Wang Et Al-2015-Journal of Internal Medicine-2 PDF

Review
doi: 10.1111/joim.12395
Human autoimmune diseases: a comprehensive update

Lifeng Wang1, Fu-Sheng Wang1 & M. Eric Gershwin2
From the 1Research Center for Biological Therapy, The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China; and
Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, Davis, CA, USA
Abstract. Wang L, Wang F-S, Gershwin ME (Research

Center for Biological Therapy, the Institute of
Translational Hepatology, Beijing 302 Hospital,
Beijing, China; and Division of Rheumatology,
Allergy and Clinical Immunology, University of
California at Davis School of Medicine, Davis, CA,
USA).
Human
autoimmune
diseases:
a
comprehensive update. (Review). J Intern Med
2015; 278: 369395.
There have been significant advances in our understanding of human autoimmunity that have led to
improvements in classification and diagnosis and,
most importantly, research advances in new therapies. The importance of autoimmunity and the
mechanisms that lead to clinical disease were first
recognized about 50 years ago following the pioneering studies of Macfarlane Burnett and his Nobel
Prize-winning hypothesis of the forbidden clone.
Such pioneering efforts led to a better understanding
not only of autoimmunity, but also of lymphoid cell
development, thymic education, apoptosis and deletion of autoreactive cells. Contemporary theories
suggest that the development of an autoimmune
disease requires a genetic predisposition and environmental factors that trigger the immune pathways
that lead, ultimately, to tissue destruction. Despite
extensive research, there are no genetic tools that can
be used clinically to predict the risk of autoimmune
disease. Indeed, the concordance of autoimmune
disease in identical twins is 1267%, highlighting not
only a role for environmental factors, but also the
potential importance of stochastic or epigenetic
phenomena. On the other hand, the identification
of cytokines and chemokines, and their cognate
receptors, has led to novel therapies that block
pathological inflammatory responses within the target organ and have greatly improved the therapeutic
effect in patients with autoimmune disease, particularly rheumatoid arthritis. Further advances
involving the use of multiplex platforms for diagnosis
and identification of new therapeutic agents should
lead to major breakthroughs within the next decade.
Keywords: Immune tolerance, Immunopathology,
genetics and autoimmunity, autoantibodies.
Abbreviations: TNF, tumour necrosis factor; Th, T

helper cell; TNFRSF14, tumour necrosis factor
receptor superfamily member 14; IL12RB2, interleukin-12 receptor, beta 2; RAD51B, RAD51 paralog
B; Sm, smith; HHV6, human herpes virus 6; Treg, T
regulatory cell; Tfh, T follicular helper cell; PDC-E2,
the E2 subunit of the pyruvate dehydrogenase
complex; mTEC, medullary thymic epithelial cells;
AD, autoimmune disease; CLEC16A, C-type lectin
domain family 16; IRF8, interferon regulatory factor
8; Olig3, oligodendrocyte transcription factor 3;
TNFAIP3, tumour necrosis factor, alpha-induced
protein 3; PTGER4, prostaglandin E receptor 4;
RGS1, regulator of G protein signalling 1; INS,
insulin; IFIH1, interferon induced with helicase C
domain 1; PTPN2, protein tyrosine phosphatase
nonreceptor type 2; PLC-L2, phospholipase C-like
protein 2; FCRL3, Fc receptor-like protein 3;
DNMT1, DNA (cytosine-5)-methyltransferase 1;
MECP2, methyl CpG binding protein 2; IRGM,
immunity-related GTPase family M protein; CEACAM6, carcinoembryonic antigen-related cell adhesion molecule 6; PARK7, Parkinsons disease
(autosomal recessive, early onset) 7; ERRFI1, ERBB
receptor feedback inhibitor 1; MMEL1, membrane
metallo-endopeptidase-like 1; BLK, B lymphoid
tyrosine kinase; APOBEC, apolipoprotein B mRNA
editing enzyme, catalytic polypeptide-like; IAA, insulin autoantibodies; GADA, glutamic acid decarboxylase antibodies; IA-2A, insulinoma-associated2 autoantibodies; ZnT8A, zinc transporter 8 autoantibody; LKM-1, liver kidney microsome-1; CCP,
cyclic citrullinated peptide; ESPGAN, European
Society for Paediatric Gastroenterology Hepatology
and Nutrition; ACR/SICCA, American College of
Rheumatology/Sjogrens International Collaborative Clinical Alliance; SLICC, Systemic Lupus International Collaborating Clinic; EULAR, European
League Against Rheumatism; T1D, type I diabetes;
PBC, primary biliary cirrhosis; SLE, systemic lupus
erythematosus; RA, rheumatoid arthritis; APS1,
autoimmune polyendocrinopathy syndrome type
1; MHC, major histocompatibility complex; AITD,
autoimmune thyroid disease; TLR, Toll-like receptor; SS, Sjogrens syndrome; EBV, EpsteinBarr
virus; ARF, acute rheumatic fever.
2015 The Association for the Publication of the Journal of Internal Medicine
369
L. Wang et al.
Introduction
The diverse immune system developed to fulfil the
primary function of protecting hosts from infectious agents. There are, however, two major areas
in which this pleiotropic immune system leads to
pathology: first, immune deficiency syndromes in
which there is an inability of one or more components of the immune system to respond in a
protective fashion to a pathogen, and secondly
autoimmune diseases. The failure to distinguish
self from nonself is often termed a breach of
tolerance and is the basis for autoimmune disease
and the focus of this review.
Historically, autoimmune diseases were considered to be rare but, through rigorous epidemiological studies, have now been shown to affect 35% of
the population, with autoimmune thyroid disease
and type I diabetes (T1D) being the most common
of these conditions. However, more importantly,
there are nearly 100 distinct autoimmune diseases, some of which are organ specific such as
primary biliary cirrhosis (PBC) and some of which
reflect a variety of immunological dysfunction
involving multiple organs such as systemic lupus
erythematosus (SLE) [1]. In the past decade, there
have been significant advances in diagnosis and
disease classification, as well as improvements in
prognosis, achieved through both the development
of novel technologies in molecular immunology and
sophisticated evidence-based clinical laboratory
testing. In this review, we provide a historical basis
for the breach of tolerance hypothesis and then
discuss issues of autoimmune aetiology and pathobiology, concluding with a general overview of new
treatment options.
The concept of immunological tolerance
In 1948, Macfarlane Burnet of the Walter and
Eliza Hall Institute for Medical Research in Melbourne, Australia, proposed that immunological
inertness to self, which he termed tolerance, is a
characteristic acquired in development, rather
than an innate feature. Several years later, in
1953, Peter Medawar and his colleagues experimentally demonstrated the ability to induce
immune tolerance in inbred mice. Ultimately, the
concept of immune tolerance was defined as an
ability of the immune system to prevent itself from
targeting self-molecules, cells or tissues [2]. Many
investigators did not believe in the concept of
autoimmunity, although it is interesting that the
370
Journal of Internal Medicine, 2015, 278; 369395
Review: Human autoimmune diseases
pioneering work of Paul Ehrlich early in the 20th

century had already introduced the concept of
horror autotoxicus [3]. In 1959, the New Zealand
black (NZB) mouse, the first murine model of
autoimmunity, was described. Subsequently, thyroid autoantibodies were demonstrated and
autoimmune thyroiditis became the prototypic
autoimmune disease [4]. These two contributions
(NZB mice and autoimmune thyroiditis) became
the impetus for the explosion of research into
autoimmune diseases.
Several key concepts should be introduced to
understand immune tolerance, including central
tolerance, peripheral anergy, T regulatory cells
(Tregs) and the homeostasis produced by cytokines
and chemokines and their cognate receptors. Central tolerance in the thymus and bone marrow
plays a key role in shaping immune system homeostasis. In the thymus, developing lymphocytes
undergo positive selection in the cortex before
maturing and entering the circulation. Of note, in
an otherwise healthy host, lymphocytes with
potential reactivity against self-peptides are negatively selected and deleted in the thymic medulla.
Importantly, after exiting the thymus, mature T
cells are subjected to secondary selection (peripheral tolerance) by which the majority of self-reactive T cells are deleted or rendered anergic. In
addition, if immature B cells express surface IgM
that recognizes ubiquitous self cell-surface antigens, they are eliminated by a process known as
clonal deletion or clonal anergy. Autoreactive B
cells can escape deletion by a process known as
receptor editing. Mature B cells are also under the
control of peripheral tolerance. These concepts are
illustrated in Fig. 1.
It is important to note however that even under the
strict vigilance of central and peripheral tolerance,
small numbers of potentially self-reacting lymphocytes can still leak out into the periphery, even in
otherwise normal individuals. The existence of
these potential self-reactive T and/or B lymphocytes, and/or the ability of these cells to produce
autoantibodies, does not necessarily lead to pathology [5]. Accordingly, autoimmunity can sometimes
be classified as physiological and pathological
autoimmunity [6, 7]. Physiological autoimmunity is
usually transient without evidence of clinical disease. This is exemplified by the presence of socalled natural autoantibodies [8], which help eliminate degraded self- and foreign antigens for maintenance of homeostasis. As another example, two of
L. Wang et al.
Fig. 1 Positive and negative selection in the thymus. (i) Early thymic progenitors derived from bone marrow enter the
thymus via blood vessels from the corticomedullary junction. The more immature double-negative (DN; CD4 CD8 )
thymocytes are divided into DN1 to DN4 cells. Rearrangement of the T-cell receptor (TCR) b locus allows thymocytes to reach
the first development checkpoint (b-selection). This leads to survival, proliferation and differentiation into double-positive
thymocytes (DP; CD4+CD8+). (ii) Next TCR+ DP cells undergo positive selection in the cortex. With low affinity for selfpeptide MHC class I or class II molecules presented by thymic epithelial cells (TECs), the TCR+ DP thymocytes continue
differentiating into single-positive (SP) thymocytes (e.g. CD4+ and CD8+ SP). DP thymocytes that fail to express an MHCrestricted TCR will undergo death by neglect. (iii) SP cells with high avidity for self-peptide MHC class I or II molecules die by
apoptosis via negative selection in the thymic medullary region. Medullary thymic epithelial cells (mTEC) as well as dendritic
cells (DCs) or macrophages play important roles in this process. Some autoreactive CD4 or CD8 cells can still leak out of the
double selection process. (iv) Through positive and negative selection, mature naive T cells will be released into the periphery
and differentiate into subsets, including T regulatory cells (Tregs), which will maintain peripheral tolerance.
Fig. 2 Summary of the development of autoimmune disease. Even under the most strict control by central and peripheral
tolerance, a small number of autoreactive T and B cells leak out into the periphery in normal individuals. However, they will
remain harmless unless there is a genetic predisposition to break tolerance and an environment trigger or triggers.
the more common autoantibodies, antinuclear

antibodies and rheumatoid factor, are often
observed in healthy individuals and their prevalence increases with age. When immune tolerance is
broken and autoantibodies and self-reactive lymphocytes become involved in inflammation, classical or pathological autoimmunity develops (Fig. 2)
which finally leads to tissue damage.
371
L. Wang et al.
The epidemiology of autoimmunity

Autoimmune diseases are generally thought of as
being relatively uncommon, but their effects on
mortality and morbidity are significant. The overall
prevalence of autoimmunity is approximately 35%
in the general population [9, 10]. Yet, ironically,
despite enormous advances in the diagnosis and
the treatment of autoimmune diseases, there is still
a paucity of data on the aetiological events that
lead to clinical pathology.
Incidence and prevalence vary amongst the
autoimmune diseases. The geoepidemiology
becomes more complex when variations in age,
gender, ethnicity and other demographic features
are considered (Table 1). Autoimmune diseases
can occur at any age, but different diseases have
their own characteristic age of onset. In almost all
patients, the prevalence is increased in first-degree
relatives and is even higher in monozygotic twins
[11]. There is an increased frequency of autoimmune diseases in women, with a female-to-male
ratio ranging from 10 : 1 to 1 : 1 [an exception is

Crohns disease, with a ratio of 1 : 1.2]. The sex
bias of autoimmunity has attracted enormous
attention, but remains unresolved.
The incidence and prevalence of autoimmune diseases differ between geographical regions. For
example, multiple sclerosis (MS) is unevenly distributed throughout the world; its prevalence
varies between <5 cases per 100 000 persons in
tropical areas and also in Asia and >200 cases per
100 000 persons in temperate areas. The incidence
of MS has been reported to be 0.88.7 per 100 000
person-years in Europe, 2.77.5 per 100 000 person-years in North America and 0.73.6 per
100 000 person-years in Asia and the Middle East
[12]. The incidence of T1D is 510, 1020 and <1
per 100 000 person-years in populations from
Europe, the USA and China, respectively. Between
1990 and 2011, the incidence of coeliac disease
(CeD) increased from 5.2 to 19.1 per 100 000
person-years in the UK [13]. However, an annual
1.8% decline in incidence of SLE in the UK between
Table 1 Geoepidemiology of selected human autoimmune diseases

Gender
Monozygotic
Incidence (per 100 000 person-years)

North
Asia and
Age at onset
(female/
twin
Disease
(years)
male)
concordancea
Europe
America
Middle East
References
Multiple sclerosis
2040
2/1
931%
0.88.7
2.77.5
0.73.6
[12, 145]
Type 1 diabetes
613
Primary biliary
5060
1/1
10/1
1348%
>20
1020
<1
[146, 147]
63%
1.43.1
2.7 (USA)
0.340.42
[148151]
Only case
1.073.0
0.5 (USA)
0.080.15
[152154]
cirrhosis
Autoimmune
hepatitis
<40 (T1)
214 (T2)
4/1 (T1)
10/1 (T2)
reports
(Japan)
Graves disease
5060
5/1
1760%
2150
38
120
[155, 156]
Crohns disease
1530, 6080
1/1.2
4%
3.112.7
6.920.2
0.241.34
[157159]
Ulcerative colitis
1530, 6080
1/1
6.318.8%
4.116.5
8.319.2
0.366.02
[159, 160]
Coeliac disease
Childhood
1/1
7583%
1.58.7
0.99.1
Unclear
[161, 162]
(all ages)
Addisons disease
1545
Sjogrens
4050
0.82.4/1
Discordant
(all ages)
0.566.20
1 (USA)
Unclear
[163, 164]
5.3 (north-west
35 (USA)
6.57
[165167]
pair
9/1
syndrome
Systemic lupus
Only case
reports
Greece)
3050
9/1
1125%
1.05.0
1.28.7
0.93.1
[168170]
4455
2/1
1530%
936
3145
842
[171173]
erythematosus
Rheumatoid
arthritis
a
Data from [144].
372
L. Wang et al.
1999 and 2012 was reported, whilst the prevalence

increased from 64.99 to 97.04 per 100 000 persons per year during the same period [14]. For
rheumatoid arthritis (RA), the global prevalence
was estimated to be 0.24% in 2010, which was
essentially no different from the prevalence of
0.25% in 1990 [15]. Traditional analytical epidemiological studies have shown that genetic susceptibility and environmental factors are the key risk
factors that lead to loss of tolerance [16].
The genetic basis of autoimmunity
Many of the concepts of autoimmunity can be
exemplified by discussing the rare monogenic
autoimmune diseases, which pinpoint the concept
of genetic background [17]. For example, autoimmune polyendocrinopathy syndrome type 1 (APS1)
is a multiple organ-specific autoimmune disease,
often starting in childhood or during the teenage
years. Hallmark symptoms include chronic Candida
infection
followed
by
autoimmune
hypoparathyroidism and Addisons disease [18
20]. A mutation in the autoimmune regulator
(AIRE) gene was first identified by positional
cloning in Finnish APS1 families [21]; it affects
negative selection in the thymus and thus self-antigen presentation. Another example of a monogenic
autoimmune disease is the autoimmune lymphoproliferative syndrome, which is characterized by
the accumulation of a polyclonal population of
double-negative T cells (CD3+TCRab+CD4 CD8 )
[22]. Mutations in tumour necrosis factor (TNF)
receptor superfamily member 6 (TNFRSF6),
TNFRSF6 membrane-bound ligand and caspase

10 cysteine protease also influence apoptosis of
lymphocytes, resulting in massive accumulation of
mononuclear cells within lymphoid tissue and
subsequent failure to delete autoreactive cells
[23]. Two other examples of a monogenic autoimmune disease that illustrate these principles of
selection are the immunodysregulation polyendocrinopathy enteropathy X-linked syndrome
(IPEX) (in which there is a defect in the Foxp3
gene, localized to Xp11.23) [24] and IL-2Ra deficiency (in which there is a deletion of the CD25
gene); in both cases, these mutations alter the
functional development of CD4+CD25+ Tregs, leading to loss of peripheral tolerance [25] (Fig. 3).
The majority of autoimmune diseases are not
monogenic, but rather have multiple genetic factors that play a role. Although there have been a
variety of early studies showing associations with
the major histocompatibility complex (MHC) in
human autoimmune diseases, the results have
often have failed to lead to associations that have
significant predictive strength for the clinician. The
MHC is located on the short arm of chromosome 6
and harbours genes encoding molecules involved
in antigen presentation and therefore is critical in
distinguishing self from nonself. In humans, the
gene products of MHC are termed human leucocyte
antigens (HLAs). A number of linkage studies have
identified genetic variants associated with autoimmune diseases [26] including in T1D (HLA-II: DQ2
and DQ8; HLA-I: HLA-A and DQB1*0602), SLE
(HLA-II: DR3, DR2 and DR8; HLA-III: SCIVaL, CFB,
Fig. 3 Genetic basis of

autoimmunity. Multiple genes
with specific gene mutations
(i.e. AIRE, TNFRSF6, FOXP3
and CD25), HLA susceptible,
non-HLA loci (i.e. PRPN22,
IRF5-TNFO3 and BACH2) as
well as epigenetic mechanisms
(methylation, acetylation,
ubiquination, sumoylation,
phosphorylation and
microRNA) have been
implicated in specific
373
L. Wang et al.
Table 2 Genetic associations with autoimmune diseases

Disease
HLA*
Non-HLA loci
Epigenetic aberrations
References
Multiple
HLA class II:
L2RA, IL-7Ra,
DNA methylation:
[47, 48, 145,
sclerosis
DRB1*15:01
CLEC16A, CD6,
DRB1*03:01-DQB1
CD58, IRF8,
*02:01
BACH2, IL-12A,
DRB1*13:03-DQB1
Olig3-TNFAIP3,
Hyperacetylation of H3
*03:01
PTGER4, RGS1,
promoter region in
HLA class I:
Hypomethylation of PAD2
Hypomethylation of SHP-1
Acetylation:
TNFRSF1A
HLA-A*02:01
174, 175]
white matter
miRNA:
miR-326, miR-17-5p,
19a/b, miR-20a, miR-92b,
miR-21, miR-106b, miR34a, miR-155, miR-326,
and others
Type 1 diabetes
HLA class II:
INS,CTLA4,
DNA methylation:
DQ2(DRB1
PTPN22, IL-2RA,
HLA, INS, IL-2RB, CD226
*0301-DQA1
IFIH1, STAT4,
Acetylation:
*0501-DQB1*0201)
BACH2, PTPN2
Increase H3k9me2 in
DQ8(DRB1
lymphocyte genes:
*04-DQA1
TGF-b, NF-kB, IL-6, HLA,
*0301-DQB1
CTLA4
*0302)
miRNA:
HLA class I:
miR-375, miR-25, miR-
HLA-A
326, miR-342, miR-19,
HLA-B: protective
miR-510, miR-21,
effect, DQB1*0602
Primary biliary
cirrhosis
HLA class II:
[46, 176179]
and others
IL-12, IL-12R, IL-
DNA methylation:
DRB1*08,
7R, CD80,
DRB1*11, and
STAT4, TYK2,
DRB1*13 protective
SOCS1, IRF5,
miR-122-5p, miR-141-3p,
SPIB, PLC-L2,
miR-26b-5p, miR-506,
IRF8, CXCR5,
miR-2, miR-let-7b, miR-
IKZF3
505-3p, miR-197-3p,
[2, 49, 180]
CD40L
miRNA:
and others
Autoimmune
hepatitis
HLA class II:
CTLA-4, TNF-a,
DR3(DRB1*03:01)
TGF-b1, TBX21,
and DR4
VDR, FAS
(DRB1*04:01) for
AIH-1
DR3(DRB1*03:01)
and DR7
(DRB1*07:01) for
AIH-2
374
[152, 153, 181]
L. Wang et al.
Table 2 (Continued )
Disease
HLA*
Non-HLA loci
References
Graves disease
HLA class II:
CTLA-4, PTPN22,
DNA methylation:
[182186]
DR3(DRB1*03 or
CD25, CD40,
ICMA1, DNMT1,
DQA1*0501)
FCRL3
MECP2, IRF1
HLA class I:
miRNA:
HLA-B8
miR-17, miR-155, miR146, miR-200a1
Crohns disease
Ulcerative colitis
HLA class II:
TLR4, CARD9, IL-
DNA methylation:
DR7, DRB3
23R, JAK2,
CEACAM6, VMP1/
*03:01, DR4;
STAT3, CCR6,
miR-21, HLA loci
DR2 and DR3
ICOSLG,
protective
BACH2, IRGM,
miR-199a-5p, miR-362-
IBD5, DMBT1,
3p, miR-532-3p, miR-505,
XBP1, PTPN22,
miR-195, miR-16, miR-93,
IL-12B
miR-140, 200c, 532-3p
HLA class II:
TNFRSF14,
miRNA:
DNA methylation:
DR2, DR15, DR9;
PARK7, ERRFI1,
DR4 protective
CARD9, IL-23R,
IL-17c, IL-4R, IFITM1,
IRF5, RNF186,
ITGB2, S100A9, SLPI,
IL-17, IL-10,
PUS10
[187191]
[187, 192194]
CXCL14 CXCL5, GATA3,
SAA1, STST3
miRNA:
miR-29a, miR-505, miR28-5p, miR-151-5p, miR340, miR-532-3p, miR-16,
miR-21, miR-28-5p, miR155, miR-188-5p,
miR-422a
Coeliac disease
HLA class II:
IL-2, IL-21,
DNA methylation:
DQ2(DRB1
THEMIS, PTPRK,
NF-kB pathway
*03:01-DQA1
BACH2, BACH2,
miRNA:
*05:01-DQB1
RGS1, MMEL1,
miR-449a, miR194-5p,
*02:01)
SH2B3, IRAQ1
miR-31-5p, miR-192-3p,
DQ8(DRB1
miR-551a, miR-551b,
*04-DQA1
miR-638, miR-1290, and
*03:01-DQB1
others
[195198]
*03:02)
Addisons disease
HLA class II:
UGT2B28,
DNA methylation:
DR3/DQ2
ADAM3A
Hypomethylated
(DRB1*03:01-DQB1
*02:01)
DR4.4/DQ8
[199201]
status in CD4+ T cells

miRNA:
miR-200a
(DRB1*04:04-DQA1
*03:01-DQB1*03:02)
375
L. Wang et al.
Disease
HLA*
Non-HLA loci
References
Sjogrens syndrome
HLA class II:
STAT4, IL-12A,
DNA methylation:
[52, 202206]
DRB1*15, DRB1*03
TNIP1, IRF5,
DRB1*11,
BLK, CXCR5
DRB1*04
Hypomethylated CD4+T,
HERVs
Acetylation:
DRB1*08:03
Acetylation of histone H4
and 16:02
in AQP5 gene promoter
DRB1*12:01
miRNA:
protective
miR-146a, miR-155,Let7b, mir-21
Systemic lupus
erythematosus
HLA Class II:
STAT4, IFIH1, IRF5,
DR3(DRB1
TNFAIP3, PTPN22,
NLRP2, CD300LB, S1PR3
*03:01-DRB1*02:01)
TNFSF4, IL-10,
Hypomethylation in CD4+T
DR2(DRB1
IL-21, ITGAM,
Histone modification:
*15:01-DRB1*06:02)
ATG5, TNFAIP3
Global H3 and H4
DR8(DRB1
miR-146a, miR-638, miR-
and 14:03)
16, miR-27a, miR-21,
protective
miR-31, miR-125a, miR155, miR-371-5p, miR-
HLA Class III:

TNF,C2,C4,SCIV2L,
1224-3p, miR-423-5p,
CFB, RDBP,DOM3Z,
miR-15, miR-148a, and

others
STK19C4A, C4B,
arthritis
PADI4, PTPN22,
DNA methylation:
DR4(DRB1*04:01,
CTLA4, STAT4,
C5, TET, APOBEC, IL-6
*04:04,*04:05,
TNFAIP3, CD40,
promoter,
*04:02,*04:03,*01:01)
IL-2RA, CD28,
DR1
CCR6, IRF5,
HLA Class III:
207211]
miRNA:
DR6(DRB1*13:02
HLA Class II:
[50, 143,
hyperacetylation in CD4T
*08:01-DRB1*04:02)
Rheumatoid
DNA methylation:
RUNX1, GATA3
TNF
[51, 212215]
CD40L promoter, CXCL12

Histone modification:
Alteration of histone
modification in PBMCs
and synovium/
synoviocytes
HDAC inhibitors
miRNA:
miR-146a, miR-155, miR223, miR-124, miR-34,
miR-346, miR-203a, miR363, miR-498, miR-let-7a,
miR-323-3p, miR-140,
miR-132, miR-16, and others
miR, microRNA; HDAC, histone deacetylase; PBMC, peripheral blood mononuclear cell; HLA, human leucocyte antigen.
The genes highlighted in bold text were found in more than three different autoimmune diseases, respectively.
376
L. Wang et al.
RDBP, DOM3Z, STK19C4A and C4B) and RA (HLAII: DR4; HLA-III: TNF); autoimmune thyroid disease
(AITD) (HLA-II: DR3 and DR4), psoriasis (HLA-I:
Cw*0602, Cw1203, and HCP5) and CeD (HLA-II:
DQ2 and DQ8) are also strongly associated with
specific HLA alleles (Table 2) [26]. However, despite
a massive effort to identify the genetic basis of a
number of autoimmune diseases through genomewide association studies (GWAS), the results have
failed to have major predictive value. Of interest,
however, the strongest component for genetic
bias in human autoimmunity still remains the
MHC [27, 28].
Although genomewide association studies have not
led to the anticipated predictive properties, they
have described several uncommon variants that
would not otherwise have been identified [29].
Indeed, in the past 10 years, hundreds of nonHLA loci have been reported to be associated with
RA, SLE, MS, T1D, ulcerative colitis (UC), PBC,
autoimmune hepatitis and many other autoimmune diseases [30]. These risk factors appear to be
associated with gene products involved in both
innate and adaptive immune responses. But, more
importantly, this has led to the idea that the
occurrence of multiple autoimmune diseases
within one individual as well as an increased risk
for developing an autoimmune disease in a family
member can be explained [31]. This concept is
illustrated by the protein tyrosine phosphatase
nonreceptor type 22 (PTPN22) gene [32, 33],
expressed by hematopoietic cells. PTPN22 has a
dual role and is critically involved in the regulation
of immune cell signalling. In the adaptive immune
system, PTPN22 inhibits T-cell activation by
restricting signalling downstream of the T-cell
receptor. By contrast, in the innate immune system, PTPN22 selectively promotes myeloid cell type
I interferon production by enhancing signalling
downstream of pattern recognition receptors.
PTPN22, a classical shared autoimmunity gene,
has been found in patients with many autoimmune
disorders, including T1D, RA, SLE, Graves disease
and Crohns disease.
There are several other loci that illustrate the
overlap and the predisposition to autoimmunity
within families. These include IRF5-TNPO3 encoding interferon regulatory factor 5 and transportin 3.
This gene is involved in the accumulation of lymphocytes within lymphoid organs and the failure to
delete autoreactive native T cells. This gene also
has a role in the Toll-like receptor (TLR) signalling
pathway and mediates apoptosis induced by the

TNF-related apoptosis-induced ligand. Furthermore, it contributes to the development of dendritic
cells and promotes inflammatory macrophage
polarization and Th1Th17 responses. In RA,
SLE, PBC, UC and Sjogrens syndrome (SS), IRF5TNPO3 is a susceptibility locus [34]. Similarly, BTB
and CNC homolog 2 (BACH2) is a transcription
repressor that belongs to the basic-region leucine
zipper family and binds to Maf recognition elements (MAREs). It has critical roles in both
acquired and innate immunity, including
immunoglobulin class-switch recombination [35],
somatic hypermutation of immunoglobulin-encoding genes, the pre-B-cell antigen receptor (pre-BCR)
checkpoint, development of B cells [36] and effector
and regulatory T cells [37], and the activation of
tissue macrophages. BACH2 has been identified as
a key regulator controlling the balance between
tolerance and immunity and is associated with loss
of tolerance in AITD [38], CeD [39], T1D [40],
Crohns disease [41], MS [42] and vitiligo [43].
Other loci that are shared by several autoimmune
diseases include TNFRSF14, IL-12RB2, pseudouridylate synthase 10 (PUS10), signal transducer and activator of transcription 4 (STAT4),
cytotoxic T lymphocyte-associated protein 4
(CTLA4), CD80, IL-12B, thymocyte selection associated (THEMIS), chemokine C-C motif receptor 6
(CCR6), RNA-binding motif protein 17 (RBM17),
RAD51B, suppressor of cytokine signalling 1
(SOCS1), IKAROS family zinc finger 3 (IKZF3),
tyrosine kinase 2 (TYK2), intercellular adhesion
molecule 3 (ICAM3), runt-related transcription factor 1 (RUNX1) and mitogen-activated protein kinase
1 (MAPK1). The presence of these loci supports the
optimistic hypothesis that one cure for many
diseases may be possible [44].
The concordance rate of autoimmune disease in
monozygotic twins ranges from 12% to 67% [45],
suggesting that factors other than genetic susceptibility may coexist. Clearly, there are requirements
for environmental interactions, which are discussed
below. However, there is increasing focus on the
likelihood that autoimmunity is at least partially
modulated by epigenetic mechanisms, including
DNA methylation. Numerous examples of epigenetic
changes in DNA have been associated with loss of
tolerance, including insulin DNA hypermethylation
in T1D [46], hypomethylation of peptidylarginine
deaminase 2 (PAD2) [47] and Src homology region 2
domain-containing phosphatase-1 (SHP-1) [48] in
MS, methylation of the CD40L promoter in PBC [49],
377
L. Wang et al.
histone modification (global acetylation of histones

H3 and H4) in active CD4 T cells in SLE [50], histone
deacetylase (HDAC) inhibitors in RA [51], acetylation of histone H4 in aquaporin 5 (AQP5) gene
promoter in SS [52] and microRNA (e.g. miR-21)
signalling in T1D, MS, SLE, SS, UC and psoriasis
[5355]. Epigenetic or stochastic events may
become a critical bridge in understanding genetic
and environmental interactions that lead to autoimmunity; this emerging concept will require considerable research effort, in particular with regard to
mechanisms of action [56].
The environmental influence of autoimmunity
The identification of specific environmental factors
has critical importance for understanding individual susceptibility, but there are very few agents
that clearly have a role and identification of generic
risk factors remains elusive. These environmental
factors include nutrition, the microbiota, infectious
processes and xenobiotics, such as tobacco smoke,
pharmaceutical agents, hormones, ultraviolet
light, silica solvents, heavy metals, vaccines and
collagen/silicone implants [5759].
Infectious agents have long been the most wellstudied environmental factors [60]. The best example of a relation between infection and immunity is
acute rheumatic fever, which occurs following
exposure in genetically susceptible hosts to Streptococcus pyogenes [61]. The mechanism of autoimmunity in acute rheumatic fever is thought to be
molecular mimicry between the bacterial M protein and human lysoganglioside that leads to loss
of immunological tolerance and the development of
cardiac reactive T cells [62]. The term molecular
mimicry was first coined by Damian in 1964, who
suggested that selected antigenic determinants of
microorganisms could potentially resemble host
epitopes and were therefore capable of eliciting an
autoimmune response [63, 64]. Multiple examples
of molecular mimicry in infectious agents have
been identified, but it is not always clear whether
or not such mimicry is clinically significant. However, it should be noted that similarities have been
reported between the EpsteinBarr virus (EBV)
peptide PPPGRRP and the PPPGMRPP peptide of
Sm in EBV-infected SLE patients [65]; similarly,
sequence homology between myelin basic protein
and HHV6-encoded U24, and cross-reactive T cells
have been reported in patients with MS [66], and
nine Helicobacter pylori proteins, each harbouring
a T-cell epitope, cross-reactive with the gastric H+,
378
K+-ATPase a chain have been found in human

gastric autoimmunity [67].
Any discussion of molecular mimicry and loss of
tolerance must also include the concept of epitope
spreading, that is a diversification of epitope specificity from a dominant epitope to subdominant
(cryptic) epitopes [68]. The switch from dominant
to cryptic epitopes begins with the initial mimicry to
the dominant epitope, followed by protein processing and antigen presentation, resulting in responses
directed at neo-epitopes [69]. Epitope spreading in
autoimmunity was first noted in experimental
autoimmune encephalomyelitis (induced by priming mice with myelin antigens), stimulating the
production/expression of myelin basic protein, proteolipid protein, myelin oligodendrocyte glycoprotein and myelin peptides [70]. A number of other
mechanisms have been proposed, including bystander activation [71], viral persistence and polyclonal
activation, which have the potential to induce/
modulate
postinfection
autoimmunity
[72]
(Table 3). Although there is no direct evidence that
it fulfils Kochs postulates, EBV has been reported to
be a cofactor in numerous autoimmune diseases,
including SLE, SS, RA [73], MS [74] and PBC [75].
The majority of such studies are difficult to interpret,
and it is possible that EBV serves as a generic
polyclonal activator that amplifies underlying
autoimmunity.
Numerous other infectious agents have been suggested but not proved to have a role, including
bacteria (Gram negative and positive), other viruses
(herpes simplex virus, mouse mammary tumour
virus and cytomegalovirus), parasites (trypanosomes and Ascaridia galli) and fungi (Saccharomyces cerevisiae) [2, 76]. Perhaps more important
than the presence of specific agents is the suggestion
that predisposition to autoimmunity may be influenced by the microflora. This concept has been
termed the hygiene hypothesis and was first suggested by Strachan in 1989 [77]. It was suggested
that the increase in autoimmune diseases observed
in the Western world was due in part to a decline in
infectious disease exposure and subsequent
improved hygiene. This hypothesis applies to almost
all autoimmune diseases and has become particularly attractive in T1D and in inflammatory bowel
disease. Early supporting evidence was based on
retrospective epidemiological studies [72].
The relationships between the microbiota, host
immune responses and autoimmunity have
L. Wang et al.
Table 3 Proposed mechanisms for infection-related autoimmunity

Mechanisms
Infections
Diseases
References
Molecular mimicry: Sequence
Streptococcus pyogenes
Acute rheumatic
[61]
similarities between
pathogen-derived peptides
and self-peptides
(bacterial M protein)
fever (ARF)
Escherichia coli (PDC-
PBC
[2]
Gastric autoimmunity,
[67]
E2212226, PDC-E2212226), Pseudomonas

aeruginosa (PDC-E2159167)
Helicobacter pylori (H+,
K -ATPase a chain)
+
SS, PBC
EBV (PPPGRRP peptide)
SLE,
[65]
HHV6 (U24)
MS
[66]
Cytomegalovirus;
T1D
[216218]
AIH (type 2)
[219]
SLE, MS, RA
[220222]
SLE
[223]
Measles virus
MS
[224],
EBV
MS
[217]
EBV
MS, SLE, RA, SS, PBC, MS
[7375]
Enterovirus
T1D
[225]
Enteroviruses;
Rotavirus
Epitope spreading: Changes
from primary epitope
to other epitopes
HCV (polypeptide
precursor)
EBV (EpsteinBarr virus
nuclear antigen-1)
Cytomegalovirus
infection
Bystander activation:
Activation of pre-existing
autoreactive immune cells
Viral persistence and
polyclonal activation:
Constant presence of viral
antigen driving the immune
response or epitope spreading
PDC-E2, the E2 subunit of the pyruvate dehydrogenase complex; EBV, EpsteinBarr virus; HHV6, human herpes virus 6;
ARF, acute rheumatic fever.
become a subject of intense interest, particularly

as microbes are located at the hostenvironment
interface, for example the skin, gastrointestinal
tract, genital tract and respiratory mucosal barrier.
With improved methods, including sophisticated
sequencing and high-throughput technology, it
has been demonstrated that changes in the microbiota even in normal hosts are pivotal to normal
immune development and homoeostasis. Of interest, available data suggest that changes in the gut
microbiome precede the onset of T1D and are also
associated with the progression of disease [78].
From a microbiological perspective, changes in
Firmicutes [79, 80] and Bacteroidetes [81, 82] in
the upper small bowel mucosal and faecal flora
have been detected particularly in coeliac disease.
Interestingly, in RA, the oral (Porphyromonas gin-
givalis [83] and Prevotella nigrescens [84]) and

intestinal (Bacteroidetes and Bifidobacterium) [85,
86] microbiota have been correlated with the onset
and course of disease. Recent data have demonstrated that changes in the colonization of
segmented filamentous bacteria influence autoimmunity even into adult life [87] (Fig. 4).
The best example of the importance of noninfectious environmental agents is the relationship
between gluten ingestion and CeD [88]. However,
perhaps of more interest is the appearance of
autoimmune diseases following exposure to many
common pharmaceutical agents, for example the
many drugs that induce lupus. This subject has
been extensively reviewed elsewhere, but it should
be emphasized that such lupus-like syndromes
379
L. Wang et al.
Fig. 4 Environmental factors

in autoimmunity. Multiple
environmental factors have
been implicated in the
development of autoimmunity.
Molecular mimicry is the most
common mechanism that
activates autoreactive T and B
cells. Epitope spreading is a
mechanism that results in
generation of multiple neoepitopes. In addition, by
modulating innate and
adaptive immunity, the
microbiota and nutrition (e.g.
vitamin D, iodine and gluten)
may also contribute to loss of
tolerance.
become reversible when drugs are discontinued.

However, there remains the possibility that the
autoimmune disease may persist in some patients
and it is very difficult if not impossible to identify a
specific trigger in such individuals by epidemiological analysis. There is, however, considerable data
to suggest that chemical modifications can lead to
loss of tolerance in two other diseases. First, in
PBC, modification of mitochondrial antigens by
food additives, in particular 2-octynoic acid, may
lead to the development of the hallmark antimitochondrial antibodies [16]. Secondly, higher consumption of dietary iodine increases the incidence
and severity of AITD. Iodine incorporation in thyroglobulin augments the antigenicity of this molecule by increasing the affinity of its determinants
for the T-cell receptor or the MHC-presenting
molecule [89]. A list of other suggested noninfectious agents and their mechanisms of action is
presented in Table 4. Patients often inquire about
the risks of vaccination. Vaccination is a longestablished and extremely important public health
measure, and fortunately, side effects are rare.
However, for genetically predisposed individuals,
there are rare instances of autoimmune reactions
and autoimmune disease that have been precipitated by vaccines, likely via the mechanisms of
molecular mimicry. This should not, however,
prevent the use of vaccination [90]. Less well
known is whether vaccination can exacerbate
autoimmune disease and our recommendations
are to avoid vaccination during an active phase of
autoimmunity.
380
Of interest to the clinician is the relationship

between vitamin D levels and the immune response.
It has long been known that vitamin D is a natural
immune modulator [91], in addition to its role in
modulation of calcium metabolism, cellular growth,
proliferation and apoptosis [92]. Epidemiological
studies have demonstrated that reduced levels of
vitamin D lead to an increased risk for loss of
tolerance. In fact, reduced levels of vitamin D have
now been demonstrated in multiple human autoimmune diseases [93]. With the large number of
individuals living in large cities, and often indoors
with insufficient sunlight exposure, this deficiency
may be prevented by vitamin D supplementation.
Once again, more studies are needed.
Smoking is by far the most well-recognized risk
factor for RA [94] as well as for SLE [95]. It might
contribute to disease development via several
pathways. Cigarette smoke contains several TLRstimulating compounds, including lipopolysaccharide (a TLR4 agonist), which can elicit an innate
immune response. By interacting with the HLA
haplotype [96] and changing gene expression in the
joint [97], smoking may promote the development
of RA. It has also been reported that other autoimmune diseases, including PBC, SS and AITD, are
associated with tobacco smoke [98].
Environmental factors have also been found to
induce changes in apoptosis [99]. Autoantigens
have been demonstrated within apoptotic bodies
and apoptotic cells and appear critical for the
L. Wang et al.
Table 4 Noninfectious agents and autoimmunity

Agent
Mechanisms
Diseases
References
Vitamin D
1) Participate in cellular growth,
SLE, RA, SS, MS, CD, CeD,
[93]
proliferation, apoptosis
T1D, PBC, others
2) Modulate innate (DC, macrophage)

and adaptive responses
(Th1, Th2, Th17, B cells)
Smoke
1) Activate DC-mediated adaptive immunity
SLE, RA, PBC, SS, AITD
[98]
SLE, RA, MS, T1D
[226228]
Autoimmune thyroid
[89]
Most of the ADs (SLE, MS, RA)
[229, 230]
SEL, PBC, T1D, CeD, AIH
[100, 102, 104107]
SLE, RA, MS, AIH, PBC
[90]
SLE, AIH, RA, SS
[227, 231]
2) Increase circulating T lymphocytes

3) Augment autoreactive B cells
4) Exposure and release of autoantibodies
Ultraviolet
light
1) Oxidative damage to DNA and RNA

2) Induce apoptotic and necrotic cell death
3) Promote the release of TLR7
and TLR9 ligands
Iodine
1 Increase the affinity of its determinants

for the T-cell receptor or the
MHC-presenting molecule
Hormones
1) Influence both innate and adaptive

immune responses
2) Affect signal pathway: HoxC4,
activation-induced deaminase,
miR-155, or miR-181b
Apoptosis
1) Presentation of antigens
2) Activate innate immunity
3) Regulate macrophage cytokine secretion
Vaccines
1) Stimulate the immune system via

pattern recognition receptors, such as
TLRs, increase the risk of initiation
or progression of ADs
Heavy metals
1) Deregulate balance of Th1 and Th2,

and enhance the production of
antibodies to self-antigens
2) Change the cytokine network
3) Augmentation of T- and B-cell response
AD, autoimmune disease; DC, dendritic cell; Th, T helper cell; TLR, Toll-like receptor; MHC, major histocompatibility
complex; miR, microRNA.
presentation of antigens, activation of innate

immunity and regulation of macrophage cytokine
secretion [100]. A classical experimental model
that illustrates these principles is lymphoproliferation (Lpr) and generalized lymphoproliferative
disease (gld), in which mice develop an autoimmune disease that resembles human SLE [101]. In
humans, defects in apoptosis have been reported
in SLE [102, 103], PBC [104], T1D [105], CeD [106]

and autoimmune hepatitis [107].
Mechanisms of tissue destruction
Tissue destruction can be divided into a variety of
effector pathways depending on the autoimmune
disease. Of note, the immune system is promiscu 2015 The Association for the Publication of the Journal of Internal Medicine
381
L. Wang et al.
ous and there is often an orchestrated response

that involves a multitude of diverse cell populations. This has made treatment of some diseases,
such as SLE and SS, very difficult. The effector
mechanisms for a number of autoimmune diseases
are illustrated in Fig. 5.
The presence of autoantibodies is a common
feature of autoimmune diseases [108], and a
large number of serum antibodies are directed
against functional structures of the cell (nucleic
acids, nuclear molecules, receptors or other functional cell components). They not only play a
central role in diagnosis and classification, but
may also be involved in tissue damage. One of the
best-established pathogenic effects of autoantibodies is the cytotoxic destruction of cells by cell
surface binding and lysis. In this process, com-
plement activation and/or antibody-dependent

cell-mediated cytotoxicity (ADCC) are the most
common pathways of destruction [109]. Classical
ADCC is mediated by natural killer cells that
carry the receptor for the Fc portion of IgG;
binding stimulates the release of hydrogen peroxide and hydroxyl radicals. Other cells, that is
monocytes and eosinophils, can also mediate
ADCC. ADCC is a known mechanism in AITD
mediated by antithyroperoxidase antibodies [110].
Immune complex-mediated damage is another
important pathogenic mechanism; SLE is a typical example of damage by immune complex. In
RA, rheumatoid factor-IgG complexes are also a
component of synovial damage. Autoantibodies
may also interact with cell surface receptors,
which can both activate (antithyroid-stimulating
hormone for Graves disease) and block selective
Fig. 5 Autoimmunity is a result of a multi-orchestrated immune response. (1) Through molecular mimicry, xenobiotics and
antigens are recognized by antigen-presenting cells (APCs), which subsequently activate innate immune cells, that is
dendritic cells (DCs), macrophages and natural killer cells (NKs). (2) T-cell immunogenic peptides are generated by APCs and
are presented to uncommitted T helper (Th0) lymphocytes, which then differentiate into Th2, T follicular helper (Tfh), Th17,
Th1 and T regulatory cells (Tregs). (3) Th2 and Tfh cells facilitate B-cell activation, maturation and differentiation into
plasma cells and ultimately autoantibody production. Through different mechanisms, autoantibodies may mediate tissue
damage. (4) Th1 cells stimulate development of cytotoxic T lymphocytes. By secretion of cytotoxic granules, activation of
FasFas ligand or release of cytokines, autoreactive cytotoxic T lymphocytes (CTLs) cause tissue injury. (5) Increased Th17
has also been reported to correlate with the progression of autoimmunity. (6) Decreased Tregs, which negatively regulate
innate and adaptive immunity, facilitate loss of tolerance in several autoimmune diseases, including systemic lupus
erythematosus (SLE), multiple sclerosis (MS), type 1 diabetes (T1D), rheumatoid arthritis (RA), autoimmune thyroid disease
(AITD), psoriasis, inflammatory bowel disease (IBD), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC)
and autoimmune hepatitis (AIH).
382
L. Wang et al.
pathways (anti-acetylcholine receptor for myasthenia gravis). Another mechanism includes binding to extracellular molecules (such as in the
antiphospholipid antibody syndrome) where
autoantibodies are directed against b2-glycoprotein I in plasma [111].
Unlike autoantibodies, relevant (disease-associated) autoreactive T cells [112] act on the target
tissue and circulate only at very low precursor
levels. In other words, the autoreactive T-cell
precursor level in the target tissue is much higher,
often more than 100-fold in the target organ, than
in the peripheral blood. Autoreactive cytotoxic T
lymphocytes (CTL) recognize a target cell by binding the T-cell receptor (TCR) to the appropriate
combination of MHC I and autoantigen-derived
peptides. Then, a complex of MHC I and autoantigen-derived peptides directly kills target cells
through different mechanisms: (i) secretion of
cytotoxic granules (perforin and granzyme B)
resulting in disintegration of the cell membrane
and induced apoptosis; (ii) activation of FasFas
ligand, which induces apoptosis; and (iii) release of
cytokines (such as TNF-a and interferon-c), leading
to tissue injury [113]. The paradigm of Th1/Th2

balance has shifted due to the increasing body of
information on other CD4 subsets, including Th17
[114], Tregs [115] and T follicular helper cells (Tfh)
[116].
PBC: a model autoimmune disease
Autoimmune disorders are a spectrum of diseases
ranging from those that are organ specific, in which
antibodies and T cells react to self-antigens localized in a specific tissue, to organ-non-specific or
systemic diseases characterized by reactivity
against antigens spread throughout various tissues (Fig. 6). Numerous classifications have been
proposed for autoimmune diseases, even for the
same autoimmune disease, and these generally
depend upon clinical features, serology and
histopathology (Table 5). The diagnostic and clinical classifications of a variety of autoimmune
diseases have been reviewed recently [117131].
However, with the development of proteomic,
genomic and metabolomics, far more sensitive
and specific methodologies will be developed in
the future (Fig. 7).
Fig. 6 Representative organspecific and systemic

383
384
Crohns disease
Graves disease
cholangitis
Primary sclerosing
hepatitis
Autoimmune
cirrhosis
Primary biliary
Type 1 diabetes
Myelin protein, (MBP,
Multiple sclerosis
Autoantibodies
isoform 5?
cerevisiae, Tubulin-b
Desmin, saccharomyces
transporter
TSHR, sodium iodide
Tubulin-b isoform 5
Anti-TG2, antigliadin
autoantibodies
Anti-TSHR
antibody
anticardiolipin
antibody,
endothelial cell
ANA, anti-SM, anti-
cytoplasmic antibody,
tract
Gastrointestinal
Thyroid
pyloric gland metaplasia
intra-epithelial lymphocytes,
crypt injury), increased
granulomas (not related to
transmural inflammation,
crypt architectural irregularity,
chronic inflammation, focal
Focal (discontinuous)
Thyroid follicles
Ludwigs stage IIV
Typical onion-skinning lesions
necroinflammatory infiltrate
Bile ducts
with a predominantly
perseptal) hepatitis
Interface (periportal or
Ludwigs stage IIV
cells into the islets (insulitis)
infiltration of mononuclear
Decreased b cell mass with
in the brain matter
lymphoplasmacytic
Antineutrophil
Liver
bile ducts
intrahepatic
medium-sized
Small- and
Pancreas b-islets
system
Pathology (or biopsy)

Freshly demyelinated plaques
(CYP2D6), F-actin
antibody, anti-actin
asialoglycoprotein receptor,
Target organ
Central nervous
cytochrome P4502D6
antismooth muscle
ANA, anti-LKM-1,
AMA
ZnT8A
IAA, GADA, IA-2A,
diagnostic specificity)
myelin protein (lack
Antibodies against
ribonucleoproteins,
Chromatin,
Mitochondrial (PDC-E2)
IA-2 (ICA512), insulin
(GAD-65), insulin receptor,
Glutamate decarboxylase
MOG, PLP, MAG, lipids)
Known antigen
Disease
Table 5 Diagnosis of organ-specific and organ-non-specific autoimmune disease (for some classical autoimmune diseases)
Diagnostic criteria
criteria [239]
2010 diagnostic
criteria [238]
2010 diagnostic
criteria [237]
2010 diagnostic
[236] criteria
1999 [235] and 2008
criteria [234]
2009 diagnostic
criteria [233]
2010 diagnostic
criteria [232]
McDonald diagnostic
Revised 2010
L. Wang et al.
lacrimal glands
antibody
(95, 97, 160, 180), C1q,
CCP, collagen, fibronectin
Rheumatoid factor, keratin,

Carp
RF-IgG, ACPA, anti-
Anti-CCP
kidneys, and
antiphospholipid
(RNP), fibronectin, golgin
synovium of joints
nervous system)
blood vessels, liver,
anti-Sm,
polymerase IIII
histone H2A-H2B-DNA
joints, skin, lungs,
Several organs (heart,
anti-dsDNA antibody,
Antinuclear antibody,
II, collagen, RNA
Cardiolipin, carbonic anhydrase
Pathological changes in synovium
Nephritis compatible with lupus
salivary and lacrimal glands
lymphoepithelial lesions in
(Lymphocytic sialadenitis),
the active phase)
cells, and macrophages, during
(containing lymphocytes, plasma
infiltrate in adrenal glands
Widespread mononuclear cell
crypt hyperplasia, villous atrophy
Intra-epithelial lymphocytosis,
goblet cells
reduction of mucus-secreting
Diagnostic criteria
criteria [245]
2010 ACR/EULAR
criteria [168, 244]
classification
2012 new SLICC
criteria [242, 243]
ACR/SICCA
2012 revised
2014 criteria [163]
criteria [88, 241]
1990 revised ESPGAN
criteria [240]
2008 diagnostic
ACR/SICCA, American College of Rheumatology/Sj

ogrens International Collaborative Clinical Alliance; SLICC, Systemic Lupus International
Collaborating Clinic; EULAR, European League Against Rheumatism.
Rheumatoid arthritis
erythematosus
Systemic lupus
mainly salivary and
nervous system),
Ro60/TROVE2, La/SSB
(e.g. lungs, liver,
Several organs
Adrenal glands
kidneys, central
SSB, ANA
Anti-Ro/SSA, anti-La/
ACA
antibodies
transglutaminase
antitissue
antibodies and
Ro52/TRIM21,
golgin (95, 97, 160, 180)
La phosphoprotein (La 55-B),
Sjogrens
syndrome
21-hydroxylase (CYP21)
Tissue transglutaminase
Small intestine
Pathology (or biopsy)

Diffuse inflammatory cell infiltration
plasmacytosis, crypt architecture,
Endomysial IgA
Target organ
Colon
of the mucosa with basal
Addisons disease
disease
Coeliac
Autoantibodies
ANCA, GAB
isoform 5?
Desmin, saccharomyces
Ulcerative colitis
cerevisiae, tubulin-b
Known antigen
Disease
L. Wang et al.
385
L. Wang et al.
Fig. 7 Diagnostic platform for

PBC has long been considered a model example of

human autoimmunity because of its serological
hallmarks (antimitochondrial antibodies), specific
pathology within small and medium intrahepatic
bile ducts, the female predominance and the similarity of clinical outcomes across multiple regions
and ethnic groups [56, 132, 133]. As such, PBC will
be discussed here because it reflects a number of
similarities with both organ-specific and organnon-specific autoimmune diseases. First, as with
other autoimmune diseases, there are specific
diagnostic criteria based upon (i) biochemical evidence of cholestasis, that is alkaline phosphatase
elevation; (ii) the presence of the signature antimitochondrial antibodies; and (iii) histological
evidence of nonsuppurative destructive cholangitis
and destruction of interlobular bile ducts. Secondly, there is considerable recent evidence to
show that PBC also displays features that are
generically similar to those of other human autoimmune diseases. For example, the hallmark serological
feature
of
PBC,
antimitochondrial
antibodies (AMA), can be detected in asymptomatic
patients and are often found in serum samples for
many years before clinical onset [134]. There is also
evidence that autoantibodies precede the onset of
clinical disease in RA [135], MS and T1D [136]. In
addition, the effector mechanisms that lead to the
biliary duct cytotoxicity appear to be promiscuous
and involve multiple autoreactive adaptor path386
ways as well as the key elements of innate immunity and bystander-induced inflammation [137].
Once again, as noted previously, this is similar to
other autoimmune diseases in which multiple
cytopathic pathways are involved [138]. Thirdly,
highly specific autoantigen-specific autoreactive
CD4 and CD8 cells are present within the liver
and regional lymph nodes of affected patients but,
interestingly, levels of such cells in peripheral
blood are much lower than in liver [139]. Indeed,
there is a 100- to 150-fold increase in the number
of PDC-E2-specific CD4 T cells in the hilar lymph
nodes and liver compared with the peripheral blood
in patients with PBC [140]. Again, this is similar to
other autoimmune diseases in which the frequency
of autoreactive cells is significantly higher in the
target tissue than the blood. This is of particular
importance because it means that mechanistic
studies must depend on obtaining target tissue,
therefore often requiring invasive technology.
Fourthly, it should be noted that PBC is a good
example for understanding the importance of
genetic and environmental interactions. The incidence of PBC in identical twins is approximately
60% and, importantly, a number of environmental
factors have been implicated in its pathogenesis
[141]. Fifthly, although there are multiple mouse
models of PBC, as with the many experimental
models of SLE, they do not faithfully represent the
disease and so far have proven inadequate for the
L. Wang et al.
Table 6 Agents used to treat autoimmunity

Agents
Treatment effect
Side effects
References
Glucocorticoid (cortisone,
Suppress the whole activated
1) Increase the rates
[246248]
prednisone, budesonide)
immune system (most ADs)
of infections
2) Osteoporosis
3) General toxicity
4) Hormone-induced
drug addiction
Mycophenolate mofetil
Immunosuppressive agent;
1) Adverse effects (gastrointestinal
PMID: 24505016;
inosine monophosphate
or hematopoietic system, such
21720247;
dehydrogenase inhibitor,
as diarrhoea, nausea, vomiting,
21780898;
which exerts antiproliferative
leukopenia, anaemia)
19834629
and pro-apoptotic effects,
2) Increased risk of developing
particularly on activated T
lymphoma and other
cells, and suppresses
malignancies (particularly skin)
antibody formation by B
3) Increased risk of serious
cells (SLE, MS, AIH, etc.).
infections
4) Foetal harm
Methotrexate
Directly inhibits the
1) Predisposition to infection
metabolism of folic acid,
2) Pulmonary fibrosis
which will inhibit T-cell
3) Hair loss
activation, selectively
4) Nausea
downregulate B-cell function
5) Headache
(RA, SLE, psoriasis, IBD,
6) Skin pigmentation
[249]
PBC, etc.)
Belimumab
Binds to soluble B cell activation
1) Adverse events
[250]
factor from the TNF
(infection, neoplasm)
family ( BAFF) and
2) Infusion reactions
inhibits its binding to
3) Hypersensitivity reactions
receptors, which will deplete

activated and naive B cells
and plasma cells but not
memory B cells (only
approved for SLE, still in
clinical trials for other ADs)
CTLA4-immunoglobulin
(abatacept, RG2077)
Inhibits T-cell activation (only
1) Adverse events
PMID: 14614165;
approved for RA, still in
(infection, malignancies)
clinical trials for other ADs)
2) Acute infusion events
23800448
3) Autoimmunity
(psoriasis, vasculitis)
Azathioprine (purine
analogues)
Inhibits synthesis of DNA (SLE,
1) Increase risk of malignancy
CD, MS, PBC, myasthenia
2) Bone marrow suppression
gravis, AIH, etc.)
3) Nausea and vomiting
[251254]
387
L. Wang et al.
development of novel therapeutic agents. At present, ursodeoxycholic acid is the only agent
approved to treat PBC; the mechanism of action
is not entirely understood, but it may reduce the
bystander inflammatory response. Liver transplantation is the final option for patients with end-stage
disease and, importantly, PBC may recur following
transplantation despite the absence of MHC
matching [142]. Finally, as with many other
autoimmune diseases, there is considerable ongoing research to identify specific activation pathways, the blockade of which might reduce the
inflammatory and therefore cytopathic response.
New approaches to therapy
The new paradigm in the treatment of autoimmune
diseases is the use of biological agents that modify
specific inflammatory and/or effector pathways.
The agents that block TNF-a were the first drugs
approved and since then drugs have been developed
not only for the treatment of RA, but also for SLE,
psoriasis, psoriatic arthritis, inflammatory bowel
disease, MS and many others. It is beyond the scope
of this review to discuss the individual agents (see
Table 6 for a list of the more commonly used agents
and their side effects). It is clear that the goal for
treating patients with autoimmunity is a specific
agent that will completely reverse if not cure the
disease. At present, this does not exist for any
autoimmune disease. By contrast, it is hoped that it
would also be possible to modify the host immune
system to restore tolerance. Although this is possible in selected mouse models of autoimmunity, it
has not proven effective as yet in humans despite
many attempts using immunotherapy, including
stem cell therapies. However, our understanding of
human autoimmune disease has and continues to
be developed through a huge number of molecular
studies investigating not only genetic factors, but
also the role of epigenetics [143], the environment,
infection and the microbiota. In addition, there have
Agents
Treatment effect
Side effects
References
TNF inhibitors (infliximab,
Treat various inflammatory
1) Infusion reactions
[255]
etanercept, adalimumab,
conditions within the main
(acute and delayed)
certolizumab, golimumab)
categories of systemic
2) Infections
rheumatic
3) Malignancies
disease and IBD

IL-6 inhibitor (tocilizumab)
Blocks the signal pathway
4) Neurological disorders
1) Infection
of IL-6 (only approved for RA,
2) Gastrointestinal complaints
still in clinical trials for
3) Rash
other ADs)
4) Headache
[256]
5) Biochemical abnormalities
Ustekinumab
Blocks the signal pathway

of IL-12
1) Increased incidence of
[257]
nonmelanoma skin cancer

2) Headache
3) Back pain
Anti-CD20 antibody
Selective B-cell depletion
(rituximab)
1) Infusion reaction
[258, 259]
2) Infections (progressive
multifocal leukoencephalopathy,
Hepatitis B virus (HBV),
tuberculosis)
3) Hypogammaglobulinemia
4) Herpes zoster reactivation
AD, autoimmune disease; TNF, tumour necrosis factor; CD, Crohns disease; AIH, autoimmune hepatitis; RA, rheumatoid
arthritis; SLE, systemic lupus erythematosus; MS, multiple sclerosis; PBC, primary biliary cirrhosis; IBD, inflammatory
bowel disease.
388
L. Wang et al.
been improvements in laboratory testing methods,

including standardization of serology and development of new autoantibody tests. Further, improved
understanding of geoepidemiology has led to a
much better appreciation of what is happening to
individual patients during a breach of tolerance.
Autoimmunity is a challenge for all clinicians;
nevertheless, the prognosis for patients with these
diseases has dramatically improved in the past
decade and we anticipate further improvements in
the future.
Conflict of interest statement
No conflicts of interest to declare.
Acknowledgements
This work was supported by the National Natural
Science Foundation of China, grant 81470837, and
National Institutes of Health grant DK39588. We
thank Lei Jin and all other persons who contributed to this work
References
1 Yu C, Gershwin ME, Chang C. Diagnostic criteria for
systemic lupus erythematosus: a critical review. J Autoimmun 2014; 4849: 103.
2 Wang L, Wang FS, Chang C, Gershwin ME. Breach of
tolerance: primary biliary cirrhosis. Semin Liver Dis 2014;
34: 297317.
3 Silverstein AM. Paul Ehrlich, archives and the history of
immunology. Nat Immunol 2005; 6: 639.
4 Rose NR, Witebsky E. Studies on organ specificity. V.
Changes in the thyroid glands of rabbits following active
immunization with rabbit thyroid extracts. J Immunol 1956;
76: 41727.
5 Salinas GF, Braza F, Brouard S, Tak PP, Baeten D. The
role of B lymphocytes in the progression from autoimmunity to autoimmune disease. Clin Immunol 2013; 146: 34
45.
6 Hang LM, Nakamura RM. Current concepts and advances in
clinical laboratory testing for autoimmune diseases. Crit Rev
Clin Lab Sci 1997; 34: 275311.
7 Avrameas S, Selmi C. Natural autoantibodies in the physiology and pathophysiology of the immune system. J Autoimmun 2013; 41: 469.
8 Panda S, Ding JL. Natural antibodies bridge innate and
adaptive immunity. J Immunol 2015; 194: 1320.
9 Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol
Immunopathol 1997; 84: 22343.
10 Eaton WW, Rose NR, Kalaydjian A, Pedersen MG, Mortensen
PB. Epidemiology of autoimmune diseases in Denmark. J
Autoimmun 2007; 29: 19.
11 Wahren-Herlenius M, Dorner T. Immunopathogenic mechanisms of systemic autoimmune disease. Lancet 2013; 382:
81931.
12 Milo R, Kahana E. Multiple sclerosis: geoepidemiology,
genetics and the environment. Autoimmun Rev 2010; 9:
A38794.
13 West J, Fleming KM, Tata LJ, Card TR, Crooks CJ. Incidence
and prevalence of celiac disease and dermatitis herpetiformis in the UK over two decades: population-based study.
Am J Gastroenterol 2014; 109: 75768.
14 Rees F, Doherty M, Grainge M, Davenport G, Lanyon P,
Zhang W. The incidence and prevalence of systemic lupus
erythematosus in the UK, 19992012. Ann Rheum Dis 2014;
doi: 10.1136/annrheumdis-2014-206334.
15 Cross M, Smith E, Hoy D et al. The global burden of
rheumatoid arthritis: estimates from the global burden of
disease 2010 study. Ann Rheum Dis 2014; 73: 131622.
16 Leung PS, Wang J, Naiyanetr P et al. Environment and
primary biliary cirrhosis: electrophilic drugs and the induction of AMA. J Autoimmun 2013; 41: 7986.
17 Ulmanen I, Halonen M, Ilmarinen T, Peltonen L. Monogenic
autoimmune diseases lessons of self-tolerance. Curr Opin
Immunol 2005; 17: 60915.
18 Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical
variation of autoimmune polyendocrinopathy-candidiasisectodermal dystrophy (APECED) in a series of 68 patients. N
Engl J Med 1990; 322: 182936.
19 Barrera MJ, Bahamondes V, Sepulveda D et al. Sjogrens
syndrome and the epithelial target: a comprehensive review.
J Autoimmun 2013; 42: 718.
20 Endo T, Kobayashi T. Immunization of mice with a newly
identified thyroid-stimulating hormone receptor splice variant induces Graves-like disease. J Autoimmun 2013; 43:
1825.
21 Nagamine K, Peterson P, Scott HS et al. Positional cloning of
the APECED gene. Nat Genet 1997; 17: 3938.
22 Le Deist F, Emile JF, Rieux-Laucat F et al. Clinical,
immunological, and pathological consequences of Fas-deficient conditions. Lancet 1996; 348: 71923.
23 Shah S, Wu E, Rao VK, Tarrant TK. Autoimmune lymphoproliferative syndrome: an update and review of the literature. Curr Allergy Asthma Rep 2014; 14: 462.
24 Gambineri E, Torgerson TR, Ochs HD. Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked inheritance (IPEX), a syndrome of systemic autoimmunity caused
by mutations of FOXP3, a critical regulator of T-cell homeostasis. Curr Opin Rheumatol 2003; 15: 4305.
25 Sakaguchi
S.
Naturally
arising
Foxp3-expressing
CD25+CD4+ regulatory T cells in immunological tolerance
to self and non-self. Nat Immunol 2005; 6: 34552.
26 Sollid LM, Pos W, Wucherpfennig KW. Molecular mechanisms for contribution of MHC molecules to autoimmune
diseases. Curr Opin Immunol 2014; 31: 2430.
27 Cui Y, Sheng Y, Zhang X. Genetic susceptibility to SLE:
recent progress from GWAS. J Autoimmun 2013; 41: 2533.
28 Lu Q. The critical importance of epigenetics in autoimmunity. J Autoimmun 2013; 41: 15.
29 Hu X, Daly M. What have we learned from six years of GWAS
in autoimmune diseases, and what is next? Curr Opin
Immunol 2012; 24: 5715.
30 Deitiker P, Atassi MZ. Non-MHC genes linked to autoimmune disease. Crit Rev Immunol 2012; 32: 193285.
389
L. Wang et al.
31 Cho JH, Gregersen PK. Genomics and the multifactorial

nature of human autoimmune disease. N Engl J Med 2011;
365: 161223.
32 Stanford SM, Bottini N. PTPN22: the archetypal non-HLA
autoimmunity gene. Nat Rev Rheumatol 2014; 10: 60211.
33 Wiede F, Ziegler A, Zehn D, Tiganis T. PTPN2 restrains CD8
(+) T cell responses after antigen cross-presentation for the
maintenance of peripheral tolerance in mice. J Autoimmun
2014; 53: 10514.
34 Kottyan LC, Zoller EE, Bene J et al. The IRF5-TNPO3
association with systemic lupus erythematosus has two
components that other autoimmune disorders variably
share. Hum Mol Genet 2015; 24: 58296.
35 Muto A, Tashiro S, Nakajima O et al. The transcriptional
programme of antibody class switching involves the repressor Bach2. Nature 2004; 429: 56671.
36 Itoh-Nakadai A, Hikota R, Muto A et al. The transcription
repressors Bach2 and Bach1 promote B cell development by
repressing the myeloid program. Nat Immunol 2014; 15:
117180.
37 Roychoudhuri R, Hirahara K, Mousavi K et al. BACH2
represses effector programs to stabilize T(reg)-mediated
immune homeostasis. Nature 2013; 498: 50610.
38 Plagnol V, Howson JM, Smyth DJ et al. Genome-wide
association analysis of autoantibody positivity in type 1
diabetes cases. PLoS Genet 2011; 7: e1002216.
39 Dubois PC, Trynka G, Franke L et al. Multiple common
variants for celiac disease influencing immune gene expression. Nat Genet 2010; 42: 295302.
40 Cooper JD, Smyth DJ, Smiles AM et al. Meta-analysis of
genome-wide association study data identifies additional
type 1 diabetes risk loci. Nat Genet 2008; 40: 1399401.
41 Franke A, McGovern DP, Barrett JC et al. Genome-wide
meta-analysis increases to 71 the number of confirmed
Crohns disease susceptibility loci. Nat Genet 2010; 42:
111825.
42 International Multiple Sclerosis Genetics Consortium, Wellcome Trust Case Control Consortium 2, Sawcer S et al.
Genetic risk and a primary role for cell-mediated immune
mechanisms in multiple sclerosis. Nature 2011; 476: 214
9.
43 Jin Y, Birlea SA, Fain PR et al. Genome-wide association
analyses identify 13 new susceptibility loci for generalized
vitiligo. Nat Genet 2012; 44: 67680.
44 Zhernakova A, Withoff S, Wijmenga C. Clinical implications
of shared genetics and pathogenesis in autoimmune diseases. Nat Rev Endocrinol 2013; 9: 64659.
45 Quintero-Ronderos P, Montoya-Ortiz G. Epigenetics and
autoimmune diseases. Autoimmune Dis 2012; 2012:
593720.
46 Fradin D, Le Fur S, Mille C et al. Association of the CpG
methylation pattern of the proximal insulin gene promoter
with type 1 diabetes. PLoS ONE 2012; 7: e36278.
47 Calabrese R, Zampieri M, Mechelli R et al. Methylationdependent PAD2 upregulation in multiple sclerosis peripheral blood. Mult Scler 2012; 18: 299304.
48 Kumagai C, Kalman B, Middleton FA, Vyshkina T, Massa PT.
Increased promoter methylation of the immune regulatory
gene SHP-1 in leukocytes of multiple sclerosis subjects. J
Neuroimmunol 2012; 246: 517.
49 Lleo A, Liao J, Invernizzi P et al. Immunoglobulin M levels
inversely correlate with CD40 ligand promoter methylation
390
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
65
66
67
in patients with primary biliary cirrhosis. Hepatology 2012;

55: 15360.
Hu N, Qiu X, Luo Y et al. Abnormal histone modification
patterns in lupus CD4+ T cells. J Rheumatol 2008; 35: 804
10.
Young DA, Lakey RL, Pennington CJ et al. Histone deacetylase inhibitors modulate metalloproteinase gene expression
in chondrocytes and block cartilage resorption. Arthritis Res
Ther 2005; 7: R50312.
Yamamura Y, Motegi K, Kani K et al. TNF-alpha inhibits
aquaporin 5 expression in human salivary gland acinar cells
via suppression of histone H4 acetylation. J Cell Mol Med
2012; 16: 176675.
Xu WD, Pan HF, Li JH, Ye DQ. MicroRNA-21 with therapeutic potential in autoimmune diseases. Expert Opin Ther
Targets 2013; 17: 65965.
Qu Z, Li W, Fu B. MicroRNAs in autoimmune diseases.
Biomed Res Int 2014; 2014: 527895.
Pauley KM, Cha S, Chan EK. MicroRNA in autoimmunity
and autoimmune diseases. J Autoimmun 2009; 32: 18994.
Wang Z, Zheng Y, Hou C et al. DNA methylation impairs
TLR9 induced Foxp3 expression by attenuating IRF-7 binding activity in fulminant type 1 diabetes. J Autoimmun 2013;
41: 509.
Colafrancesco S, Perricone C, Priori R, Valesini G, Shoenfeld
Y. Sjogrens syndrome: another facet of the autoimmune/
inflammatory syndrome induced by adjuvants (ASIA). J
Autoimmun 2014; 51: 106.
Kivity S, Arango MT, Ehrenfeld M et al. Infection and
autoimmunity in Sjogrens syndrome: a clinical study and
comprehensive review. J Autoimmun 2014; 51: 1722.
Peng J, Narasimhan S, Marchesi JR, Benson A, Wong FS,
Wen L. Long term effect of gut microbiota transfer on
diabetes development. J Autoimmun 2014; 53: 8594.
Bogdanos DP, Smyk DS, Invernizzi P et al. Infectome: a
platform to trace infectious triggers of autoimmunity. Autoimmun Rev 2013; 12: 72640.
Cunningham MW. Rheumatic fever, autoimmunity, and
molecular mimicry: the streptococcal connection. Int Rev
Immunol 2014; 33: 31429.
Guilherme L, Oshiro SE, Fae KC et al. T-cell reactivity
against streptococcal antigens in the periphery mirrors reactivity of heart-infiltrating T lymphocytes in rheumatic heart disease patients. Infect Immun 2001; 69:
534551.
Blank M, Barzilai O, Shoenfeld Y. Molecular mimicry and
auto-immunity. Clin Rev Allergy Immunol 2007; 32: 1118.
Kremer JM, Westhovens R, Leon M et al. Treatment of
rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003; 349:
190715.
James JA, Neas BR, Moser KL et al. Systemic lupus erythematosus in adults is associated with previous Epstein-Barr
virus exposure. Arthritis Rheum 2001; 44: 11226.
Mirandola P, Stefan A, Brambilla E, Campadelli-Fiume G,
Grimaldi LM. Absence of human herpesvirus 6 and 7 from
spinal fluid and serum of multiple sclerosis patients. Neurology 1999; 53: 13678.
Amedei A, Bergman MP, Appelmelk BJ et al. Molecular
mimicry between Helicobacter pylori antigens and H+, K+
adenosine triphosphatase in human gastric autoimmunity.
J Exp Med 2003; 198: 114756.
L. Wang et al.
68 Vanderlugt CL, Miller SD. Epitope spreading in immunemediated diseases: implications for immunotherapy. Nat
Rev Immunol 2002; 2: 8595.
69 Lehmann PV, Targoni OS, Forsthuber TG. Shifting T-cell
activation thresholds in autoimmunity and determinant
spreading. Immunol Rev 1998; 164: 5361.
70 Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading
of T-cell autoimmunity to cryptic determinants of an
autoantigen. Nature 1992; 358: 1557.
71 Duke RC. Self recognition by T cells. I. Bystander killing of
target cells bearing syngeneic MHC antigens. J Exp Med
1989; 170: 5971.
72 Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. Infections
and autoimmunityfriends or foes? Trends Immunol 2009;
30: 40914.
73 Draborg AH, Duus K, Houen G. Epstein-Barr virus in
systemic autoimmune diseases. Clin Dev Immunol 2013;
2013: 535738.
74 Abdelrahman HS, Selim HS, Hashish MH, Sultan LI. Epstein-Barr virus in multiple sclerosis. J Egypt Public Health
Assoc 2014; 89: 905.
75 Morshed SA, Nishioka M, Saito I, Komiyama K, Moro I.
Increased expression of Epstein-Barr virus in primary biliary
cirrhosis patients. Gastroenterol Jpn 1992; 27: 7518.
76 Root-Bernstein R, Fairweather D. Complexities in the relationship between infection and autoimmunity. Curr Allergy
Asthma Rep 2014; 14: 407.
77 Strachan DP. Hay fever, hygiene, and household size. BMJ
1989; 299: 125960.
78 Dunne JL, Triplett EW, Gevers D et al. The intestinal
microbiome in type 1 diabetes. Clin Exp Immunol 2014;
177: 307.
79 Olivares M, Neef A, Castillejo G et al. The HLA-DQ2 genotype
selects for early intestinal microbiota composition in infants
at high risk of developing coeliac disease. Gut 2015; 64: 406
17.
80 Nistal E, Caminero A, Herran AR et al. Differences of small
intestinal bacteria populations in adults and children with/
without celiac disease: effect of age, gluten diet, and disease.
Inflamm Bowel Dis 2012; 18: 64956.
81 Sellitto M, Bai G, Serena G et al. Proof of concept of
microbiome-metabolome analysis and delayed gluten exposure on celiac disease autoimmunity in genetically at-risk
infants. PLoS ONE 2012; 7: e33387.
82 Schippa S, Iebba V, Barbato M et al. A distinctive microbial
signature in celiac pediatric patients. BMC Microbiol 2010;
10: 175.
83 Martinez-Martinez RE, Abud-Mendoza C, Patino-Marin N,
Rizo-Rodriguez JC, Little JW, Loyola-Rodriguez JP. Detection of periodontal bacterial DNA in serum and synovial fluid
in refractory rheumatoid arthritis patients. J Clin Periodontol
2009; 36: 100410.
84 Moen K, Brun JG, Valen M et al. Synovial inflammation in
active rheumatoid arthritis and psoriatic arthritis facilitates
trapping of a variety of oral bacterial DNAs. Clin Exp
Rheumatol 2006; 24: 65663.
85 Vaahtovuo J, Munukka E, Korkeamaki M, Luukkainen R,
Toivanen P. Fecal microbiota in early rheumatoid arthritis. J
Rheumatol 2008; 35: 15005.
86 Scher JU, Sczesnak A, Longman RS et al. Expansion of
intestinal Prevotella copri correlates with enhanced susceptibility to arthritis. eLife 2013; 2: e01202.
87 Van Praet JT, Donovan E, Vanassche I et al. Commensal

microbiota influence systemic autoimmune responses.
EMBO J 2015; 34: 46674.
88 Green PH, Cellier C. Celiac disease. N Engl J Med 2007; 357:
173143.
89 Rose NR, Bonita R, Burek CL. Iodine: an environmental
trigger of thyroiditis. Autoimmun Rev 2002; 1: 97103.
90 van der Laan JW, Gould S, Tanir JY, Vaccines IH, Adjuvants
Safety Project Committee. Safety of vaccine adjuvants: focus
on autoimmunity. Vaccine 2015; 33: 150714.
91 Antico A, Tampoia M, Tozzoli R, Bizzaro N. Can supplementation with vitamin D reduce the risk or modify the course of
autoimmune diseases? A systematic review of the literature.
Autoimmun Rev 2012; 12: 12736.
92 Samuel S, Sitrin MD. Vitamin Ds role in cell proliferation
and differentiation. Nutr Rev 2008; 66: S11624.
93 Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin
D in systemic and organ-specific autoimmune diseases. Clin
Rev Allergy Immunol 2013; 45: 25666.
94 Afridi HI, Kazi TG, Talpur FN, Naher S, Brabazon D. Relationship between toxic metals exposure via cigarette smoking and
rheumatoid arthritis. Clin Lab 2014; 60: 173545.
95 Ekblom-Kullberg S, Kautiainen H, Alha P, Leirisalo-Repo M,
Miettinen A, Julkunen H. Smoking, disease activity, permanent damage and dsDNA autoantibody production in
patients with systemic lupus erythematosus. Rheumatol Int
2014; 34: 3415.
96 Klareskog L, Gregersen PK, Huizinga TW. Prevention of
autoimmune rheumatic disease: state of the art and future
perspectives. Ann Rheum Dis 2010; 69: 20626.
97 Ospelt C, Camici GG, Engler A et al. Smoking induces
transcription of the heat shock protein system in the joints.
Ann Rheum Dis 2014; 73: 14236.
98 Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on
immunity, inflammation and autoimmunity. J Autoimmun
2010; 34: J25865.
99 Mackay IR, Leskovsek NV, Rose NR. Cell damage and
autoimmunity: a critical appraisal. J Autoimmun 2008; 30:
511.
100 Lleo A, Selmi C, Invernizzi P, Podda M, Gershwin ME. The
consequences of apoptosis in autoimmunity. J Autoimmun
2008; 31: 25762.
101 Cohen PL, Eisenberg RA. Lpr and gld: single gene models of
systemic autoimmunity and lymphoproliferative disease.
Annu Rev Immunol 1991; 9: 24369.
102 Pieterse E, van der Vlag J. Breaking immunological tolerance in systemic lupus erythematosus. Front Immunol 2014;
5: 164.
103 Shao WH, Cohen PL. Disturbances of apoptotic cell clearance in systemic lupus erythematosus. Arthritis Res Ther
2011; 13: 202.
104 Lleo A, Bowlus CL, Yang GX et al. Biliary apotopes and
anti-mitochondrial antibodies activate innate immune
responses in primary biliary cirrhosis. Hepatology 2010;
52: 98798.
105 Vives-Pi M, Rodriguez-Fernandez S, Pujol-Autonell I. How
apoptotic beta-cells direct immune response to tolerance or
to autoimmune diabetes: a review. Apoptosis 2015; 20: 263
72.
106 Hoffmanova I, Sanchez D, Habova V, Andel M, Tuckova L,
Tlaskalova-Hogenova H. Serological markers of enterocyte
damage and apoptosis in patients with celiac disease,
391
L. Wang et al.
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
392
autoimmune diabetes mellitus and diabetes mellitus type 2.

Physiol Res 2014; [Epub ahead of print].
Czaja AJ. Targeting apoptosis in autoimmune hepatitis. Dig
Dis Sci 2014; 59: 2890904.
Damoiseaux J, Andrade LE, Fritzler MJ, Shoenfeld Y.
Autoantibodies 2015: from diagnostic biomarkers toward
prediction, prognosis and prevention. Autoimmun Rev 2015;
14: 55563.
Ohishi K, Kanoh M, Shinomiya H, Hitsumoto Y, Utsumi S.
Complement activation by cross-linked B cell-membrane
IgM. J Immunol 1995; 154: 31739.
Rodien P, Madec AM, Ruf J et al. Antibody-dependent cellmediated cytotoxicity in autoimmune thyroid disease: relationship to antithyroperoxidase antibodies. J Clin Endocrinol
Metab 1996; 81: 2595600.
Lleo A, Invernizzi P, Gao B, Podda M, Gershwin ME. Definition
of human autoimmunityautoantibodies versus autoimmune disease. Autoimmun Rev 2010; 9: A25966.
Hewagama A, Gorelik G, Patel D et al. Overexpression of Xlinked genes in T cells from women with lupus. J Autoimmun
2013; 41: 6071.
Davidson A, Diamond B. Autoimmune diseases. N Engl J
Med 2001; 345: 34050.
Han L, Yang J, Wang X, Li D, Lv L, Li B. Th17 cells in
autoimmune diseases. Front Med 2015; 9: 109.
Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS.
Regulatory T-cells in autoimmune diseases: challenges,
controversies and-yet-unanswered questions. Autoimmun
Rev 2015; 14: 10516.
Craft JE. Follicular helper T cells in immunity and systemic
autoimmunity. Nat Rev Rheumatol 2012; 8: 33747.
Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic
and clinical classification of autoimmune myasthenia
gravis. J Autoimmun 2014; 4849: 1438.
Gomez-Puerta JA, Cervera R. Diagnosis and classification of
the antiphospholipid syndrome. J Autoimmun 2014; 4849:
205.
Hajj-Ali RA, Calabrese LH. Diagnosis and classification of
central nervous system vasculitis. J Autoimmun 2014; 48
49: 14952.
Hernandez-Rodriguez J, Alba MA, Prieto-Gonzalez S, Cid
MC. Diagnosis and classification of polyarteritis nodosa. J
Autoimmun 2014; 4849: 849.
Iaccarino L, Ghirardello A, Bettio S et al. The clinical
features, diagnosis and classification of dermatomyositis. J
Autoimmun 2014; 4849: 1227.
Karussis D. The diagnosis of multiple sclerosis and the
various related demyelinating syndromes: a critical review. J
Autoimmun 2014; 4849: 13442.
Kuhn A, Landmann A. The classification and diagnosis of
cutaneous lupus erythematosus. J Autoimmun 2014; 48
49: 149.
Mahroum N, Mahagna H, Amital H. Diagnosis and classification of adult Stills disease. J Autoimmun 2014; 4849: 347.
Maverakis E, Patel F, Kronenberg DG et al. International
consensus criteria for the diagnosis of Raynauds phenomenon. J Autoimmun 2014; 4849: 605.
Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S. The
diagnosis and classification of undifferentiated connective
tissue diseases. J Autoimmun 2014; 4849: 502.
Mouthon L, Dunogue B, Guillevin L. Diagnosis and classification of eosinophilic granulomatosis with polyangiitis
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
145
146
147
148
(formerly named Churg-Strauss syndrome). J Autoimmun

2014; 4849: 99103.
Moutsopoulos HM. Sjogrens syndrome: a forty-year scientific journey. J Autoimmun 2014; 51: 19.
Nesher G. Polymyalgia rheumaticadiagnosis and classification. J Autoimmun 2014; 4849: 768.
Raychaudhuri SP, Deodhar A. The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun 2014;
4849: 12833.
Sanchez-Manubens J, Bou R, Anton J. Diagnosis and
classification of Kawasaki disease. J Autoimmun 2014; 48
49: 1137.
Lleo A, Zhang W, McDonald WH et al. Shotgun proteomics: identification of unique protein profiles of apoptotic bodies from biliary epithelial cells. Hepatology 2014;
60: 131423.
Zhang J, Zhang W, Leung PS et al. Ongoing activation of
autoantigen-specific B cells in primary biliary cirrhosis.
Hepatology 2014; 60: 170816.
Imam MH, Lindor KD. The natural history of primary biliary
cirrhosis. Semin Liver Dis 2014; 34: 32933.
Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E. Diagnosis and classification of rheumatoid arthritis. J Autoimmun 2014; 4849: 2630.
Bizzaro N. Autoantibodies as predictors of disease: the
clinical and experimental evidence. Autoimmun Rev 2007;
6: 32533.
Liaskou E, Hirschfield GM, Gershwin ME. Mechanisms of
tissue injury in autoimmune liver diseases. Semin Immunopathol 2014; 36: 55368.
Eilat D. Introduction: mechanisms of tissue injury in autoimmune diseases. Semin Immunopathol 2014; 36: 4913.
Hirschfield GM, Gershwin ME. The immunobiology and
pathophysiology of primary biliary cirrhosis. Annu Rev
Pathol 2013; 8: 30330.
Shimoda S, Ishikawa F, Kamihira T et al. Autoreactive T-cell
responses in primary biliary cirrhosis are proinflammatory
whereas those of controls are regulatory. Gastroenterology
2006; 131: 60618.
Juran BD, Lazaridis KN. Environmental factors in
primary biliary cirrhosis. Semin Liver Dis 2014; 34: 265
72.
Raczynska J, Habior A, Paczek L, Foroncewicz B, Pawelas A,
Mucha K. Primary biliary cirrhosis in the era of liver
transplantation. Ann Transplant 2014; 19: 48893.
Zhao M, Liu S, Luo S et al. DNA methylation and mRNA
and microRNA expression of SLE CD4+ T cells correlate with disease phenotype. J Autoimmun 2014; 54: 127
36.
Bogdanos DP, Smyk DS, Rigopoulou EI et al. Twin studies in
autoimmune disease: genetics, gender and environment. J
Autoimmun 2012; 38: J15669.
Sawcer S, Franklin RJ, Ban M. Multiple sclerosis genetics.
Lancet Neurol 2014; 13: 7009.
Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ.
Epidemiology of type 1 diabetes. Endocrinol Metab Clin
North Am 2010; 39: 48197.
DIAMOND Project Group. Incidence and trends of childhood
Type 1 diabetes worldwide 1990-1999. Diabet Med 2006;
23: 85766.
Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl
J Med 2005; 353: 126173.
L. Wang et al.
149 Griffiths L, Dyson JK, Jones DE. The new epidemiology of

primary biliary cirrhosis. Semin Liver Dis 2014; 34: 318
28.
150 Selmi C, Invernizzi P, Zuin M, Podda M, Gershwin ME.
Genetics and geoepidemiology of primary biliary cirrhosis:
following the footprints to disease etiology. Semin Liver Dis
2005; 25: 26580.
151 Feld JJ, Heathcote EJ. Epidemiology of autoimmune liver
disease. J Gastroenterol Hepatol 2003; 18: 111828.
152 Heneghan MA, Yeoman AD, Verma S, Smith AD, Longhi MS.
Autoimmune hepatitis. Lancet 2013; 382: 143344.
153 Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoimmune hepatitis: a comprehensive review. J Autoimmun
2013; 41: 12639.
154 Francque S, Vonghia L, Ramon A, Michielsen P. Epidemiology and treatment of autoimmune hepatitis. Hepat Med
2012; 4: 110.
155 Menconi F, Marcocci C, Marino M. Diagnosis and classification of Graves disease. Autoimmun Rev 2014; 13: 398
402.
156 McLeod DS, Cooper DS. The incidence and prevalence of
thyroid autoimmunity. Endocrine 2012; 42: 25265.
157 Laass MW, Roggenbuck D, Conrad K. Diagnosis and classification of Crohns disease. Autoimmun Rev 2014; 13: 467
71.
158 Molodecky NA, Soon IS, Rabi DM et al. Increasing incidence
and prevalence of the inflammatory bowel diseases with
time, based on systematic review. Gastroenterology 2012;
142: 4654 e42; quiz e30.
159 Ng SC. Epidemiology of inflammatory bowel disease: focus
on Asia. Best Pract Res Clin Gastroenterol 2014; 28: 36372.
160 Conrad K, Roggenbuck D, Laass MW. Diagnosis and classification of ulcerative colitis. Autoimmun Rev 2014; 13:
4636.
161 Kang JY, Kang AH, Green A, Gwee KA, Ho KY. Systematic
review: worldwide variation in the frequency of coeliac
disease and changes over time. Aliment Pharmacol Ther
2013; 38: 22645.
162 Paul SP, Spray C. Diagnosing coeliac disease in children. Br
J Hosp Med 2014; 75: 26870.
163 Brandao Neto RA, de Carvalho JF. Diagnosis and classification of Addisons disease (autoimmune adrenalitis). Autoimmun Rev 2014; 13: 40811.
164 Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003; 361:
188193.
165 Alamanos Y, Tsifetaki N, Voulgari PV, Venetsanopoulou AI,
Siozos C, Drosos AA. Epidemiology of primary Sjogrens
syndrome in north-west Greece, 19822003. Rheumatology
2006; 45: 18791.
166 Larche MJ. A short review of the pathogenesis of Sjogrens
syndrome. Autoimmun Rev 2006; 5: 1325.
167 Liang Y, Yang Z, Qin B, Zhong R. Primary Sjogrens
syndrome and malignancy risk: a systematic review and
meta-analysis. Ann Rheum Dis 2014; 73: 11516.
168 Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus
erythematosus. Lancet 2014; 384: 187888.
169 Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper GS.
Understanding the epidemiology and progression of systemic lupus erythematosus. Semin Arthritis Rheum 2010;
39: 25768.
170 Nasonov E, Soloviev S, Davidson JE et al. The prevalence
and incidence of systemic lupus erythematosus (SLE) in
171
172
173
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
selected cities from three Commonwealth of Independent

States countries (the Russian Federation, Ukraine and
Kazakhstan). Lupus 2014; 23: 2139.
McInnes IB, Schett G. The pathogenesis of rheumatoid
arthritis. N Engl J Med 2011; 365: 220519.
Tobon GJ, Youinou P, Saraux A. The environment, geoepidemiology, and autoimmune disease: rheumatoid arthritis. J Autoimmun 2010; 35: 104.
Sung YK, Cho SK, Choi CB, Bae SC. Prevalence and
incidence of rheumatoid arthritis in South Korea. Rheumatol
Int 2013; 33: 152532.
Cree BA. Multiple sclerosis genetics. Handb Clin Neurol
2014; 122: 193209.
Picascia A, Grimaldi V, Pignalosa O, De Pascale MR, Schiano
C, Napoli C. Epigenetic control of autoimmune diseases:
from bench to bedside. Clin Immunol 2015; 157: 115.
Morran MP, Vonberg A, Khadra A, Pietropaolo M. Immunogenetics of type 1 diabetes mellitus. Mol Aspects Med 2015;
42: 4260.
Stankov K, Benc D, Draskovic D. Genetic and epigenetic
factors in etiology of diabetes mellitus type 1. Pediatrics
2013; 132: 111222.
Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y. DNA
methylation profiles in type 1 diabetes twins point to
strong epigenetic effects on etiology. J Autoimmun 2014;
50: 337.
Chen H, Lan HY, Roukos DH, Cho WC. Application of
microRNAs in diabetes mellitus. J Endocrinol 2014; 222:
R110.
Bianchi I, Carbone M, Lleo A, Invernizzi P. Genetics and
epigenetics of primary biliary cirrhosis. Semin Liver Dis
2014; 34: 25564.
Tang J, Zhou C, Zhang ZJ, Zheng SS. Association of
polymorphisms in non-classic MHC genes with susceptibility to autoimmune hepatitis. Hepatobiliary Pancreat Dis Int
2012; 11: 12531.
Li K, Du Y, Jiang BL, He JF. Increased microRNA-155 and
decreased microRNA-146a may promote ocular inflammation and proliferation in Graves ophthalmopathy. Med Sci
Monit 2014; 20: 63943.
Wei H, Guan M, Qin Y et al. Circulating levels of miR-146a
and IL-17 are significantly correlated with the clinical
activity of Graves ophthalmopathy. Endocr J 2014; 61:
108792.
Cai TT, Muhali FS, Song RH et al. Genome-wide DNA
methylation analysis in Graves disease. Genomics 2015;
105: 20410.
Tomer Y. Mechanisms of autoimmune thyroid diseases: from
genetics to epigenetics. Annu Rev Pathol 2014; 9: 14756.
Marino M, Latrofa F, Menconi F, Chiovato L, Vitti P. Role of
genetic and non-genetic factors in the etiology of Graves
disease. J Endocrinol Invest 2014; [Epub ahead of print]
Kalla R, Ventham NT, Kennedy NA et al. MicroRNAs: new
players in IBD. Gut 2015; 64: 50413.
Van Limbergen J, Wilson DC, Satsangi J. The genetics of
Crohns disease. Annu Rev Genomics Hum Genet 2009; 10:
89116.
Stokkers PC, Reitsma PH, Tytgat GN, van Deventer SJ. HLADR and -DQ phenotypes in inflammatory bowel disease: a
meta-analysis. Gut 1999; 45: 395401.
Denizot J, Desrichard A, Agus A et al. Diet-induced hypoxia
responsive element demethylation increases CEACAM6
393
L. Wang et al.
191
192
193
194
195
196
197
198
199
200
201
202
203
204
205
206
207
208
394
expression, favouring Crohns disease-associated Escherichia coli colonisation. Gut 2015; 64: 42837.
Adams AT, Kennedy NA, Hansen R et al. Two-stage genomewide methylation profiling in childhood-onset Crohns Disease implicates epigenetic alterations at the VMP1/MIR21
and HLA loci. Inflamm Bowel Dis 2014; 20: 178493.
Lv B, Liu Z, Wang S et al. miR-29a promotes intestinal
epithelial apoptosis in ulcerative colitis by down-regulating
Mcl-1. Int J Clin Exp Pathol 2014; 7: 854252.
Karatzas PS, Mantzaris GJ, Safioleas M, Gazouli M. DNA
methylation profile of genes involved in inflammation and
autoimmunity in inflammatory bowel disease. Medicine
2014; 93: e309.
Harris RA, Nagy-Szakal D, Mir SA et al. DNA methylationassociated colonic mucosal immune and defense responses
in treatment-naive pediatric ulcerative colitis. Epigenetics
2014; 9: 11317.
Bascunan-Gamboa KA, Araya-Quezada M, Perez-Bravo F.
MicroRNAs: an epigenetic tool to study celiac disease. Rev
Esp Enferm Dig 2014; 106: 32533.
Lundin KE, Sollid LM. Advances in coeliac disease. Curr
Opin Gastroenterol 2014; 30: 15462.
Kaukinen K, Maki M. Coeliac disease in 2013: new insights
in dietary-gluten-induced autoimmunity. Nat Rev Gastroenterol Hepatol 2014; 11: 802.
Fernandez-Jimenez N, Castellanos-Rubio A, Plaza-Izurieta L
et al. Coregulation and modulation of NFkappaB-related
genes in celiac disease: uncovered aspects of gut mucosal
inflammation. Hum Mol Genet 2014; 23: 1298310.
Bernecker C, Halim F, Haase M, Willenberg HS, Ehlers M,
Schott M. MicroRNA expressions in PMBCs, CD4+,
and CD8+ T-cells from patients suffering from autoimmune
Addisons disease. Horm Metab Res 2013; 45: 599604.
Bjanesoy TE, Andreassen BK, Bratland E et al. Altered DNA
methylation profile in Norwegian patients with Autoimmune
Addisons Disease. Mol Immunol 2014; 59: 20816.
Bronstad I, Wolff AS, Lovas K, Knappskog PM, Husebye ES.
Genome-wide copy number variation (CNV) in patients with
autoimmune Addisons disease. BMC Med Genet 2011; 12:
111.
Gallo A, Tandon M, Illei G, Alevizos I. Discovery and
validation of novel microRNAs in Sjogrens syndrome salivary glands. Clin Exp Rheumatol 2014; 32: 7612.
Shi H, Zheng LY, Zhang P, Yu CQ. miR-146a and miR-155
expression in PBMCs from patients with Sjogrens syndrome. J Oral Pathol Med 2014; 43: 7927.
Konsta OD, Thabet Y, Le Dantec C et al. The contribution of
epigenetics in Sjogrens Syndrome. Front Genet 2014; 5: 71.
Lessard CJ, Li H, Adrianto I et al. Variants at multiple loci
implicated in both innate and adaptive immune responses
are associated with Sjogrens syndrome. Nat Genet 2013;
45: 128492.
Huang R, Yin J, Chen Y et al. The amino acid variation
within the binding pocket 7 and 9 of HLA-DRB1 molecules
are associated with primary Sjogrens syndrome. J Autoimmun 2015; 57: 539.
Guerra SG, Vyse TJ, Cunninghame Graham DS. The genetics of lupus: a functional perspective. Arthritis Res Ther
2012; 14: 211.
Miao CG, Yang YY, He X et al. The emerging role of
microRNAs in the pathogenesis of systemic lupus erythematosus. Cell Signal 2013; 25: 182836.
209 Zhang Y, Zhang J, Yang J et al. Meta-analysis of GWAS on

two Chinese populations followed by replication identifies
novel genetic variants on the X chromosome associated with
systemic lupus erythematosus. Hum Mol Genet 2015; 24:
27484.
210 Deng Y, Tsao BP. Advances in lupus genetics and epigenetics. Curr Opin Rheumatol 2014; 26: 48292.
211 Wong M, Tsao BP. Current topics in human SLE genetics.
Springer Semin Immunopathol 2006; 28: 97107.
212 Bottini N, Firestein GS. Epigenetics in rheumatoid arthritis:
a primer for rheumatologists. Curr Rheumatol Rep 2013; 15:
372.
213 Yamamoto K, Okada Y, Suzuki A, Kochi Y. Genetics of
rheumatoid arthritis in Asia-present and future. Nat Rev
Rheumatol 2015; 11: 3759.
214 Diogo D, Okada Y, Plenge RM. Genome-wide association
studies to advance our understanding of critical cell types
and pathways in rheumatoid arthritis: recent findings and
challenges. Curr Opin Rheumatol 2014; 26: 8592.
215 Kochi Y, Suzuki A, Yamamoto K. Genetic basis of rheumatoid arthritis: a current review. Biochem Biophys Res Commun 2014; 452: 25462.
216 Harkonen T, Lankinen H, Davydova B, Hovi T, Roivainen M.
Enterovirus infection can induce immune responses that
cross-react with beta-cell autoantigen tyrosine phosphatase
IA-2/IAR. J Med Virol 2002; 66: 34050.
217 Honeyman MC, Stone NL, Falk BA, Nepom G, Harrison LC.
Evidence for molecular mimicry between human T cell
epitopes in rotavirus and pancreatic islet autoantigens. J
Immunol 2010; 184: 220410.
218 Hiemstra HS, Schloot NC, van Veelen PA et al. Cytomegalovirus in autoimmunity: T cell crossreactivity to
viral antigen and autoantigen glutamic acid decarboxylase.
Proc Natl Acad Sci USA 2001; 98: 398891.
219 Hintermann E, Holdener M, Bayer M et al. Epitope spreading of the anti-CYP2D6 antibody response in patients with
autoimmune hepatitis and in the CYP2D6 mouse model. J
Autoimmun 2011; 37: 24253.
220 Poole BD, Scofield RH, Harley JB, James JA. Epstein-Barr
virus and molecular mimicry in systemic lupus erythematosus. Autoimmunity 2006; 39: 6370.
221 Lunemann JD, Huppke P, Roberts S, Bruck W, Gartner J,
Munz C. Broadened and elevated humoral immune response
to EBNA1 in pediatric multiple sclerosis. Neurology 2008;
71: 10335.
222 Petersen J, Rhodes G, Roudier J, Vaughan JH. Altered
immune response to glycine-rich sequences of Epstein-Barr
nuclear antigen-1 in patients with rheumatoid arthritis and
systemic lupus erythematosus. Arthritis Rheum 1990; 33:
9931000.
223 Rozenblyum EV, Allen UD, Silverman ED, Levy DM.
Cytomegalovirus infection in childhood-onset systemic
lupus erythematosus. Int J Clin Rheumatol 2013; 8: 137
46.
224 Tucker WG, Andrew Paskauskas R. The MSMV hypothesis:
measles virus and multiple sclerosis, etiology and treatment. Med Hypotheses 2008; 71: 6829.
225 Alidjinou EK, Sane F, Engelmann I, Geenen V, Hober D.
Enterovirus persistence as a mechanism in the pathogenesis
of type 1 diabetes. Discov Med 2014; 18: 27382.
226 Andrade F, Casciola-Rosen LA, Rosen A. Generation of novel
covalent RNA-protein complexes in cells by ultraviolet B
L. Wang et al.
227
228
229
230
231
232
233
234
235
236
237
238
239
240
241
242
243
244
irradiation: implications for autoimmunity. Arthritis Rheum

2005; 52: 116070.
Cooper GS, Wither J, Bernatsky S et al. Occupational and
environmental exposures and risk of systemic lupus erythematosus: silica, sunlight, solvents. Rheumatology 2010; 49:
217280.
Caricchio R, McPhie L, Cohen PL. Ultraviolet B radiationinduced cell death: critical role of ultraviolet dose in inflammation and lupus autoantigen redistribution. J Immunol
2003; 171: 577886.
Incorvaia E, Sicouri L, Petersen-Mahrt SK, Schmitz KM.
Hormones and AID: balancing immunity and autoimmunity.
Autoimmunity 2013; 46: 12837.
Shoenfeld Y, Tincani A, Gershwin ME. Sex gender and
autoimmunity. J Autoimmun 2012; 38: J713.
Cojocaru M, Chicos B. The role of heavy metals in autoimmunity. Rom J Intern Med 2014; 52: 18991.
Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria
for multiple sclerosis: 2010 revisions to the McDonald
criteria. Ann Neurol 2011; 69: 292302.
American Diabetes A. Diagnosis and classification of diabetes mellitus. Diabetes Care 2010; 33(Suppl 1): S629.
Lindor KD, Gershwin ME, Poupon R et al. Primary biliary
cirrhosis. Hepatology 2009; 50: 291308.
Alvarez F, Berg PA, Bianchi FB et al. International Autoimmune Hepatitis Group Report: review of criteria for diagnosis of autoimmune hepatitis. J Hepatol 1999; 31: 92938.
Hennes EM, Zeniya M, Czaja AJ et al. Simplified criteria for
the diagnosis of autoimmune hepatitis. Hepatology 2008;
48: 16976.
Chapman R, Fevery J, Kalloo A et al. Diagnosis and management of primary sclerosing cholangitis. Hepatology 2010;
51: 66078.
Shoenfeld Y, Cervera R, Gershwin ME. Diagnostic Criteria in
Autoimmune Diseases. New Jersey: Springer Science &
Business Media, 2010.
Van Assche G, Dignass A, Panes J et al. The second
European evidence-based Consensus on the diagnosis and
management of Crohns disease: definitions and diagnosis. J
Crohns Colitis 2010; 4: 727.
Stange EF, Travis SP, Vermeire S et al. European evidence-based
Consensus on the diagnosis and management of ulcerative
colitis: definitions and diagnosis. J Crohns Colitis 2008; 2: 123.
Revised criteria for diagnosis of coeliac disease. Report of
Working Group of European Society of Paediatric Gastroenterology and Nutrition. Arch Dis Child 1990; 65: 90911.
Fox RI. Sjogrens syndrome. Lancet 2005; 366: 32131.
Shiboski SC, Shiboski CH, Criswell L et al. American College
of Rheumatology classification criteria for Sjogrens syndrome: a data-driven, expert consensus approach in the
Sjogrens International Collaborative Clinical Alliance
cohort. Arthritis Care Res 2012; 64: 47587.
Petri M, Orbai AM, Alarcon GS et al. Derivation and validation of the Systemic Lupus International Collaborating
245
246
247
248
249
250
251
252
253
254
255
256
257
258
259
Clinics classification criteria for systemic lupus erythematosus. Arthritis Rheum 2012; 64: 267786.
Aletaha D, Neogi T, Silman AJ et al. 2010 rheumatoid
arthritis classification criteria: an American College of
Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis 2010; 69: 15808.
Rau R. Glucocorticoid treatment in rheumatoid arthritis.
Expert Opin Pharmacother 2014; 15: 157583.
Flammer JR, Rogatsky I. Minireview: glucocorticoids in
autoimmunity: unexpected targets and mechanisms. Mol
Endocrinol 2011; 25: 107586.
Goodin DS. Glucocorticoid treatment of multiple sclerosis.
Handb Clin Neurol 2014; 122: 45564.
Hashkes PJ, Becker ML, Cabral DA et al. Methotrexate: new
uses for an old drug. J Pediatr 2014; 164: 2316.
Hahn BH. Belimumab for systemic lupus erythematosus. N
Engl J Med 2013; 368: 152835.
Invernizzi P, Benedetti MD, Poli S, Monaco S. Azathioprine in multiple sclerosis. Mini Rev Med Chem 2008; 8:
91926.
Louis E, Irving P, Beaugerie L. Use of azathioprine in IBD:
modern aspects of an old drug. Gut 2014; 63: 16959.
Sieb JP. Myasthenia gravis: an update for the clinician. Clin
Exp Immunol 2014; 175: 40818.
Johnson PJ, McFarlane IG, Williams R. Azathioprine for
long-term maintenance of remission in autoimmune hepatitis. N Engl J Med 1995; 333: 95863.
Willrich MA, Murray DL, Snyder MR. Tumor necrosis factor
inhibitors: clinical utility in autoimmune diseases. Transl
Res 2015; 165: 27082.
Song SN, Yoshizaki K. Tocilizumab for treating rheumatoid
arthritis: an evaluation of pharmacokinetics/pharmacodynamics and clinical efficacy. Expert Opin Drug Metab Toxicol
2015; 11: 30716.
Meng Y, Dongmei L, Yanbin P et al. Systematic review and
meta-analysis of ustekinumab for moderate to severe psoriasis. Clin Exp Dermatol 2014; 39: 696707.
Edwards JC, Szczepanski L, Szechinski J et al. Efficacy of
B-cell-targeted therapy with rituximab in patients
with rheumatoid arthritis. N Engl J Med 2004; 350: 2572
81.
Mok CC. Rituximab for the treatment of rheumatoid
arthritis: an update. Drug Des Devel Ther 2014; 8: 87
100.
Correspondence: Fu-Sheng Wang, Research Center for Biological

Therapy, Institute of Translational Hepatology, Beijing 302
Hospital, Beijing 100039, China.
(fax: +8610-63879735; e-mail: fswang302@163.com).
or M. Eric Gershwin, Division of Rheumatology, Allergy and
Clinical Immunology, University of California at Davis School of
Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA
95616, USA.
(fax: 1-530-752-4669; e-mail: megershwin@ucdavis.edu).
395

Wang Et Al-2015-Journal of Internal Medicine-2 PDF

Diunggah oleh

Informasi Dokumen

Deskripsi Asli:

Judul Asli

Hak Cipta

Format Tersedia

Bagikan dokumen Ini

Bagikan atau Tanam Dokumen

Opsi Berbagi

Apakah menurut Anda dokumen ini bermanfaat?

Apakah konten ini tidak pantas?

Hak Cipta:

Format Tersedia

Wang Et Al-2015-Journal of Internal Medicine-2 PDF

Diunggah oleh

Hak Cipta:

Format Tersedia

Review

Human autoimmune diseases: a comprehensive update

Abstract. Wang L, Wang F-S, Gershwin ME (Research

Abbreviations: TNF, tumour necrosis factor; Th, T

Review: Human autoimmune diseases

pioneering work of Paul Ehrlich early in the 20th

Review: Human autoimmune diseases

the more common autoantibodies, antinuclear

Review: Human autoimmune diseases

The epidemiology of autoimmunity

ratio ranging from 10 : 1 to 1 : 1 [an exception is

Table 1 Geoepidemiology of selected human autoimmune diseases

Incidence (per 100 000 person-years)

Data from [144].

1999 and 2012 was reported, whilst the prevalence

Review: Human autoimmune diseases

TNFRSF6 membrane-bound ligand and caspase

Fig. 3 Genetic basis of

Review: Human autoimmune diseases

Table 2 Genetic associations with autoimmune diseases

HLA class II:

[47, 48, 145,

HLA class II:

HLA, INS, IL-2RB, CD226

TGF-b, NF-kB, IL-6, HLA,

miR-375, miR-25, miR-

326, miR-342, miR-19,

HLA class II:

miR-2, miR-let-7b, miR-

[2, 49, 180]

HLA class II:

[152, 153, 181]

Review: Human autoimmune diseases

HLA class II:

miR-17, miR-155, miR146, miR-200a1

HLA class II:

TLR4, CARD9, IL-

miR-21, HLA loci

DR2 and DR3

3p, miR-532-3p, miR-505,

miR-195, miR-16, miR-93,

miR-140, 200c, 532-3p

HLA class II:

DR2, DR15, DR9;

IL-17c, IL-4R, IFITM1,

ITGB2, S100A9, SLPI,

CXCL14 CXCL5, GATA3,

HLA class II:

miR-638, miR-1290, and

HLA class II:

status in CD4+ T cells

Review: Human autoimmune diseases

HLA class II:

in AQP5 gene promoter

miR-146a, miR-155,Let7b, mir-21

HLA Class II:

STAT4, IFIH1, IRF5,

NLRP2, CD300LB, S1PR3

miR-146a, miR-638, miR-

16, miR-27a, miR-21,

miR-31, miR-125a, miR155, miR-371-5p, miR-

HLA Class III: