [57,58].
Negative selection requires the tyrosine kinase zeta chain of T cell receptor
associated protein kinase of 70 kDa (ZAP70). Mice deficient in ZAP70
develop a systemic inflammatory disorder resembling rheumatoid arthritis
[59]. In addition, the following factors have been identified as being essential
for negative selection: growth-factor-receptorebound (GRB) protein 2 [60],
misshapen/Nck-interacting kinaseerelated kinase [61], extracellular signal-
regulated kinase (ERK), and p38 and Jun kinase activation [62]. Induction
of cell death of autoreactive T cells requires BIM expression, which antago-
nizes BCL-2 and related proteins to release proapoptotic BAX and BAK.
Furthermore, members of the Nur77 family of orphan nuclear receptors are
induced during negative selection. T cell receptoreinduced thymocyte death is
blocked in the absence of Nur77 [63].

5. CLONAL ANERGY AND TUNING

The intrinsic cellular mechanisms of anergy are particularly well studied in B
cells with self-reactive receptors [64]. Self-reactive B cell receptors can be
internalized through accelerated endocytosis, resulting in reduction of up to
99% of the initial surface expression of a self-reactive receptor. Similarly, the
transport of new receptors to the surface can be blocked [65]. It has been
reported that self-reactive B cell receptors activate tyrosine kinase signaling
poorly, which limits cell survival because of weak NF-kB1 activation. In
parallel, weak signaling induces BIM expression to promote cell death [66]
and ERK pathways that block Toll-like receptor 9 (TLR9)-induced differen-
tiation into plasma cells [67].
So-called biochemical tuning can be achieved by increasing the threshold
of B cell receptor activation, regardless of its specificity. Recruitment of the
SH2-domainecontaining protein tyrosine phosphatase 1 through the surface
proteins CD22 and PD1 to the activated B cell receptors increases its threshold
for signaling [49]. Another example is the recruitment of the lipid phosphatase
SH2-domainecontaining inositol-5-phosphatase to the activated B cell re-
ceptor through Fc receptor-g [68]. Spontaneous autoantibody production can
occur if either one of these mechanisms is defective.
Tuning of self-reactive T cells is achieved by increased expression of
the inhibitory receptor CD5 [69,70]. Cytotoxic T lymphocyte antigen 4
(CTLA4) is another inhibitory receptor that acts through competition with
CD28 for ligation with B7 molecules and transmitting inhibitory signals.
CTLA4 was found to be upregulated in self-reactive T cells [71,72].
Massive accumulation of self-reactive T cells occurs in peripheral
lymphoid and nonlymphoid tissues in the absence of CTLA4. Functional
variants of the CTLA4 gene can lead to thyroid autoimmunity and type 1
diabetes in humans and mice [73].
10 SECTION j I Introduction

The ubiquitin ligases cbl-b, GRAIL, and Itch have been identified to be
highly expressed in chronic T cell receptor signaling in vitro [74e76].
Ubiquitinylation of T cell receptors, CD28, and cytokine receptor signaling
molecules can alter intracellular trafficking, promote proteolytic degradation,
or can allosterically interfere with signaling [77,78]. Their importance for
preventing autoimmunity in rodents has been clearly demonstrated: cbl-b
deficiency coupled with a particular MHC haplotype causes type 1 diabetes
in the Komeda diabetes prone rat strain [79]. Large numbers of activated
T cells and high titers of autoantibodies can be found in mice lacking Itch, or
cbl-b and its close relative c-cbl [77,78].

6. EXTRINSIC CONTROLS OF SELF-REACTIVE

LYMPHOCYTES
A well-documented extrinsic control mechanism of autoreactive B cells is their
dependence on BAFF, which is produced in limiting quantities by lymphoid
stromal cells [53]. Binding of BAFF to its receptor increases NF-kB2 activity
maintaining peripheral B cell survival through induction of BCL-2 expression
[80]. It also induces the expression of PIM2, a serine-threonine kinase, which
has prosurvival effects by interfering with the proapoptotic protein BAD [81].
On the one hand, given the large numbers of circulating B cells with strong
receptor signaling through high affinity to antigen, the self-reactive B cells do
not receive enough BAFF and are competitively deleted [82]. On the other
hand, in states of B cell lymphopenia or in phases when BAFF synthesis is
high, i.e., during infection, self-reactive B cells are more likely to survive
[53,66].
As with B cells, T cell survival in the periphery depends on continuous
signaling through contact with MHC ligands and exposure to IL-7 [83e85].
Under normal circumstances, IL-7 levels are low and maintain T cells in
interphase. However, in lymphopenia, IL-7 levels rise and amplify T cell re-
ceptor signaling and proliferation. This so-called homeostatic proliferation
may also activate self-reactive T cells causing autoimmune diseases in
extralymphatic sites, a common feature seen in people after T lymphopenia.
Lymphopenia and defective T cell function in WiskotteAldrich syndrome is
leading to an array of autoimmune and inflammatory conditions [86].

7. LIMITATION OF COSTIMULI
To secrete antibodies, B cells must receive two signals: First, an antigen must
bind to the B cell receptor; second, T-helper cells must signal through CD40
ligand (CD40L) and cytokines IL-2, IL-4, IL-5, and IL-21 to initiate B cell
proliferation and differentiation into plasma cells [87,88]. Because
negative selection in the thymus should have reduced the number of
self-antigenespecific T cells, the latter signal to self-reactive B cells is limited.
 Digestive System and Autoimmunity Chapter j 1 11

However, self-reactive B cells may receive signals from T-helper cells

responding to foreign antigens during infections, so-called bystander activa-
tion. More importantly, infections only rarely trigger autoantibody diseases,
like GuillaineBarré syndrome. Efficient B cell intrinsic tolerance mechanisms
must be responsible for the fact that only 1 in 1000 people infected with
Campylobacter pylori develops autoantibodies that cross-react with compo-
nents of peripheral nerves [89].
Interestingly, antibody production can be partially independent of T cell
help, when B cells receive stimulatory signals from bacterial flagellins, cell-
wall lipopolysaccharides, and unmethylated CpG dinucleotides, which are
recognized by TLRs [90]. How this potentially dangerous pathway is damp-
ened is not known in detail. Dysregulated activity of the TLR9 pathway leads
to pathological accumulation of circulating IgGeself-DNA complexes and is a
potent driver of the production of autoantibodies against IgG and DNA [91].
Inadequate clearance of apoptotic cells with exposed CpG DNA and other
nuclear antigens may account for the striking association between systemic
lupus erythematosus (SLE) and genetic deficiencies in classical complement
pathway components [92].
Mature T cells are activated by T cell receptor ligation and costimulation.
Without costimulation, tolerance is favored. The most important costimulus is
the interaction of CD28 on T cells and the B7 proteins CD80 and CD86 on
antigen-presenting cells. TLR signaling induces expression of B7 molecules
and enhances the survival and clonal expansion of T cells. Therefore, blocking
B7eCD28 interactions may be an attractive way to induce tolerance. However,
this treatment may also decrease thymic deletion and interfere with regulatory
T cell function and intrinsic T cell regulation by CTLA4.

8. REGULATION OF SELF-REACTIVE LYMPHOCYTES IN

FOLLICLES
Somatic hypermutation occurs in the periphery in germinal center follicles of
secondary lymphoid organs [93,94]. Antibodies created by this process can
have markedly increased affinities for self-antigens. Follicular B cell differ-
entiation generates long-lived plasma and memory cells, which are able to
secrete antibodies indefinitely [95]. Autologous DNA, an important self-
antigen target in SLE, is abundantly presented by numerous apoptotic cells
in germinal centers [96], where it represents a powerful potential stimulus for
autoantibody production. It has been found that anti-double-stranded DNA
antibodies are somatically mutated in animal models of SLE [93].
In addition to CD40L, follicular T cells display high levels of ICOS
(inducible T-cell costimulator), which is required for germinal center antibody
responses in mice and humans [71,97]. Follicular T cells are also dependent on
costimulation through OX40L [98]. T cell entry into follicles is not induced in
the absence of microbial TLR agonist [99]. Because self-antigens usually do
12 SECTION j I Introduction

not stimulate TLR signaling, this strict regulation of follicular T-helper cell
differentiation may block self-reactive T cells from delivering help to germinal
center B cells.

9. TOLERANCE AT THE EFFECTOR PHASE

The mechanisms involved in preventing autoimmunity at target organs are
only just beginning to be elucidated. Often pathology is limited to focal areas,
such as circumscribed skin lesions in pemphigus or single-joint inflammation
in rheumatoid arthritis. Pathology depends on multiple factors, including
immunologic cascades involving Fc receptors, mast cells, neutrophils, and
complement [100,101].

10. CONCLUSIONS
The mucosa of the gastrointestinal tract is a major site of pathogen entry. The
gut-associated immune system needs to remain hyporesponsive to food anti-
gens and commensal bacteria while mounting an efficient response against
pathogens. Immune responses must be exactly coordinated and regulated to
effectively cure an infection and to avoid chronic inflammation. Autoimmune
diseases can be considered as immune responses with defects in mechanisms
that control self-tolerance. Every organ of the digestive system can be the
target of an autoimmune response, either in systemic or in organ-specific
autoimmune diseases. Although many self-tolerance mechanisms exist, de-
fects in a single checkpoint can lead to autoimmune disease. Clinical mani-
festations of autoimmune diseases are often seen only after a latent period of
many years and then only against a few proteins or organs. There seems to be
hundreds of genes involved in the checkpoints of self-tolerance. Common
analysis of DNA polymorphisms will not be effective in identifying predis-
posing defects, rather exon resequencing of individuals with autoimmune
disease will be required.

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Another random document with
no related content on Scribd:
The Project Gutenberg eBook of The Big Night
This ebook is for the use of anyone anywhere in the United States
and most other parts of the world at no cost and with almost no
restrictions whatsoever. You may copy it, give it away or re-use it
under the terms of the Project Gutenberg License included with this
ebook or online at www.gutenberg.org. If you are not located in the
United States, you will have to check the laws of the country where
you are located before using this eBook.

Title: The Big Night

Author: Henry Kuttner

Release date: June 17, 2022 [eBook #68335]

Language: English

Original publication: United States: Standard Magazines, Inc, 1947

Credits: Greg Weeks, Mary Meehan, Alex White & the online
Distributed Proofreaders Canada team at
https://www.pgdpcanada.net.

*** START OF THE PROJECT GUTENBERG EBOOK THE BIG

NIGHT ***
THE BIG NIGHT

A Novelet of the Spaceways

 By Henry Kuttner

Writing under the pseudonym Hudson Hastings.

When the outmoded space-ship “La Cucaracha”

battles against the inroads of space transmission,
Logger Hilton must choose between a bright future
or a daring venture for a lost cause!

[Transcriber’s Note: This etext was produced from

Thrilling Wonder Stories, June 1947.
Extensive research did not uncover any evidence that
the U.S. copyright on this publication was renewed.]
 CHAPTER I
Last of the Hyper Ships

She came lumbering up out of the ecliptic plane of the planets like a
wallowing space-beast, her jet tubes scarred and stained, a molten
streak across her middle where Venus’s turgid atmosphere had
scarred her, and every ancient spot-weld in her fat body threatened
to rip apart the moment she hit stress again.
The skipper was drunk in his cabin, his maudlin voice echoing
through the compartments as he bewailed the unsympathetic
harshness of the Interplanetary Trade Commission.
There was a mongrel crew from a dozen worlds, half of them
shanghaied. Logger Hilton, the mate, was trying to make sense out
of the tattered charts, and La Cucaracha, her engines quaking at the
suicidal thought, was plunging ahead through space into the Big
Night.
In the control room a signal light flared. Hilton grabbed a mike.
“Repair crew!” he yelled. “Get out on the skin and check jet A-six.
Move!”
He turned back to his charts, chewing his lip and glancing at the
pilot, a tiny, inhuman Selenite, with his arachnoid multiple limbs and
fragile-seeming body. Ts’ss—that was his name, or approximated it
—was wearing the awkward audio-converter mask that could make
his sub-sonic voice audible to human ears, but, unlike Hilton, he
wasn’t wearing space-armor. No Lunarian ever needed protection
against deep space. In their million years on the Moon, they had got
used to airlessness. Nor did the ship’s atmosphere bother Ts’ss. He
simply didn’t trouble to breathe it.
“Blast you, take it easy!” Hilton said. “Want to tear off our hide?”
Through the mask the Selenite’s faceted eyes glittered at the mate.
“No, sir. I’m going as slowly as I can on jet fuel. As soon as I know
the warp formulae, things’ll ease up a bit.”
“Ride it! Ride it—without jets!”
“We need the acceleration to switch over to warp, sir.”
“Never mind,” Hilton said. “I’ve got it now. Somebody must have
been breeding fruit-flies all over these charts. Here’s the dope.” He
dictated a few equations that Ts’ss’ photographic memory
assimilated at once.
A distant howling came from far off.
“That’s the skipper, I suppose,” Hilton said. “I’ll be back in a minute.
Get into hyper as soon as you can, or we’re apt to fold up like an
accordion.”
“Yes, sir. Ah—Mr. Hilton?”
“Well?”
“You might look at the fire extinguisher in the Cap’n’s room.”
“What for?” Hilton asked.
Several of the Selenite’s multiple limbs pantomimed the action of
drinking. Hilton grimaced, rose, and fought the acceleration down the
companionway. He shot a glance at the visio-screens and saw they
were past Jupiter already, which was a relief. Going through the
giant planet’s gravity-pull wouldn’t have helped La Cucaracha’s
aching bones. But they were safely past now. Safely! He grinned
wryly as he opened the captain’s door and went in.

Captain Sam Danvers was standing on his bunk, making a speech to

an imaginary Interplanetary Trade Commission. He was a big man,
or rather he had been once, but now the flesh had shrunk and he
was beginning to stoop a little. The skin of his wrinkled face was
nearly black with space-tan. A stubble of gray hair stood up angrily.
Somehow, though, he looked like Logger Hilton. Both were deep-
space men. Hilton was thirty years younger, but he, too, had the
same dark tan and the same look in his blue eyes. There’s an old
saying that when you go out into the Big Night, beyond Pluto’s orbit,
that enormous emptiness gets into you and looks out through your
eyes. Hilton had that. So did Captain Danvers.
Otherwise—Hilton was huge and heavy where Danvers was a little
frail now, and the mate’s broad chest bulged his white tunic. He
hadn’t had time yet to change from dress uniform, though he knew
that even this cellulose fabric couldn’t take the dirt of a space-run
without showing it. Not on La Cucaracha, anyway.
But this would be his last trip on the old tub.
Captain Danvers interrupted his speech to ask Hilton what the devil
he wanted. The mate saluted.
“Routine inspection, sir,” he observed, and took down a fire
extinguisher from the wall. Danvers sprang from the bunk, but Hilton
moved too fast. Before the captain reached him, Hilton had emptied
the tank down the nearest disposal vent.
“Old juice,” he explained. “I’ll refill her.”
“Listen, Mr. Hilton,” Danvers said, swaying slightly and stabbing a
long forefinger at the mate’s nose. “If you think I had whisky in there,
you’re crazy.”
“Sure,” Hilton said. “I’m crazy as a loon, skipper. How about some
caffeine?”
Danvers weaved to the disposal port and peered down it vaguely.
“Caffeine. Huh? Look, if you haven’t got sense enough to take La
Cucaracha into hyper, you ought to resign.”
“Sure, sure. But in hyper it won’t take long to get to Fria. You’ll have
to handle the agent there.”
“Christie? I—I guess so.” Danvers sank down on the bunk and held
his head. “I guess I just got mad, Logger. ITC—what do they know
about it? Why, we opened that trading post on Sirius Thirty.”
“Look, skipper, when you came aboard you were so high you forgot
to tell me about it,” Hilton said. “You just said we’d changed our
course and to head for Fria. How come?”
“Interplanetary Trade Commission,” Danvers growled. “They had
their crew checking over La Cucaracha.”
“I know. Routine inspection.”
“Well, those fat slobs have the brass-bound nerve to tell me my
ship’s unsafe! That the gravity-drag from Sirius is too strong—and
that we couldn’t go to Sirius Thirty!”
“Could be they’re right,” Hilton said thoughtfully. “We had trouble
landing on Venus.”
“She’s old.” Danvers voice was defensive. “But what of it? I’ve taken
La Cucaracha around Betelgeuse and plenty closer to Sirius than
Sirius Thirty. The old lady’s got what it takes. They built atomic
engines in those days.”
“They’re not building them now,” Hilton said, and the skipper turned
purple.
“Transmission of matter!” he snarled. “What kind of a crazy set-up is
that? You get in a little machine on Earth, pull a switch, and there
you are on Venus or Bar Canopus or—or Purgatory, if you like! I
shipped on a hyper-ship when I was thirteen, Logger. I grew up on
hyper-ships. They’re solid. They’re dependable. They’ll take you
where you want to go. Hang it, it isn’t safe to space-travel without an
atmosphere around you, even if it’s only in a suit.”
“That reminds me,” Hilton said. “Where’s yours?”
“Ah, I was too hot. The refrigerating unit’s haywire.”
The mate found the lightweight armor in a closet and deftly began to
repair the broken switch.
“You don’t need to keep the helmet closed, but you’d better wear the
suit,” he said absently. “I’ve issued orders to the crew. All but Ts’ss,
and he doesn’t need any protection.”
Danvers looked up. “How’s she running?” he asked quickly.
“Well, she could use an overhaul,” Hilton said. “I want to get into
hyper-space fast This straight running is a strain. I’m afraid of
landing, too.”
“Uh. Okay, there’ll be an overhaul when we get back—if we make a
profit. You know how much we made this last trip. Tell you what—you
supervise the job and take a bigger cut for it.”

Hilton’s fingers slowed on the switch. He didn’t look around.

“I’ll be looking for a new berth,” he said. “Sorry, skipper. But I won’t
be aboard after this voyage.”
There was silence behind him. Hilton grimaced and began to work
again on the spacesuit He heard Danvers say:
“You won’t find many hyper-ships needing mates these days.”
“I know. But I’ve got engineering training. Maybe they would use me
on the matter-transmitters. Or as an outposter—a trader.”
“Oh, for the love of Pete! Logger, what are you talking about? A—
trader? A filthy outposter? You’re a hyper-ship man!”
“In twenty years there won’t be a hyper-ship running,” Hilton said.
“You’re a liar. There’ll be one.”
“She’ll fall apart in a coupla of months!” Hilton said angrily. “I’m not
going to argue. What are we after on Fria, the fungus?”
After a pause Danvers answered.
“What else is there on Fria? Sure, the fungus. It’s pushing the
season a little. We’re not due there for three weeks Earth-time, but
Christie always keeps a supply on hand. And that big hotel chain will
pay us the regular cut. Blamed if I know why people eat that
garbage, but they pay twenty bucks a plate for it.”
“It could mean a profit, then,” Hilton said. “Provided we land on Fria
without falling apart.” He tossed the repaired suit on the bunk beside
Danvers. “There you are, skipper. I’d better get back to controls.
We’ll be hitting hyper pretty soon.”
Danvers leaned over and touched a button that opened the
deadlight. He stared at the star-screen.
“You won’t get this on a matter-transmitter,” he said slowly. “Look at
it, Logger.”
Hilton leaned forward and looked across the Captain’s shoulder. The
void blazed. To one side a great arc of Jupiter’s titan bulk glared
coldly bright. Several of the moons were riding in the screen’s field,
and an asteroid or two caught Jupiter’s light in their tenuous
atmospheres and hung like shining veiled miniature worlds against
that blazing backdrop. And through and beyond the shining stars and
moons and planets showed the Big Night, the black emptiness that
beats like an ocean on the rim of the Solar System.
“So it’s pretty,” Hilton said. “But it’s cold, too.”
“Maybe. Maybe it is. But I like it. Well, get a job as a trader, you
jackass. I’ll stick to La Cucaracha. I know I can trust the old lady.”
For answer the old lady jumped violently and gave a wallowing lurch.

CHAPTER II
Bad News
Hilton instantly exploded out of the cabin. The ship was bucking
hard. Behind him the mate heard Danvers shouting something about
incompetent pilots, but he knew it probably wasn’t the Selenite’s
fault. He was in the control cabin while La Cucaracha was still
shuddering on the downswing of the last jump. Ts’ss was a tornado
of motion, his multiple legs scrabbling frantically at a dozen
instruments.
“I’ll call the shot!” Hilton snapped, and Ts’ss instantly concentrated
on the incredibly complicated controls that were guiding the ship into
hyper.
The mate was at the auxiliary board. He jerked down levers.
“Hyper stations!” he shouted. “Close helmets! Grab the braces, you
sun-jumpers! Here we go!”
A needle swung wildly across a gauge, hovering at the mark. Hilton
dropped into a seat, sliding his arms under the curved braces and
hooking his elbows around them. His ankles found similar supports
beneath him. The visor screens blurred and shimmered with crawling
colors, flicking back and forth, on and off, as La Cucaracha fought
the see-saw between hyper and normal space.
Hilton tried another mike. “Captain Danvers. Hyper stations. All
right?”
“Yeah, I’m in my suit,” Danvers’ voice said. “Can you take it? Need
me? What’s wrong with Ts’ss?”
“The vocor at my board blew out, Cap’n,” Ts’ss said. “I couldn’t reach
the auxiliary.”
“We must need an overhaul bad,” Danvers said, and cut off.
Hilton grinned. “We need a rebuilding job,” he muttered, and let his
fingers hang over the control buttons, ready in case Ts’ss slipped.
But the Selenite was like a precision machine; he never slipped. The
old Cucaracha shook in every brace. The atomic engines channeled
fantastic amounts of energy into the dimensional gap. Then,
suddenly, the see-saw balanced for an instant, and in that split-
second the ship slid across its power-bridge and was no longer
matter. It no longer existed, in the three-dimensional plane. To an
observer, it would have vanished. But to an observer in hyper-space,
it would have sprung into existence from white nothingness.
Except that there were no hyper-spatial observers. In fact, there
wasn’t anything in hyper—it was, as some scientist had once
observed, just stuff, and nobody knew what the stuff was. It was
possible to find out some of hyper’s properties, but you couldn’t go
much farther than that. It was white, and it must have been energy,
of a sort, for it flowed like an inconceivably powerful tide, carrying
ships with it at speeds that would have destroyed the crew in normal
space. Now, in the grip of the hyper current, La Cucaracha was
racing toward the Big Night at a velocity that would take it past
Pluto’s orbit in a matter of seconds.
But you couldn’t see Pluto. You had to work blind here, with
instruments. And if you got on the wrong level, it was just too bad—
for you!
Hastily Hilton checked the readings. This was Hyper C-758-R. That
was right. On different dimensional levels of hyper, the flow ran in
various directions. Coming back, they’d alter their atomic structure to
ride Hyper M-75-L, which rushed from Fria toward Earth and beyond
it.
“That’s that,” Hilton said, relaxing and reaching for a cigarette. “No
meteors, no stress-strain problems—just drift till we get close to Fria.
Then we drop out of hyper, and probably fall apart.”
An annunciator clicked. Somebody said:
“Mr. Hilton, there’s some trouble.”
“There is. Okay, Wiggins. What now?”
“One of the new men. He was out skinside making repairs.”
“You had plenty of time to get back inside,” snapped Hilton, who
didn’t feel quite as sure of that as he sounded. “I called hyper
stations.”
“Yes, sir. But this fella’s new. Looks like he never rode a hyper-ship
before. Anyhow, his leg’s broken. He’s in sick bay.”
Hilton thought for a moment. La Cucaracha was understaffed
anyway. Few good men would willingly ship on such an antique.
“I’ll come down,” he said, and nodded at Ts’ss. Then he went along
the companionway, glancing in at the skipper, who had gone to
sleep. He used the handholds to pull himself along, for there was no
accelerative gravity in hyper. In sick bay he found the surgeon, who
doubled in brass as cook, finishing a traction splint on a pale,
sweating youngster who was alternately swearing feebly and
groaning.
“What’s the matter with him?” Hilton asked.
Bruno, the sawbones, gave a casual soft salute. “Simple fracture. I’m
giving him a walker-splint, so he’ll be able to get around. And he shot
his cookies, so he can’t be used to hyper.”
“Looks like it,” Hilton said, studying the patient. The boy opened his
eyes, glared at Hilton.
“I was shanghaied!” he yelped. “I’ll sue you for all you’re worth!”

The first officer was unperturbed.

“I’m not the skipper, I’m mate,” Hilton said. “And I can tell you right
now that we’re not worth much. Ever hear about discipline?”
“I was shanghaied!”
“I know it. That’s the only way we can get a full crew to sign articles
on La Cucaracha. I mentioned discipline. We don’t bother much with
it here. Just the same, you’d better call me Mister when people are
around. Now shut up and relax. Give him a sedative, Bruno.”
“No! I want to send a spacegram!”
“We’re in hyper. You can’t. What’s your name?”
“Saxon. Luther Saxon. I’m one of the consulting engineers on
Transmat.”
“The matter-transmission gang? What were you doing around the
space-docks?”
Saxon gulped. “Well—uh—I go out with the technical crews to
supervise new installations. We’d just finished a Venusian
transmission station. I went out for a few drinks—that was all! A few
drinks, and—”
“You went to the wrong place,” Hilton said, amused. “Some crimp
gave you a Mickey. Your name’s on the articles, anyhow, so you’re
stuck, unless you jump ship. You can send a message from Fria, but
it’d take a thousand years to reach Venus or Earth. Better stick
around, and you can ride back with us.”
“On this crate? It isn’t safe. She’s so old I’ve got the jitters every time
I take a deep breath.”
“Well, stop breathing,” Hilton said curtly. La Cucaracha was an old
tramp, of course, but he had shipped on her for a good many years.
It was all right for this Transmat man to talk; the Transmat crews
never ran any risks.
“Ever been on a hyper-ship before?” he asked.
“Naturally,” Saxon said. “As a passenger! We have to get to a planet
before we can install a transmission station, don’t we?”
“Uh-huh.” Hilton studied the scowling face on the pillow. “You’re not a
passenger now, though.”
“My leg’s broken.”
“You got an engineering degree?”
Saxon hesitated and finally nodded.
“All right, you’ll be assistant pilot. You won’t have to walk much to do
that. The pilot’ll tell you what to do. You can earn your mess that
way.”
Saxon sputtered protests.
“One thing,” Hilton said. “Better not tell the skipper you’re a Transmat
man. He’d hang you over one of the jets. Send him for’rd when he’s
fixed up, Bruno.”
“Yessir,” Bruno said, grinning faintly. An old deep-space man, he
didn’t like Transmat either.
Hilton pulled himself back to the control room. He sat down and
watched the white visoscreens. Most of Ts’ss’ many arms were idle.
This was routine now.
“You’re getting an assistant,” Hilton said after a while. “Train him fast.
That’ll give us all a break. If that fat-headed Callistan pilot hadn’t
jumped on Venus, we’d be set.”
“This is a short voyage,” Ts’ss said. “It’s a fast hyper-flow on this
level.”
“Yeah. This new guy. Don’t tell the skipper, but he’s a Transmat
man.”
Ts’ss laughed a little.
“That will pass, too,” he said. “We’re an old race, Mr. Hilton.
Earthmen are babies compared to the Selenites. Hyper-ships are
fading out, and eventually Transmat will fade out too, when
something else comes.”
“We won’t fade,” Hilton said, rather surprised to find himself
defending the skipper’s philosophy. “Your people haven’t—you
Selenites.”
“Some of us are left, that’s true,” Ts’ss said softly. “Not many. The
great days of the Selenite Empire passed very long ago. But there
are still a few Selenites left, like me.”
“You keep going, don’t you? You can’t kill off a—a race.”
“Not easily. Not at once. But you can, eventually. And you can kill a
tradition, too, though it may take a long time. But you know what the
end will be.”
“Oh, shut up,” Hilton said. “You talk too much.”
Ts’ss bent again above the controls. La Cucaracha fled on through
the white hyper-flow, riding as smoothly as the day she had been
launched.

But when they reached Fria, it would be rough space and high
gravity. Hilton grimaced.
He thought: So what? This is just another voyage. The fate of the
universe doesn’t depend on it. Nothing depends on it, except,
maybe, whether we make enough profit to have the old lady
overhauled. And that won’t matter to me for it’s my last voyage into
the Big Night.
He watched the screens. He could not see it, but he knew that it
hung beyond the universal whiteness, in a plane invisible to his eyes.
The little sparks of worlds and suns glowed in its immensity, but
never brightened it. It was too vast, too implacable. And even the
giant suns would be quenched in its ocean, in the end. As everything
else would be quenched, as everything moved on the tides of time
into that huge darkness.
That was progress. A wave was born and gathered itself and grew—
and broke. A newer wave was behind it. And the old one slipped
back and was lost forever. A few foam-flecks and bubbles remained,
like Ts’ss, remnant of the giant wave of the ancient Selenite Empire.
The Empire was gone. It had fought and ruled a hundred worlds, in
its day. But, in the end, the Big Night had conquered and swallowed
it.
As it would swallow the last hyper-ship eventually. . . .
They hit Fria six days later, Earth time. And hit was the word. One of
Ts’ss’ chitin-covered arms was snapped off by the impact, but he
didn’t seem to mind. He couldn’t feel pain, and he could grow
another limb in a few weeks. The crew, strapped to their landing
braces, survived with minor bruises.
Luther Saxon, the Transmat man, was in the auxiliary pilot’s seat—
he had enough specialized engineering training so that he learned
the ropes fast—and he acquired a blue bump on his forehead, but
that was all. La Cucaracha had come out of hyper with a jolt that
strained her fat old carcass to the limit, and the atmosphere and
gravity of Fria was the penultimate straw. Seams ripped, a jet went
out, and new molten streaks appeared on the white-hot hull.
The crew had been expecting liberty. There was no time for that.
Hilton told off working gangs to relieve each other at six-hour
intervals, and he said, rather casually, that Twilight was out of
bounds. He knew the crew would ignore that order. There was no
way to keep the men aboard, while Twilight sold liquor and even
more effective escape-mechanisms. Still, there were few women on
Fria, and Hilton hoped that enough working stiffs would keep on the
job to get La Cucaracha repaired and spaceworthy before the fungus
cargo was loaded.
He knew that Wiggins, the second mate, would do his best. For
himself he went with the skipper in search of Christie, the Fria trader.
The way led through Twilight, the roofed settlement that was
shielded from the hot, diamond-bright glare of the primary. It wasn’t
big. But then Fria was an outpost, with a floating population of a few
hundred. They came in and out with the ships and the harvest
seasons. If necessary, Hilton thought, some of the bums could be
shanghaied. Still, it wasn’t too likely that any of the crew would
desert. None of them would be paid off till they were back in the
Solar System.
They found Christie in his plasticoid cabin, a fat, bald, sweating man
puffing at a huge meerschaum pipe. He looked up, startled, and then
resignedly leaned back in his chair and waved them to seats.
“Hello Chris,” Danvers said. “What’s new?”
“Hello, Skipper. Hi, Logger. Have a good trip?”
“The landing wasn’t so good,” Hilton said.
“Yeah, I heard about it. Drinks?”
“Afterward,” Danvers said, though his eyes gleamed. “Let’s clean up
the business first. Got a good shipment ready?”
Christie smoothed one of his fat, glistening cheeks. “Well—you’re a
couple of weeks early.”
“You keep a stock-pile.”
The trader grunted. “Fact is—look, didn’t you get my message? No, I
guess there wasn’t time. I sent a spacemail on the Blue Sky last
week for you, Skipper.”
Hilton exchanged glances with Danvers.
“You sound like bad news, Chris,” he said. “What is it?”
Christie said uncomfortably, “I can’t help it. You can’t meet
competition like Transmat You can’t afford to pay their prices. You
got running expenses on La Cucaracha. Jet-fuel costs dough, and—
well, Transmat sets up a transmitting station, pays for it, and the
job’s done, except for the power outlay. With atomic, what does that
amount to?”

Danvers was growing red.

“Is Transmat setting up a station here?” Hilton said hastily.
“Yeah. I can’t stop ’em. It’ll be ready in a couple of months.”
“But why? The fungus isn’t worth it. There isn’t enough market.
You’re pulling a bluff, Chris. What do you want? A bigger cut?”
Christie regarded his meerschaum. “Nope. Remember the ore tests
twelve years ago? There’s valuable ores on Fria, Logger. Only it’s
got to be refined plenty. Otherwise it’s too bulky for shipment. And
the equipment would cost too much to freight by spaceship. It’s big
stuff—I mean big.”
Hilton glanced at Danvers. The skipper was purple now, but his
mouth was clamped tightly.
“But—hold on, Chris. How can Transmat get around that? By
sending the crude ores to Earth in their gadgets?”
“The way I heard it,” Christie said, “is that they’re going to send the
refining machines here and set ’em up right on Fria. All they need for
that is one of their transmitters. The field can be expanded to take
almost anything, you know. Shucks you could move a planet that
way if you had the power! They’ll do the refining here and transmit
the refined ores back Earthside.”