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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

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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-
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-
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 Induction of apoptosis by inhibition of prosurvival
pathways (BIM induction) or by activation of death
receptors (FAS activation)
Receptor editing 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)
Clonal anergy and tuning 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)
Extrinsic regulation 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
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].
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.
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
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].
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.
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
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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Chapter 2
Immunopathogenesis of
Autoimmune Liver Damage
A.J. Czaja
Mayo Clinic College of Medicine, Rochester, MN, United States
1. INTRODUCTION
Autoimmune liver damage implies that an immune attack has been mis-
directed against self [1]. This loss of self-tolerance may reflect deficiencies in
the mechanisms by which immunocytes distinguish self-antigens from foreign
antigens and perturbations in the regulatory networks that influence immu-
nocyte activation, differentiation, proliferation, and disposal [2]. The predis-
posing factors for autoimmune liver damage can be extrinsic to the individual
and represent indigenous environmental, toxic, or infectious agents that
overwhelm self-tolerance by their absolute number or their repetitive stimu-
lation [3]. They may also be intrinsic to the individual and represent genetic
[4], cellular [5], or molecular [6] predispositions that favor protracted or
exaggerated immune responses to the triggering antigen.
Excess antigenic stimulation can relate to the magnitude of antigens with
homologous epitopes that bombard the individual, the frequency of antigenic
exposure, the responsiveness of the individual to a given antigen, or any
combination of these factors [1,3]. Viruses and drugs have been implicated as
triggers for autoimmune liver disease, and these reports imply that diverse
antigenic stimuli can produce the same clinical result [1,7]. CD4 and CD8 T
lymphocytes possess few antigen recognition sites [8], and molecular mimicry
between homologous peptide sequences may explain how diverse antigens can
trigger comparable immune responses [9].
The frequent concurrence of other autoimmune manifestations in patients
with autoimmune liver disease also suggests that the antigen recognition sites
on the activated immunocytes are imprecise [1,3]. Imprecise targeting by the
activated lymphocytes can extend the range of targets to tissues anatomically
different and distant from the liver (promiscuous activity) [3,10]. Epitopes
The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00002-7

Copyright © 2017 Elsevier B.V. All rights reserved. 19
triggering autoimmune liver disease are likely to have shared, easily

mimicked, amino acid sequences that can activate immunocytes with pro-
miscuous activity [1]. The long lag time between the onset of the disease and
its clinical detection and the possibility that diverse antigens with shared
epitopes can trigger the disease can complicate discovery of an initiating
event.
Host-dependent rather than disease-specific factors may also override self-
tolerance [11]. Genetic predisposition may naturally select individuals from
the general population and favor the development of disease. Genetic risk
factors for autoimmune hepatitis [12e15], primary biliary cholangitis (PBC)
[16,17], and primary sclerosing cholangitis (PSC) [18] have been described,
and certain genetic factors may also offer protection from these diseases
[13,19e21]. Complex alterations in the counterregulatory networks of immune
activation that are based on genetic factors may create a complex milieu that
promotes or prevents these diseases [2]. In this context, the components of the
milieu may vary greatly between individuals despite producing the same
clinical consequence. The ability of subtle defects in a complex homeostatic
system to be magnified into a disease state may explain the difficulty in
identifying the core defect in autoimmune liver disease.
In this review, the multifactorial nature of autoimmune liver disease is
emphasized, and the various theoretical factors contributing to its occurrence
are presented. These diverse factors are interactive, and the degree of their
involvement can vary among individuals and modify the clinical expression
and behavior of the disease.
2. ANTIGENS AND ANTIGEN RESPONSES

2.1 Target Antigen(s)
Many antigens have been proposed as targets of the immune response in
autoimmune liver disease, including components of the intestinal microbiota
(Table 2.1) [22,23]. Cytochrome P450 2D6 (CYP2D6) has been recognized as
the principal target antigen of type 2 autoimmune hepatitis [24], and anti-
bodies to liver kidney microsome type 1 (anti-LKM1), which characterize type
2 autoimmune hepatitis, react mainly to the peptides spanning positions
193e212 of the recombinant molecule [25]. Formiminotransferase cyclo-
deaminase is the target antigen of antibodies to liver cytosol type 1 (anti-LC1),
and anti-LC1 also characterize type 2 autoimmune hepatitis [26,27]. Both
CYP2D6 and formiminotransferase cyclodeaminase have been able to induce
autoimmune hepatitis in animals [23,28,29], and the body of clinical and
laboratory evidence supports their candidacy as the principal targets of this
form of autoimmune hepatitis.
Other self-antigens have been less well-studied or strongly advanced in
autoimmune liver disease. The cytochromes, CYP2A2 and CYP2A6, have been
TABLE 2.1 Antigens and Antigen Responses
Antigens and Responses Nature Possible Pathogenic Effects

Target antigens (main) Cytochrome P450 2D6 (CYP2D6) [24] CYP2D6 targeted by anti-LKM1 [24]
Formiminotransferase cyclodeaminase FTCD targeted by anti-LC1 [26,27]
(FTCD) [26,27] Associated with type 2 AIH [164]
Immunopathogenesis of Autoimmune Liver Damage Chapter j 2

Antigenic homologues (molecular Diverse antigens have similar peptide Different antigens trigger the same immune response [9]
mimicry) sequences or conformational epitopes Effectors have promiscuous targeting [10]
[3] Protracted or repeated exposures induce loss of self-tolerance
Foreign and self-antigens are similar [9] [29,45]
Humoral and cellular cross-reactivity Molecular mimicry not identity required [45]
[45] Noncontiguous sites can be targeted [3]
Cryptic self-antigens or New antigens uncovered or created Increase pool of homologous peptides [36,44]
neoantigens during primary immune responses Increase the immune response and its outcome [44]
[36,44] Trigger or sustain adaptive immune response [67]
May be products of apoptosis [67] May induce self-amplification loop [67]
Epitope spread Immune response broadens with Sensitization of new effector cells and activation of memory cells
duration of disease to involve [44]
neighboring and remote regions of the Could intensify or sustain the immune response [44]
triggering antigen [44]
Promiscuous lymphocytic activity TCRs have imprecise antigen Inability to distinguish self from foreign antigens [10]
recognition [10] Extend immune response to diverse sites [3,9,10]
Cells unable to distinguish between
epitopes in different antigens [10]
Loss of self-tolerance Cross-reacting humoral and cellular Self-perpetuating immune response against homologous self-
immune responses triggered by epitopes (autoimmunity) [29]
homologous foreign antigens and
sustained by deficient immune
21
regulatory responses [1e3,29,79]
AIH, autoimmune hepatitis; anti-LC1, antibodies to liver cytosol type 1; anti-LKM1, antibodies to liver kidney microsome type 1; TCRs, T cell antigen receptors.
Numbers in square brackets are references.
implicated as target antigens in the autoimmune polyglandular syndrome type 1,

which includes autoimmune hepatitis [30]. Uridine triphosphate glucuronosyl-
transferase [31], glutathione S-transferase [32], Sep (O-phosphoserine) transfer
ribonucleic acid:Sec (selenocysteine) transfer ribonucleic acid synthase [33],
alpha-actinin [34], and subunits of an inner mitochondrial membrane enzyme
(F1 ATPase) [35] have also been proposed. The search for the principal target
antigens in autoimmune liver disease is complicated by homologies between
antigens that extend the range of candidates and the emergence of neoantigens
during the inflammatory process [36].
2.2 Molecular Mimicry

Molecular mimicry implies that multiple antigenic targets have the same or
similar epitopes against which activated lymphocytes with imprecise antigen
recognition sites (promiscuous activity) can be directed (Fig 2.1). Molecular
mimicry can explain autoreactivity [9], but it has been difficult to prove in
human disease [37,38]. Humoral cross-reactivity has been well described in
autoimmune conditions [39e41], but cellular cross-reactivity has been diffi-
cult to demonstrate [42e45]. The hypothesis that protracted or repeated
exposure to homologous peptide sequences can result in loss of self-tolerance
has been supported mainly in animal models [43e45].
In the mouse model of experimental autoimmune hepatitis, infection with
an adenovirus expressing human CYP2D6, the antigen implicated in one form
of autoimmune hepatitis, breaks tolerance to mouse homologues of CYP2D6
[45]. In contrast, in transgenic mice expressing human CYP2D6, infection
with the same human antigen delays the occurrence and reduces the severity of
experimental autoimmune hepatitis [45]. Furthermore, mouse T cells specif-
ically sensitized to human CYP2D6 react to human CYP2D6 peptides that
have intermediate homology to mouse homologues, whereas they do not react
to human CYP2D6 peptides that have close homology to mouse homologues
[45]. These findings suggest that molecular mimicry can disrupt immune
tolerance of homologous self-antigens, whereas molecular identity may
enhance self-tolerance [45].
Molecular mimicry can occur when there are homologous amino acid
sequences within peptides or similar conformational epitopes in structurally
dissimilar peptides (Table 2.1) [3,9]. Cryptic self-antigens may be uncovered
during the disease, and neoantigens may also be created that enlarge the pool
of homologous sensitizing peptides [36,44]. The net effect of this prolifer-
ation of antigens is to favor additional molecular mimicries to sustain and
extend the disease process. In patients with autoimmune hepatitis and ani-
mals infected with adenovirus expressing CYP2D6, the humoral response
early in the course of the disease is against the immune-dominant epitope of
the human antigen, whereas the immune response broadens later in the
disease to involve epitopes in neighboring and remote regions of the human
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The same reflection is forced upon us when we observe that the
Λόγος or Divine Word conceived as a cosmic power plays no part in
the earliest Hellenic theology of which we have any cognisance (we
are not here concerned with the later history of the concept): nor can
we find in the earliest Greek period the name of God exalted into the
position of a divine creative force; although, as I have shown
elsewhere, the earliest Hellene, as the later, was fully sensitive to the
magico-divine efficacy of names.179.1
We may also gather something for our present purpose from a
comparison between the cosmogony or cosmic myths of East and
West. Of these it is only the Babylonian and Hebraic that can claim a
great antiquity of record. What is reported of Phoenician belief
concerning these matters is of late authority, Eusebios quoting from
Sanchuniathon or Philo Byblios, and this is too much permeated with
later elements to be useful here. As regards the Hellenic theory of
the origin of the world and of man, putting aside a few scattered hints
in the Homeric poems, we have Hesiod for our first and insufficient
witness. If we can detect Babylonian influence in the Hesiodic
system, we must not hastily conclude that this was already rife in the
second millennium: on the other hand, if Hesiod seems to have
escaped it, it is far less likely that it was strong upon the proto-
Hellenes.
For early Babylonian cosmogony our main evidence is the epic
poem of creation, preserved on tablets found in the library of King
Assurbanipal, which elucidates, and in the main corroborates, the
fragments of the story given by Berosos in the third century B.C. Our
earliest record, then, is actually of the seventh century, but
Assyriologists have given reasons for the view that the epic copied
for Assurbanipal descends from a period as early as B.C. 2000; for
part of it accords with an old Babylonian hymn that has been
discovered.179.2 The document is therefore ancient enough for the
purposes of our comparison. It is well known through various
publications, and can be read conveniently in the detailed exposition
of King in his handbook on Babylonian religion.180.1
When we consider carefully the more significant features in this
cosmogony, we are struck with its almost total unlikeness to anything
that we can discover or surmise in early Hellenic thought. It is true
that the Babylonian theory starts with the dogma that the earliest
cosmic fact was the element of water. Apsu and Tiâmat are the first
powers in an unordered universe, and these seem to be the personal
forms of the upper and lower waters, the fresh and the salt. We find
the parallel thought in Homer, who speaks of Okeanos as “the
source of all things,”180.2 including even the gods. But the value of
such a parallelism is of the slightest, for the vague theory of a watery
origin of created things appears widely diffused in the myths of
remote peoples, for instance, North-American Indians, Aztecs, the
Vedic Aryans, and there is a glimmer of it in the old Norse.180.3 No
conclusion, then, can be drawn from so slight a coincidence. If we
know anything of the cosmogony of the pre-Homeric society we
know it from Hesiod, for Homer himself shows no interest and makes
no revelation on the subject. With certain reservations and after
careful criticism we may be able to regard some parts of the
Hesiodic statement as reflecting the thought of an age anterior to
Homer’s. Therefore it is of some present value to observe how little
of characteristically Babylonian speculation appears in the Hesiodic
Theogony or Works and Days. Both systems agree with each other,
and—it may be said—with all theogonies and religious cosmogonies,
in regarding the primeval creative forces as personal powers who
work either by the method of sexual generation or through
mechanical processes of creation: the first of these methods, which
though mythical in form has more affinity with organic science, is
predominant over the other in the Hesiodic narrative. But the
personal powers are different in the two systems. In the Babylonian
the greatest of the primeval dynasts is Tiâmat, the sea, the mother of
the gods and also of all monsters: in the Hesiodic it is Gaia, the
Earth-mother, who does not appear at all in the Eastern cosmogony,
but who claimed this position in the Hellenic through her deep-
seated influence in the ancient religion. We note also that the
Babylonian Sea is decidedly evil, the aboriginal foe of the gods of
light, a conception alien to ordinary Hellenic thought. Again, the
Babylonian creation of an ordered cosmos is a result of the great
struggle between Marduk and Tiâmat, the power of light and the
sovereign of chaos: it is preceded by hate and terror. In the Hellenic
account the generation of the heavens, the mountains, the sea, and
the early dynasty of Titan-powers is peaceful and is stimulated by the
power of love, Eros, who has his obvious double in the Kāma or
principle of desire in a cosmogonic hymn of the Rig-Veda, but is not
mentioned by the Babylonian poet. (Nor does it concern us for the
moment that this Eros is in respect of mere literary tradition post-
Homeric: we may surmise at least that he was a pre-Homeric power
in Boeotia.) Again, when we come to the theomachy in Hesiod, as an
event it has no cosmogonic value at all: it has the air merely of a
dynastic struggle between elder and younger divinities, and the myth
may really have arisen in part from the religious history of a shifting
of cults corresponding to a shifting of population: nor are the Titans
more representative of evil or of a lower order of things than the
Olympian deities; and cosmic creation, so far as Hesiod treats of it at
all, seems over before the struggle begins. On the other hand, after
Marduk has destroyed Tiâmat he constructs his cosmos out of her
limbs, and then proceeds to assign their various stations to the great
gods, his compeers. Thus the struggle of the god with the principle of
disorder has a cosmic significance which is not expressed in the
Titanomachy. The curious conception also that the universe was
compacted out of the dismembered limbs of a divine personage,
which reminds us of the Vedic story of the giant Purusa182.1 and of
the Norse legend of Ymir, is not clearly discoverable in Hellenic
mythology: for the Hesiodic myth of the forms and growths that
spring from the blood of the mutilated Ouranos is no real parallel.
And there is another trait in the Babylonian theory of a world-conflict
that distinguishes it from the Hellenic myths of a Titanomachy or
Gigantomachy; it was sometimes regarded not as a single event,
finished with once for all, but as a struggle liable to be repeated at
certain periods.182.2 On the other hand, Hesiod’s narrative of the
oppression of Gaia’s children by Ouranos and the outrage inflicted
on him by Kronos has its parallels in Maori and savage legend,182.3
but none in Mesopotamian, so far as our knowledge goes at present.
A different Babylonian mythological text from the library of
Assurbanipal speaks of another battle waged by Marduk against
Labbu, a male monster imagined mainly as a huge snake; and
Marduk is described as descending to the conflict in clouds and
lightning:183.1 the legend has no obvious significance for cosmogony,
for it places the event after the creation of the world and of men and
cities. But it has this interest for us, that it may be the prototype for
the legend of Zeus’ struggle with Typhoeus, which is known to
Homer, and which he places in the country of the Arimoi, regarded
by many of the ancient interpreters, including Pindar, as Cilicia.183.2
Now, the story of this conflict in Hesiod’s theogony has no
connections with the Titanomachy or the Gigantomachy, nor is it
there linked by any device to any known Hellenic myth; nor is it
derived, like the legend of Apollo and Python, from genuine Hellenic
cult-history. It has an alien air and character. Typhoeus is on the
whole regarded as a monstrous dragon, but one of his voices is that
of a lion, another that of a bull. The resemblance of this narrative to
the Babylonian one just mentioned is striking, and becomes all the
more salient when we compare certain Babylonian cylinders which
picture Marduk in combat with a monster, sometimes of serpent
form, sometimes with the body of a lion or a bull.183.3 The Typhoeus-
legend belongs also essentially to the Asia-Minor shores, and if
Cilicia was really the country whence it came to the knowledge of the
Homeric Greeks, it is a significant fact that it was just this corner of
the Asia-Minor coast that felt the arms of the earliest Assyrian
conquerors in the fourteenth century B.C.; and it is just such myths
that travel fast and far.
If the hypothesis of Assyrian origin is reasonable here, many will
regard it as still more reasonable in regard to the Deukalion flood-
story. Certain details in it remind us, no doubt, of the Babylonian
flood-myth; and as this latter was far diffused through Asia Minor, it
was quite easy for it to wander across the Aegean and touch Hellas.
But if it did, we have no indication that it reached the Hellenes in the
early period with which we are here concerned, as Hesiod is our
earliest authority for it.
The last theme of high interest in the cosmogonic theory of ancient
Babylonia is the creation of man. According to Berosos, this
momentous act was attributed to Bel, who, after the victory over
Chaos, commanded one of the gods to cut off his head and to make
men and animals out of earth mixed with his own blood, and this
story is partly corroborated by an old cuneiform text that is derived
from the beginning of the second millennium.184.1 This interesting
theory was not universally accepted, for another and independent
text ascribes the creation of man to Marduk and a goddess called
Aruru, simply as a mechanical act of power.184.2 The idea implicit in
the former account, of the blood-relationship of man to god, is of the
greater potentiality for religious metaphysic, and a similar notion is
found, developed into a high spiritual doctrine, in the later Orphic
Zagreus-mystery. But there is no trace of it in genuine Hellenic
thought or literature. We have no provedly early Greek version of the
origin of man: only, in the Works and Days, we are told that the
Immortals or Zeus made the men of the five ages, the third
generation, out of ash-trees: it may be that the story of Prometheus
forming them out of clay was known to Hesiod, as Lactantius
Placidus attests;185.1 in any case we may judge it to be of great
antiquity on account of its wide vogue in the later period, and its
occurrence in other primitive folklore. But nothing like it has as yet
been found in the ἱερὸς λόγος of Mesopotamia.
Generally we may say that the Hesiodic cosmogony bears no
significant resemblance to the Babylonian, and this negative fact
makes against the theory of Mesopotamian influence upon pre-
Homeric Hellas.
As a divine cosmogony implies some organic theory of the
Universe, so the polytheisms that attempted such speculations
would be confronted also with the problem of finding some principle
of order by which they might regulate the relations of the various
divinities, one to the other. We find such attempts in Mesopotamian
religion. Certain deities are affiliated to others, Marduk to Ea, Nebo
to Marduk, though such divine relationships are less clear and less
insisted on than in Hellenic theology; and the grouping of divinities
shifts according to the political vicissitudes of the peoples and cities.
We may discern a tendency at times to use the triad as a unifying
principle, giving us such trinities as Anu, Bel, Ea, or Sin, Shamash,
Adad;185.2 we have glimpses of a trinitarian cult in early
Carthage,185.3 and slight indications of it in the Minoan-Mycenaean
pillar-ritual.185.4 But I cannot find anything to suggest that among the
cultured or uncultured Semites it was ever in the ancient period a
powerful and constructive idea, able to beget a living dogma that
might capture the popular mind and spread and germinate in
adjacent lands.186.1 We have perhaps as much right to regard the
number seven as a grouping principle of Babylonian polytheism, in
the later period at least, when we find a group of seven high deities
corresponding to the seven planets.186.2 We might discover a Hittite
trinity of Father, Mother, and Son if we concentrated our attention on
the Boghaz-Keui reliefs; but the other Hittite evidence, both literary
and monumental, gives no hint of this as a working idea in the
religion. In fact, in most polytheisms of the Mediterranean type it is
easy to discover trinities and easy to deceive oneself about them.
The human family reflected into the heavens naturally suggests
the divine trio of Father, Mother, Child. And this may be found on the
Asia-Minor shore and in Hellas. It would be more important if we
could discover the worship of this triad in an indissoluble union from
which the mystic idea of a triune godhead might arise. This is not
discernible clearly in the older period on either side of the Aegean.
The cult-complex of Zeus, Semele, and Dionysos does not belong to
ancient Hellas and is rare at any period; that of Hades Demeter Kore
is occasionally found in cults of doubtful antiquity, but usually the
mother and daughter were worshipped without the male deity. The
Homeric triad so often invoked in adjurations of Zeus, Athena, and
Apollo, which misled Mr. Gladstone, is due probably to the
exigencies of hexameter verse, and is not guaranteed by genuine
cult. No divine triad in Hellas can be proved to have descended from
the earliest period of Greek religion, except probably that of the
Charites at Orchomenos.187.1 We have later evidence of a trinity of
Zeus, Poseidon, and Hades, expressing the triad that Nature
presents to us of sky, sea, and earth. But probably one of these
figures is an emanation of Zeus himself; the sky-god having become
“chthonian” in a very early period.187.2 We cannot say, then, that the
earliest period of Hellenic religion shows a trinitarian tendency; and if
it were so, we could not impute it to early Mesopotamian influence,
for the idea of a trinity does not appear in the Eastern religion with
such force and strength as to be likely to travel far.
As for the artificial group of the twelve Olympians, we should
certainly have been tempted to connect this with Babylonian lore, the
number twelve being of importance in astronomical numeration; only
that the divine group of twelve does not happen to occur in
Babylonian religious records at all. Nor does the complex cult of the
Δώδεκα θεοί appear to belong to the earliest period of Greek
religion.187.3 And so far I have been able to discern nothing that
justifies the suggestion187.4 that the principle of unification or divine
grouping in early Mediterranean polytheism came from Babylon.
A severely organised polytheism with one chief divinity, to whom
all the others were in definite degrees subordinated, might evolve a
monotheism. And in Babylonian literature we can mark certain
tendencies making in this direction. One tablet contains an
inscription proclaiming all the high gods to be forms of Marduk,
Nergal the Marduk of war, Nebo the Marduk of land.188.1 That all the
deities were mere forms or emanations of the Eternal might have
been an esoteric doctrine of certain gifted minds, though it was
difficult thus to explain away and to de-individualise the powerful
self-asserting personality of Ishtar, for an attractive goddess-cult is
always a strong obstacle to pure monotheism. A particular king might
wish at times to exalt the cult of a particular god into a monotheistic
ideal; the attempt was seriously made in Egypt and failed. It may
have been seriously intended by King Rammannirari III. (B.C. 811-
782), who introduced the cult of Nebo, always one of the most
spiritual figures of the Pantheon, into Kelach; hence comes a long
inscription on two statues now in the British Museum, set up by a
governor in honour of the king, which is valuable for its ethical
import, and still more interesting for its monotheistic exhortation at
the close:188.2 “Oh man, yet to be born, believe in Nebo, and trust in
no other gods but him.” Here is the seed that might have been
developed by a powerful prophet into pure monotheism. But the
ecstatic Babylonian votary is always falling into contradiction, for in
the earlier part of this hymn he has called Nebo, “The beloved of Bel,
the Lord of Lords.” What, then, must the congregation think of Bel?
In Greek religion the germs of monotheistic thought were still
weaker and still less likely to fructify. The earliest Hellenic tribes had
already certain deities in common, and the leading stocks at least
must have regarded Zeus as the supreme god. They must have also
adopted many indigenous deities that they found powerful in their
new homes, whose cult could not be uprooted even if they wished to
do so. We must therefore imagine the pre-Homeric societies as
maintaining a complex polytheism, with some principle of divine
hierarchy struggling to assert itself. Homer, if it is ever true to speak
of him as preaching, seems certainly the preacher of the supremacy
of Zeus. How far this idea was accepted in the various localities of
cult we have not sufficient material for deciding: much would depend
on the degree to which the individuals were penetrated by the higher
literature, which from Homer onwards proclaimed the same religious
tenet.189.1 We can at the same time be sure that in many localities
the countryfolk would be more under the spell of some ancient deity
of the place than of the sky-father of the Aryan Hellenes. And though
his cult was high placed by the progressive races, and his
personality powerfully pervading in the realm of nature and human
society, so that the higher thinkers entered on a track of speculation
that leads to monotheism, the masses did not and could not follow
them, having, in fact, the contrary bias. The popular polytheism
showed itself most tenacious of divine personalities; and owing partly
to the sacred power of divine names, the various titles of a single
divinity tend occasionally to engender distinct divine entities. I have
also already indicated that art contributed to the same effect through
multiplying idols. So far, then, from displaying monotheistic
potentialities, Greek polytheism, from the pre-Homeric period we
may suspect, and certainly after the Homeric age, tended to become
more polytheistic.
CHAPTER XI.
The Religious Temperament of the
Eastern and Western Peoples.
A more interesting and fruitful ground of comparison is that which

looks at the inward sentiment or psychic emotion of the different
religions, at the personal emotional relation of the individual towards
the godhead. As I observed before, a clear judgment on this
question is only possible when the religious memorials of a people
are numerous, varied, and personal, so that some of them at least
may be regarded as the expression of the individual spirit. Even if
the priest or the ritual dictates the expression, the pious and frequent
votary may come to feel genuinely what is dictated to him. Hence we
can gather direct testimony concerning the ancient Babylonian as we
can of the ancient Hebrew religious temper and emotion; for though
most of the Mesopotamian documents are concerned with the royal
ceremonial, which does not usually reveal genuine personal feeling,
yet in this case the royal inscriptions, whether religious narrative or
liturgies or prayers, are unusually convincing as revelations of self.
And besides these, we have many private hymns of penance and
formulae of exorcism.
On the other hand, the ancient Western world and even historic
Greece is singularly barren of this kind of religious testimony. We
know much about the State religion, but we have very few ritual
formulae or public or private prayers. Our evidence is mainly the
religious utterances of the higher poetry and literature and a few lyric
hymns composed not for the solitary worshipper, but for common
and tribal ritual-service. But we have also the mythology and the art
and the general manifestations of the Hellenic spirit in other
directions that enable us to conclude something concerning the
religious psychology of the average man in the historic periods, and
if we find this markedly different from that of the oriental, we shall
find it hard to believe that the Babylonian spirit could have worked
with any strong influence on the proto-Hellene.
A sympathetic study of the Babylonian-Assyrian documents
impresses us with certain salient traits of the Mesopotamian religious
spirit, some of which are common to other members of the great
Semitic race. In a certain sense the Babylonian might be described
as “ein Gott-betrunkener Mensch”: as one possessed with the
deepest consciousness of the ineffable greatness of God, of his own
utter dependence, and at the same time of the close personal
association between himself and the divinity. The ecstatic adoration
we have marked in the liturgies is the result of a purely mental
contemplation, will-power, and conviction, not of mystic initiation—for
Babylonia had no mysteries—nor of orgiastic rites that could afford a
physico-psychic stimulus. The individual seems to have regarded
himself at times as the son, more often as the bond-slave, of his own
tutelary divinity, who is angry when he sins and becomes favourable
and a mediator in his behalf with other gods when he repents. In
private letters of the time of Hammurabi we find the greeting, “May
thy protecting god keep thy head well.” A common formula occurs in
the incantations: “I, whose god is so-and-so, whose goddess is so-
and-so.”192.1 In the penance-liturgy the priest speaks thus of the
suppliant sinner, “Thy slave who bears the weight of thy wrath is
covered with dust,… commend him to the god who created him.”192.2
With this we may compare certain phrases in a well-known
penitential psalm, “Oh mighty Lady of the world, Queen of
mankind.… His god and goddess in sorrow with him, cry out unto
thee.… As a dove that moans I abound in sighings.”192.3 Abject
remorse, tears and sighing, casting-down of the countenance, are
part of the ritual that turns away the anger of the deity: hence fear of
God and humility are recognised religious virtues. Merodach-Baladin
of Babylon, in Sargon’s inscription, is described as a fool “who did
not fear the name of the Lord of Lords,”192.4 and the idea is shaped
in a general ethical maxim in another inscription, “He who does not
fear his god is cut down like a reed.”192.5 “I love the fear of God,”
says Nebukadnezar in the record of his life.192.6
Such emotion and mental attitude is consonant with the Hebraic
and with much of the modern religious temper; but entirely out of
harmony with all that we know of the Hellenic. The religious habit of
the Hellene strikes us by comparison as sober, well-tempered, often
genial, never ecstatically abject, but even—we may say—self-
respecting. Tears for sin, lamentations and sighs, the countenance
bowed to the ground, the body cleaving to the pavement, these are
not part of his ritual; the wrath of God was felt as a communal more
often than as an individual misfortune, and in any case was averted,
not by emotional outpourings of the individual heart, but by ritual
acts, solemn choruses, soothing sacrifice and songs, or by special
piacular lustrations that wiped off the taint of sin. Tears are never
mentioned,193.1 except indirectly in the fictitious lamentations for
some buried hero, annually and ceremoniously lamented, such as
Achilles. Nor can we find in earlier Hellenic ethic the clear
recognition of fear and humility among the religious virtues,193.2
while both are paraded in the inscriptions of the later Babylonian
kings, even in those that reveal a monstrous excess of pride.193.3
The Hellenic god might punish the haughty and high-minded, he did
not love the grovelling, but rather the man of moderate life, tone, and
act. Such is God for the civic religion of the free man; while the
Babylonian liturgy reflects the despotic society. The Hellene, for
instance, does not try to win for himself the favour of the divinity by
calling himself his slave. And the common phrase found on the
Greek Christian tombs, ὁ δοῦλος τοῦ Θεοῦ, has passed into
Christianity from Semitic sources.193.4 This single fact illustrates,
perhaps better than any other, the different temper of the old Oriental
and old European religions; and there is a curious example of it in
the bilingual Graeco-Phoenician inscription found in Malta,194.1
commemorating a dedication to Melkarth or to Herakles Ἀρχηγέτης:
the Phoenicians recommend themselves to the god as “thy slaves,”
the Greeks use neither this nor any other title of subservient flattery.
In this connection it is well to note the significance of marking the
body of the worshipper by branding, cutting, or tattooing with some
sign that consecrated him as slave or familiar follower to the divinity.
The practice, which may have been of great antiquity, though the
evidence is not earlier than the sixth century B.C., was in vogue in
Syria, Phrygia, and in early Israel, and was adopted by some
Christian enthusiasts, but no proof of it has yet been adduced from
Mesopotamia. It was essentially un-Hellenic, but was apparently
followed by some of the Dionysiac thiasoi as a Thracian
tradition.194.2
In fact, it is only in the latest periods that we find in Hellas an
individual personal religion approaching the Babylonian in intensity.
The older cult was communal and tribal rather than personal; even
the household gods, such as Zeus Κτήσιος and Ἑρκεῖος, the gods of
the closet and storehouse, the hearth-goddess, were shared by the
householder in common with the nearest circle of kindred. These
cults were partly utilitarian, and the moral emotion that they
quickened was the emotion of kinship: they do not appear to have
inspired a high personal and emotional faith and trust. Nor usually
had the average Hellene of the earlier period the conception of a
personal tutelary divinity who brought him to life, and watched over
his course, preserving, rebuking, and interceding for him. The
Babylonian fancy of the great king sitting in infancy on the lap of the
goddess and drinking milk from her breasts would not commend
itself to the religious sense in Greece.
In Mesopotamia and in the other Semitic communities the fashion
of naming a child after the high god or goddess was very common—
commoner I am inclined to think than in Hellas, though in the latter
country such names as Demetrios, Apollodoros, Zenon, Diogenes,
point to the same religious impulse; but they appear to have arisen
only in the later period. The Hellenic language did not admit, and
Hellenic thought would not have approved of, those mystic divine
names, which express as in a sacred text some quality or action of
the divinity, such as we find in the Bible (“the Lord will provide”), and
in pre-Islamitic inscriptions of Arabia, Ili-kariba, “My God hath
blessed”; Ili-azza, “My God is mighty”; Ili-padaja, “My God hath
redeemed.”195.1 Such names served as spells for the protection of
the child, and are speaking illustrations of the close personal
dependence of the individual upon the god.
This is also illustrated by another fashion, possibly ancient, of
Semitic religious nomenclature: not only was the individual frequently
named after the deity, but the deity might sometimes receive as a
cult-title the name of the individual. Of this practice among the
polytheistic Semites the only examples of which I am aware come
from a late period and from the region of Palmyra: Greek inscriptions
of the late Imperial era give such curious forms as Θεὸς Ἀὐμοῦ,
Θεὸς Οὐασεάθου, Θεὸς Ἀμέρου:196.1 and these descriptive names in
the genitive must designate the principal worshipper or founder of
the cult; they are mostly un-Greek, as the religious custom certainly
is, which is illustrated by such ancient Biblical expressions as “the
God of Abraham,” “the God of Jacob.” We may find an example of
the same point of view in the Phrygian title of Μὴν Φαρνάκου in
Pontus, if we take the most probable explanation, namely, that it is
derived from the Persian Pharnakes, the founder of the cult;196.2 and
again in a Carian dedication to Zeus Panamaros Ἀργύρου, as
Ἄργυρος is found in the same neighbourhood as the name of a living
man.196.3
The only parallel that Hellenic religion offers is the doubtful one,
Athena Αἰαντίς, whose temple is recorded at Megara:196.4 it may be
that the goddess took her title from the hero because his grave was
once associated with the temple. In any case, it is not so striking that
the mythic hero should stand in this intimate relation with the deity as
that the living individual should.
The ecstatic and self-prostrating adoration of divinity which is
characteristic of the Babylonian temper might manifest itself at times
in that excess of sentiment that we call sentimentality: we catch this
tone now and again in the childlike entreaties with which the
supplicator appeals to the deity as his father or mother; in the poetic
pathos of the hymns to Tammuz, which sometimes remind us of the
sentimentality of some of our modern hymns: he is called “Lord of
the tender voice and shining eyes”; “he of the dove-like voice.”197.1
Such language may be called “hypokoristic,” to use a Greek phrase;
it belongs to the feminine sentiment in religion, and we are familiar
with it in our own service. No echo of it is heard in the older Greek
religious literature nor in any record of Greek liturgy. We can, indeed,
scarcely pronounce on the question as to the tone to which primitive
Greek wailing-services were attuned. We have only a few hints of
some simple ancient ritual of sorrow: the pre-Homeric Greek may
have bewailed Linos and Hyakinthos, as we hear that the Elean
women in a later period bewailed Achilles; but if, indeed, the
fragment of a Linos-threnody that the Scholiast on Homer has
preserved for us is really primitive,197.2 it has some pathos, but much
brightness and nothing of the Babylonian sentimentality. The spirit of
the Greek religious lyric strikes us as always virile, and as likely to be
unsympathetic with the violent and romantic expression of sorrow or
with endearing ecstasy of appeal.
The other trait that should be considered here in the religious spirit
of the Mesopotamian Semites is fanaticism, an emotional quality
which often affords a useful basis of comparison between various
religions. This religious phenomenon is best known by its deadly
results; but in itself it is most difficult to define, as are other special
moral terms that imply blame and are highly controversial. It is only
found among those who feel their religion so deeply as to be
relatively indifferent to other functions of life. We impute fanaticism
when the tension of religious feeling destroys the moral equilibrium
or stunts development of other parts of our nature, or prompts to acts
which, but for this morbid influence, would excite moral indignation. It
may display itself in the artistic and intellectual sphere, as by
iconoclasm or the suppression of arts and sciences; or in the
discipline of individual life, as by over-ascetic self-mortification. Its
coarsest and most usual manifestation is in war and the destruction
of peoples of alien creed. A war or a slaughter is called fanatical, if
its leading motive is the extermination of a rival religion, not for the
sake of morality or civilisation, but as an act in itself acceptable to
one’s own jealous god. The ascetic type of fanaticism is specially a
product of the Far East: the murderous type is peculiar to the Semitic
spirit, when unchastened by a high ethical sympathy or a sensitive
humanism; for the chief record of it is in the pages of the history of
Israel, Islam, and Christianity, so far as this last religion has been in
bondage to certain Semitic influence. It is a question of interest
whether we find fanaticism of this type in the Mesopotamian area
and in the ancient polytheistic communities of the Western Semites.
We might expect to find it because of the intensity of the religious
spirit that seems to have been a common inheritance of all these
stocks. The more fervent the worship, the more is the likelihood that
the dangerous idea of a “jealous” god will emerge, especially when
races are living under the illusion of the “fallacy of names.” By a fatal
logic of devotion, the jealous god may be thought to favour or ordain
the destruction of those who worship the deity under other names,
which meant, for the old world, other gods. Only this must be
carefully distinguished from the other more innocent idea, proper to
all tribal religions, that the deity of the tribe, like a good citizen, will
desire victory for his people’s arms.
As regards Mesopotamia, in his History of Ancient Religions Tiele
finds in Assyrian history the same traces of murderous fanaticism as
in Israelitish.199.1 So far as I have been able as yet to collect the
evidence, this statement appears to contain some exaggeration. For
I have not found any record of a war that an Assyrian or Babylonian
ruler undertakes at the command of a “jealous god” against a people
whose only offence is an alien worship. The motives for a war
appear to be of the ordinary human and secular kind; Palestine, for
instance, is attacked, not because Marduk or Asshur personally
hates Jahwé, but because the country holds the key of the route to
Egypt. Such Biblical narratives as the destruction of Jericho, Ai, and
the Amalekites find no real parallel in Mesopotamian chronicles. Yet
in these also the temper of homicidal religion is strong enough to be
dangerous. Neither in the Babylonian nor in the Assyrian divinities is
there any spirit of mercy to the conquered. On that early relief of
Annabanini of the third millennium B.C., the goddess leads to the
king the captives by a hook in their noses to work his will upon
them.199.2 And in the later records of the great Assyrian Empire, the
deities appear prominently as motive forces, and the most cruel
treatment of captives is regarded as acceptable to them. The worst
example that Tiele quotes is the great inscription of Assurbanipal,
who, after speaking of himself as “the Compassionate, the King who
cherishes no grudge,”199.3 naïvely proceeds to narrate how he tore
out the tongues of the rebels of Babylon, hewed their flesh into small
pieces, and flung it to the dogs, swine, and vultures; and “after I had
performed these acts, I softened the hearts of the Great Gods, my
Lords.” But the lines that follow suggest that what “softened their
hearts” was not so much the tortures and massacres, which they
might approve of without directly commanding, but the religious
measures that Assurbanipal immediately undertook for the
purification of Babylon, whose temples had been polluted with
corpses. Again, Tiglath-Pileser III. speaks of himself as the Mighty
One “who in the service of Asshur broke in pieces like a potter’s
vessel all those who were not submissive to the will of his god”;200.1
and a little later, Sargon recounts how “Merodach-Baladin, King of
the Chaldaeans,… who did not fear the name of the Lord of Lords…
broke the statues of the great gods and refused his present to
me.”200.2 Yet it would be a misunderstanding to speak of these, as
Tiele does, as if they were wars of religion, like the Crusades or the
war against the Albigenses. Asshur sends the king to the war
invariably, but rather for the sake of the king’s profit and glory than
for the propagation of Asshur’s religion; for his enemies are very
frequently of the same religion as himself. The above phrases must
be understood probably in a political sense rather than a religious;
the god and the king are so intimately associated that whoever
insults or injures one, insults or injures the other. We may suspect
that Merodach-Baladin’s breach of the divine statutes consisted in
his omitting to send his usual tribute to Sargon. When two men had
spoken scornfully of the gods of Assurbanipal, both the king and the
gods would wish to avenge the insult:200.3 it was natural, therefore,
for Assurbanipal to torture and flay them. In warring against an alien
people, the king is warring against alien gods; therefore if he sacks
the alien city he may capture and take away, or—more rarely—
destroy, the city’s gods. Thus Asarhaddon had taken away the idols
of Hazailu, King of Arabia, and of Laili, King of Iadi; but when these
kings had made submission and won his favour he returned to them
the holy images, having first inscribed them with his own ideogram
and a mark of the might of Asshur:201.1 thus the gods, having the
brandmark of the great king and the imperial deity, become tributary
divinities. Or if he wished to wipe a people out, the Assyrian
conqueror might break their idols to dust. Thus Assurbanipal broke in
pieces the gods of the Elamites—the most deadly foes of Babylon—
and thereby “eased the heart of the Lord of Lords.”201.2 But many of
the Elamite deities he led away; and of one of them he speaks in
terms of reverence, Sašinak, the god of destiny, “who dwells in
hidden places, whose working no one sees.”201.3 It is more difficult to
understand why Sanherib should boast to have destroyed the deities
of Babylon after his capture of the city; for the leading Babylonian
divinities certainly belonged to the Assyrian Pantheon.
The evidence here quoted justifies us in attributing fanaticism to
the religious temper of Babylonia and Assyria; not because the wars
were evangelising, undertaken in the service of religion, but because
the savage cruelty that accompanied them is deemed, as it is in the
early Hebraic view, acceptable to the national gods. The idea of
divine mercy is potent in the liturgies; but neither morality nor religion
would appear to have inculcated any mercy towards the alien foe;
and this lack of moral sympathy may be termed a passive fanaticism.
The same fanatic temper might be traced in the savagery of the
punishments for offences against the State-religion, and was
reflected also at times in the legal code.202.1
From other polytheistic Semitic communities we have no record,
so far as I am aware, that bears on the phenomenon that we are
considering, except the famous Moabite Stone, of which the style is
in this respect strikingly Biblical. Mesha regards himself as sent by
his god Chĕmosh to take Nebo from Israel, and he explains why he
slaughtered all within the walls, man, woman, and child, “for I had
devoted it to Chĕmosh.” Fanaticism does not so naturally belong to
polytheism as to monotheism; yet it seems that at times the
polytheistic Semites could be as prone to this vice of the religious
temper as the monotheistic Israelites.
Speaking generally, and in comparison with the ancient Semitic
and the mediaeval and even later spirit of Europe, we must
pronounce the Hellenic temperament of the earlier and classical
period as wholly innocent of fanaticism. The history of Hellas is not
stained by any “war of religion”; and no religious hierarchy in Hellas
ever possessed the power or displayed the will to suppress art or
persecute science and thought. It might occasionally happen that
individuals were in danger of punishment if they insulted or openly
flouted the civic worship or introduced new deities; but that the State
should protect itself thus is not fanaticism. The least tolerant of cities
was the enlightened Athens. But her record in this matter is a
spotless page compared with the history of any later European
State. Hellas owed this happy immunity to her cooler religious
temper, to the equilibrium of the other life-forces within her, and to
her comparative freedom from dark and cruel superstitious fears.
It is specially in regard to such salient features of the religious
temperament as we have been considering that the early Hellene
asserted his spiritual independence of the East.
CHAPTER XII.
Eschatologic Ideas of East and West.
Religions are often found to differ fundamentally in their

conceptions of the fate of the departed spirit of man, and in the
prominence and importance they assign to the posthumous life.
There is, in fact, a group of religions which we might term “other-
worldly,” because certain dogmas concerning the world after death
are made the basis on which their aspirations and ideals of conduct
are constructed; to this group belong Christianity, Buddhism, Islam,
and the old Egyptian creed. There are other religions, also of a
highly developed type, in which eschatologic doctrine plays no
forcible or constructive part either in the theology or in the ethics.
Such were the Mesopotamian, primitive Judaism, and the early
Hellenic.
Our question concerning the evidences in the second millennium
of Mesopotamian influences on the Western Aegean demands, then,
at least a brief comparison of the Sumerian-Babylonian, and Hellenic
eschatology. Our knowledge of the former is derived from certain
epic poems, the Epic of Gilgamesh, “The Descent of Ishtar,” and the
poem dealing with the marriage of Nergal and Erishkigal, the Queen
of the dead; secondly, from a few inscriptions of various periods,
alluding to burial or the status of the dead; thirdly, and this is the
most important source, from the recent excavations of certain
“necropoleis.”205.1 The Hellenic facts have been sufficiently set forth
for the present purpose in a former series of lectures.
In the picture of the lower world presented by the two literatures, a
certain general agreement is discoverable, but none closer than they
reveal with the conceptions of other peoples. Both accept as an
undoubted fact the continued existence of the soul after death, and
both imagine this existence as shadowy, profitless, and gloomy. Both
also vaguely locate the abode of the soul under the earth, with a
downward entrance somewhere in the west.205.2 In both we find the
idea of a nether river to be crossed, or “the waters of death”;205.3 of a
porter at the gates of “hell,” and of a god and goddess as rulers of
the lower world; while the mountain of the Babylonian underworld on
which the gods were supposed to have been born was unknown to
Hellenic mythology.205.4 Such coincidences are no criterion of a
common origin of belief; for these traits recur in the death-lore of
many and widely scattered races.
As against them, we must take into account certain salient
differences. The lot of the departed in the Babylonian epic account
appears drearier even than in the Homeric, just as the Babylonian
religious poetry inclines to the more sombre tones and the more
violent pathos. The dead inhabit “the house wherein he who enters is
excluded from the light, the place where dust is their bread, and mud
their food. They behold not the light, they dwell in darkness, and are
clothed, like birds, in a garment of feathers; and over door and bolt
the dust is scattered.”206.1 This is more hopeless than the Homeric
meadow of Asphodel, where the souls still pursue the shadow of
their former interests, and some tidings of the earth may penetrate to
give them joy. Also, the demoniac terrors of the lower world are more
vividly presented in Babylonian than in Hellenic literature and art.
The demons of disease that perform the bidding of Allatu, the Queen
of Hell, are closely connected with the ghost-world; we learn from the
formulae of exorcism that the haunting demon that destroyed a
man’s vital energies might be a wandering spectre. “O Shamash, a
horrible spectre for many days hath fastened itself on my back, and
will not loose its hold upon me.… he sendeth forth pollution, he
maketh the hair of my head to stand up, he taketh the power from
my body, he maketh my eyes to start out, he plagueth my back, he
poisoneth my flesh, he plagueth my whole body… whether it be the
spectre of my own family and kindred, or the spectre of one who was
murdered, or whether it be the spectre of any other man that
haunteth me.”206.2
Now it is possible that the curse of the demon was powerful both
in the earlier and later periods of ancient, as it is powerful to-day in
modern, Greece; the demon might be a ghost or a revenant. And it
has been the ambition of a small group of scholars in this country to
prove that the higher literature and art of Greece, that reveals so fair
and sane an imagination of the unseen world, is only a thin veil

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The Digestive Involvement in Systemic

Autoimmune Diseases 2nd Edition

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

Volume 1 The Heart in Systemic Autoimmune Diseases

The Digestive Involvement

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

Copyright © 2017 Elsevier B.V. All rights reserved.

Library of Congress Cataloging-in-Publication Data

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For information on all Elsevier publications

Publisher: Sara Tenney

Typeset by TNQ Books and Journals

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

H. Direskeneli, Marmara University, Istanbul, Turkey

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

The second edition of The Digestive System in Systemic Autoimmune Diseases

Digestive System and

1. THE DIGESTIVE SYSTEM AND GUT-ASSOCIATED

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

TABLE 1.1 Mechanisms to Minimize Self-Reactive Lymphocyte

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

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

2. SELF-TOLERANCE AND AUTOIMMUNITY

3. TOLERANCE MECHANISMS FOR AUTOREACTIVE B CELLS

4. TOLERANCE MECHANISMS FOR AUTOREACTIVE T CELLS

diseases may stem from inefficient presentation of particular self-peptides

5. CLONAL ANERGY AND TUNING

6. EXTRINSIC CONTROLS OF SELF-REACTIVE

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

8. REGULATION OF SELF-REACTIVE LYMPHOCYTES IN

9. TOLERANCE AT THE EFFECTOR PHASE

[6] Nicoletti C. Unsolved mysteries of intestinal M cells. Gut 2000;47:735e9.

The Digestive Involvement in Systemic Autoimmune Diseases. http://dx.doi.org/10.1016/B978-0-444-63707-9.00002-7

triggering autoimmune liver disease are likely to have shared, easily

2. ANTIGENS AND ANTIGEN RESPONSES

Antigens and Responses Nature Possible Pathogenic Effects

Immunopathogenesis of Autoimmune Liver Damage Chapter j 2

implicated as target antigens in the autoimmune polyglandular syndrome type 1,

2.2 Molecular Mimicry

A more interesting and fruitful ground of comparison is that which

Religions are often found to differ fundamentally in their

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