Human Autoimmune Diseases: A Comprehensive Update: Review

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
2
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 Abbreviations: TNF, tumour necrosis factor; Th, T
Center for Biological Therapy, the Institute of helper cell; TNFRSF14, tumour necrosis factor
Translational Hepatology, Beijing 302 Hospital, receptor superfamily member 14; IL12RB2, inter-
Beijing, China; and Division of Rheumatology, leukin-12 receptor, beta 2; RAD51B, RAD51 paralog
Allergy and Clinical Immunology, University of B; Sm, smith; HHV6, human herpes virus 6; Treg, T
California at Davis School of Medicine, Davis, CA, regulatory cell; Tfh, T follicular helper cell; PDC-E2,
USA). Human autoimmune diseases: a the E2 subunit of the pyruvate dehydrogenase
comprehensive update. (Review). J Intern Med complex; mTEC, medullary thymic epithelial cells;
2015; 278: 369–395. AD, autoimmune disease; CLEC16A, C-type lectin
domain family 16; IRF8, interferon regulatory factor
There have been significant advances in our under- 8; Olig3, oligodendrocyte transcription factor 3;
standing of human autoimmunity that have led to TNFAIP3, tumour necrosis factor, alpha-induced
improvements in classification and diagnosis and, protein 3; PTGER4, prostaglandin E receptor 4;
most importantly, research advances in new thera- RGS1, regulator of G protein signalling 1; INS,
pies. The importance of autoimmunity and the insulin; IFIH1, interferon induced with helicase C
mechanisms that lead to clinical disease were first domain 1; PTPN2, protein tyrosine phosphatase
recognized about 50 years ago following the pioneer- nonreceptor type 2; PLC-L2, phospholipase C-like
ing studies of Macfarlane Burnett and his Nobel protein 2; FCRL3, Fc receptor-like protein 3;
Prize-winning hypothesis of the ‘forbidden clone’. DNMT1, DNA (cytosine-5)-methyltransferase 1;
Such pioneering efforts led to a better understanding MECP2, methyl CpG binding protein 2; IRGM,
not only of autoimmunity, but also of lymphoid cell immunity-related GTPase family M protein; CEA-
development, thymic education, apoptosis and dele- CAM6, carcinoembryonic antigen-related cell adhe-
tion of autoreactive cells. Contemporary theories sion molecule 6; PARK7, Parkinson’s disease
suggest that the development of an autoimmune (autosomal recessive, early onset) 7; ERRFI1, ERBB
disease requires a genetic predisposition and envi- receptor feedback inhibitor 1; MMEL1, membrane
ronmental factors that trigger the immune pathways metallo-endopeptidase-like 1; BLK, B lymphoid
that lead, ultimately, to tissue destruction. Despite tyrosine kinase; APOBEC, apolipoprotein B mRNA
extensive research, there are no genetic tools that can editing enzyme, catalytic polypeptide-like; IAA, in-
be used clinically to predict the risk of autoimmune sulin autoantibodies; GADA, glutamic acid decar-
disease. Indeed, the concordance of autoimmune boxylase antibodies; IA-2A, insulinoma-associated-
disease in identical twins is 12–67%, highlighting not 2 autoantibodies; ZnT8A, zinc transporter 8 autoan-
only a role for environmental factors, but also the tibody; LKM-1, liver kidney microsome-1; CCP,
potential importance of stochastic or epigenetic cyclic citrullinated peptide; ESPGAN, European
phenomena. On the other hand, the identification Society for Paediatric Gastroenterology Hepatology
of cytokines and chemokines, and their cognate and Nutrition; ACR/SICCA, American College of
receptors, has led to novel therapies that block Rheumatology/Sjogren’s International Collabora-
pathological inflammatory responses within the tar- tive Clinical Alliance; SLICC, Systemic Lupus Inter-
get organ and have greatly improved the therapeutic national Collaborating Clinic; EULAR, European
effect in patients with autoimmune disease, partic- League Against Rheumatism; T1D, type I diabetes;
ularly rheumatoid arthritis. Further advances PBC, primary biliary cirrhosis; SLE, systemic lupus
involving the use of multiplex platforms for diagnosis erythematosus; RA, rheumatoid arthritis; APS1,
and identification of new therapeutic agents should autoimmune polyendocrinopathy syndrome type
lead to major breakthroughs within the next decade. 1; MHC, major histocompatibility complex; AITD,
autoimmune thyroid disease; TLR, Toll-like recep-
Keywords: Immune tolerance, Immunopathology, tor; SS, Sjogren’s syndrome; EBV, Epstein–Barr
genetics and autoimmunity, autoantibodies. virus; ARF, acute rheumatic fever.
ª 2015 The Association for the Publication of the Journal of Internal Medicine 369
L. Wang et al. Review: Human autoimmune diseases
pioneering work of Paul Ehrlich early in the 20th

Introduction
century had already introduced the concept of
The diverse immune system developed to fulfil the ‘horror autotoxicus’ [3]. In 1959, the New Zealand
primary function of protecting hosts from infec- black (NZB) mouse, the first murine model of
tious agents. There are, however, two major areas autoimmunity, was described. Subsequently, thy-
in which this pleiotropic immune system leads to roid autoantibodies were demonstrated and
pathology: first, immune deficiency syndromes in autoimmune thyroiditis became the prototypic
which there is an inability of one or more compo- autoimmune disease [4]. These two contributions
nents of the immune system to respond in a (NZB mice and autoimmune thyroiditis) became
protective fashion to a pathogen, and secondly the impetus for the explosion of research into
autoimmune diseases. The failure to distinguish autoimmune diseases.
self from nonself is often termed a breach of
tolerance and is the basis for autoimmune disease Several key concepts should be introduced to
and the focus of this review. understand immune tolerance, including central
tolerance, peripheral anergy, T regulatory cells
Historically, autoimmune diseases were consid- (Tregs) and the homeostasis produced by cytokines
ered to be rare but, through rigorous epidemiolog- and chemokines and their cognate receptors. Cen-
ical studies, have now been shown to affect 3–5% of tral tolerance in the thymus and bone marrow
the population, with autoimmune thyroid disease plays a key role in shaping immune system home-
and type I diabetes (T1D) being the most common ostasis. In the thymus, developing lymphocytes
of these conditions. However, more importantly, undergo positive selection in the cortex before
there are nearly 100 distinct autoimmune dis- maturing and entering the circulation. Of note, in
eases, some of which are organ specific such as an otherwise healthy host, lymphocytes with
primary biliary cirrhosis (PBC) and some of which potential reactivity against self-peptides are nega-
reflect a variety of immunological dysfunction tively selected and deleted in the thymic medulla.
involving multiple organs such as systemic lupus Importantly, after exiting the thymus, mature T
erythematosus (SLE) [1]. In the past decade, there cells are subjected to secondary selection (periph-
have been significant advances in diagnosis and eral tolerance) by which the majority of self-reac-
disease classification, as well as improvements in tive T cells are deleted or rendered anergic. In
prognosis, achieved through both the development addition, if immature B cells express surface IgM
of novel technologies in molecular immunology and that recognizes ubiquitous self cell-surface anti-
sophisticated evidence-based clinical laboratory gens, they are eliminated by a process known as
testing. In this review, we provide a historical basis clonal deletion or clonal anergy. Autoreactive B
for the breach of tolerance hypothesis and then cells can escape deletion by a process known as
discuss issues of autoimmune aetiology and patho- receptor editing. Mature B cells are also under the
biology, concluding with a general overview of new control of peripheral tolerance. These concepts are
treatment options. illustrated in Fig. 1.
It is important to note however that even under the

The concept of immunological tolerance
strict vigilance of central and peripheral tolerance,
In 1948, Macfarlane Burnet of the Walter and small numbers of potentially self-reacting lympho-
Eliza Hall Institute for Medical Research in Mel- cytes can still ‘leak out’ into the periphery, even in
bourne, Australia, proposed that immunological otherwise normal individuals. The existence of
inertness to self, which he termed ‘tolerance’, is a these potential self-reactive T and/or B lympho-
characteristic acquired in development, rather cytes, and/or the ability of these cells to produce
than an innate feature. Several years later, in autoantibodies, does not necessarily lead to pathol-
1953, Peter Medawar and his colleagues experi- ogy [5]. Accordingly, autoimmunity can sometimes
mentally demonstrated the ability to induce be classified as ‘physiological’ and ‘pathological’
immune tolerance in inbred mice. Ultimately, the autoimmunity [6, 7]. Physiological autoimmunity is
concept of immune tolerance was defined as an usually transient without evidence of clinical dis-
ability of the immune system to prevent itself from ease. This is exemplified by the presence of so-
targeting self-molecules, cells or tissues [2]. Many called natural autoantibodies [8], which help elim-
investigators did not believe in the concept of inate degraded self- and foreign antigens for main-
autoimmunity, although it is interesting that the tenance of homeostasis. As another example, two of
370 ª 2015 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine, 2015, 278; 369–395
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 self-
peptide 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 MHC-
restricted 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 broken and autoantibodies and self-reactive lym-
antibodies and rheumatoid factor, are often phocytes become involved in inflammation, classi-
observed in healthy individuals and their preva- cal or pathological autoimmunity develops (Fig. 2)
lence increases with age. When immune tolerance is which finally leads to tissue damage.
ratio ranging from 10 : 1 to 1 : 1 [an exception is

The epidemiology of autoimmunity
Crohn’s disease, with a ratio of 1 : 1.2]. The sex
Autoimmune diseases are generally thought of as bias of autoimmunity has attracted enormous
being relatively uncommon, but their effects on attention, but remains unresolved.
mortality and morbidity are significant. The overall
prevalence of autoimmunity is approximately 3–5% The incidence and prevalence of autoimmune dis-
in the general population [9, 10]. Yet, ironically, eases differ between geographical regions. For
despite enormous advances in the diagnosis and example, multiple sclerosis (MS) is unevenly dis-
the treatment of autoimmune diseases, there is still tributed throughout the world; its prevalence
a paucity of data on the aetiological events that varies between <5 cases per 100 000 persons in
lead to clinical pathology. tropical areas and also in Asia and >200 cases per
100 000 persons in temperate areas. The incidence
Incidence and prevalence vary amongst the of MS has been reported to be 0.8–8.7 per 100 000
autoimmune diseases. The geoepidemiology person-years in Europe, 2.7–7.5 per 100 000 per-
becomes more complex when variations in age, son-years in North America and 0.7–3.6 per
gender, ethnicity and other demographic features 100 000 person-years in Asia and the Middle East
are considered (Table 1). Autoimmune diseases [12]. The incidence of T1D is 5–10, 10–20 and <1
can occur at any age, but different diseases have per 100 000 person-years in populations from
their own characteristic age of onset. In almost all Europe, the USA and China, respectively. Between
patients, the prevalence is increased in first-degree 1990 and 2011, the incidence of coeliac disease
relatives and is even higher in monozygotic twins (CeD) increased from 5.2 to 19.1 per 100 000
[11]. There is an increased frequency of autoim- person-years in the UK [13]. However, an annual
mune diseases in women, with a female-to-male 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)

Age at onset (female/ twin North Asia and
Disease (years) male) concordancea Europe America Middle East References
Multiple sclerosis 20–40 2/1 9–31% 0.8–8.7 2.7–7.5 0.7–3.6 [12, 145]
Type 1 diabetes 6–13 1/1 13–48% >20 10–20 <1 [146, 147]
Primary biliary 50–60 10/1 63% 1.4–3.1 2.7 (USA) 0.34–0.42 [148–151]
cirrhosis
Autoimmune <40 (T1) 4/1 (T1) Only case 1.07–3.0 0.5 (USA) 0.08–0.15 [152–154]
hepatitis 2–14 (T2) 10/1 (T2) reports (Japan)
Graves’ disease 50–60 5/1 17–60% 21–50 38 120 [155, 156]
Crohn’s disease 15–30, 60–80 1/1.2 4% 3.1–12.7 6.9–20.2 0.24–1.34 [157–159]
Ulcerative colitis 15–30, 60–80 1/1 6.3–18.8% 4.1–16.5 8.3–19.2 0.36–6.02 [159, 160]
Coeliac disease Childhood 1/1 75–83% 1.5–8.7 0.9–9.1 Unclear [161, 162]
(all ages) (all ages)
Addison’s disease 15–45 0.8–2.4/1 Discordant 0.56–6.20 1 (USA) Unclear [163, 164]
pair
Sjogren’s 40–50 9/1 Only case 5.3 (north-west 3–5 (USA) 6.57 [165–167]
syndrome reports Greece)
Systemic lupus 30–50 9/1 11–25% 1.0–5.0 1.2–8.7 0.9–3.1 [168–170]
erythematosus
Rheumatoid 44–55 2/1 15–30% 9–36 31–45 8–42 [171–173]
arthritis
a
Data from [144].
1999 and 2012 was reported, whilst the prevalence TNFRSF6 membrane-bound ligand and caspase
increased from 64.99 to 97.04 per 100 000 per- 10 cysteine protease also influence apoptosis of
sons per year during the same period [14]. For lymphocytes, resulting in massive accumulation of
rheumatoid arthritis (RA), the global prevalence mononuclear cells within lymphoid tissue and
was estimated to be 0.24% in 2010, which was subsequent failure to delete autoreactive cells
essentially no different from the prevalence of [23]. Two other examples of a monogenic autoim-
0.25% in 1990 [15]. Traditional analytical epidemi- mune disease that illustrate these principles of
ological studies have shown that genetic suscepti- selection are the immunodysregulation polyen-
bility and environmental factors are the key risk docrinopathy enteropathy X-linked syndrome
factors that lead to loss of tolerance [16]. (IPEX) (in which there is a defect in the Foxp3
gene, localized to Xp11.23) [24] and IL-2Ra defi-
ciency (in which there is a deletion of the CD25
The genetic basis of autoimmunity
gene); in both cases, these mutations alter the
Many of the concepts of autoimmunity can be functional development of CD4+CD25+ Tregs, lead-
exemplified by discussing the rare monogenic ing to loss of peripheral tolerance [25] (Fig. 3).
autoimmune diseases, which pinpoint the concept
of genetic background [17]. For example, autoim- The majority of autoimmune diseases are not
mune polyendocrinopathy syndrome type 1 (APS1) monogenic, but rather have multiple genetic fac-
is a multiple organ-specific autoimmune disease, tors that play a role. Although there have been a
often starting in childhood or during the teenage variety of early studies showing associations with
years. Hallmark symptoms include chronic Can- the major histocompatibility complex (MHC) in
dida infection followed by autoimmune human autoimmune diseases, the results have
hypoparathyroidism and Addison’s disease [18– often have failed to lead to associations that have
20]. A mutation in the autoimmune regulator significant predictive strength for the clinician. The
(AIRE) gene was first identified by positional MHC is located on the short arm of chromosome 6
cloning in Finnish APS1 families [21]; it affects and harbours genes encoding molecules involved
negative selection in the thymus and thus self-anti- in antigen presentation and therefore is critical in
gen presentation. Another example of a monogenic distinguishing self from nonself. In humans, the
autoimmune disease is the autoimmune lympho- gene products of MHC are termed human leucocyte
proliferative syndrome, which is characterized by antigens (HLAs). A number of linkage studies have
the accumulation of a polyclonal population of identified genetic variants associated with autoim-
double-negative T cells (CD3+TCRab+CD4 CD8 ) mune diseases [26] including in T1D (HLA-II: DQ2
[22]. Mutations in tumour necrosis factor (TNF) and DQ8; HLA-I: HLA-A and DQB1*0602), SLE
receptor superfamily member 6 (TNFRSF6), (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
autoimmune diseases.
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, Hypomethylation of PAD2 174, 175]
DRB1*03:01-DQB1 CD58, IRF8, Hypomethylation of SHP-1
*02:01 BACH2, IL-12A, Acetylation:
DRB1*13:03-DQB1 Olig3-TNFAIP3, Hyperacetylation of H3
*03:01 PTGER4, RGS1, promoter region in
HLA class I: TNFRSF1A white matter
HLA-A*02:01 miRNA:
miR-326, miR-17-5p,
19a/b, miR-20a, miR-92b,
miR-21, miR-106b, miR-
34a, miR-155, miR-326,
and others
Type 1 diabetes HLA class II: INS,CTLA4, DNA methylation: [46, 176–179]
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 and others
Primary biliary HLA class II: IL-12, IL-12R, IL- DNA methylation: [2, 49, 180]
cirrhosis DRB1*08, 7R, CD80, CD40L
DRB1*11, and STAT4, TYK2, miRNA:
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,
and others
Autoimmune HLA class II: CTLA-4, TNF-a, _ [152, 153, 181]
hepatitis 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
Table 2 (Continued )

Graves’ disease HLA class II: CTLA-4, PTPN22, DNA methylation: [182–186]
DR3(DRB1*03 or CD25, CD40, ICMA1, DNMT1,
DQA1*0501) FCRL3 MECP2, IRF1
HLA class I: miRNA:
HLA-B8 miR-17, miR-155, miR-
146, miR-200a1
Crohn’s disease HLA class II: TLR4, CARD9, IL- DNA methylation: [187–191]
DR7, DRB3 23R, JAK2, CEACAM6, VMP1/
*03:01, DR4; STAT3, CCR6, miR-21, HLA loci
DR2 and DR3 ICOSLG, miRNA:
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
Ulcerative colitis HLA class II: TNFRSF14, DNA methylation: [187, 192–194]
DR2, DR15, DR9; PARK7, ERRFI1, CXCL14 CXCL5, GATA3,
DR4 protective CARD9, IL-23R, IL-17c, IL-4R, IFITM1,
IRF5, RNF186, ITGB2, S100A9, SLPI,
IL-17, IL-10, SAA1, STST3
PUS10 miRNA:
miR-29a, miR-505, miR-
28-5p, miR-151-5p, miR-
340, miR-532-3p, miR-16,
miR-21, miR-28-5p, miR-
155, miR-188-5p,
miR-422a
Coeliac disease HLA class II: IL-2, IL-21, DNA methylation: [195–198]
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
*03:02)
Addison’s disease HLA class II: UGT2B28, DNA methylation: [199–201]
DR3/DQ2 ADAM3A Hypomethylated
(DRB1*03:01-DQB1 status in CD4+ T cells
*02:01) miRNA:
DR4.4/DQ8 miR-200a
(DRB1*04:04-DQA1
*03:01-DQB1*03:02)

Sjogren’s syndrome HLA class II: STAT4, IL-12A, DNA methylation: [52, 202–206]
DRB1*15, DRB1*03 TNIP1, IRF5, Hypomethylated CD4+T,
DRB1*11, BLK, CXCR5 HERVs
DRB1*04 Acetylation:
DRB1*08:03 Acetylation of histone H4
and 16:02 in AQP5 gene promoter
DRB1*12:01 miRNA:
protective miR-146a, miR-155,Let-
7b, mir-21
Systemic lupus HLA Class II: STAT4, IFIH1, IRF5, DNA methylation: [50, 143,
erythematosus DR3(DRB1 TNFAIP3, PTPN22, NLRP2, CD300LB, S1PR3 207–211]
*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 hyperacetylation in CD4T
*08:01-DRB1*04:02) miRNA:
DR6(DRB1*13:02 miR-146a, miR-638, miR-
and 14:03) 16, miR-27a, miR-21,
protective miR-31, miR-125a, miR-
HLA Class III: 155, miR-371-5p, miR-
TNF,C2,C4,SCIV2L, 1224-3p, miR-423-5p,
CFB, RDBP,DOM3Z, miR-15, miR-148a, and
STK19C4A, C4B, others
Rheumatoid HLA Class II: PADI4, PTPN22, DNA methylation: [51, 212–215]
arthritis 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, CD40L promoter, CXCL12
DR1 CCR6, IRF5, Histone modification:
HLA Class III: RUNX1, GATA3 Alteration of histone
TNF modification in PBMCs
and synovium/
synoviocytes
HDAC inhibitors
miRNA:
miR-146a, miR-155, miR-
223, miR-124, miR-34,
miR-346, miR-203a, miR-
363, 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.
RDBP, DOM3Z, STK19C4A and C4B) and RA (HLA- pathway and mediates apoptosis induced by the
II: DR4; HLA-III: TNF); autoimmune thyroid disease TNF-related apoptosis-induced ligand. Further-
(AITD) (HLA-II: DR3 and DR4), psoriasis (HLA-I: more, it contributes to the development of dendritic
Cw*0602, Cw1203, and HCP5) and CeD (HLA-II: cells and promotes inflammatory macrophage
DQ2 and DQ8) are also strongly associated with polarization and Th1–Th17 responses. In RA,
specific HLA alleles (Table 2) [26]. However, despite SLE, PBC, UC and Sjogren’s syndrome (SS), IRF5-
a massive effort to identify the genetic basis of a TNPO3 is a susceptibility locus [34]. Similarly, BTB
number of autoimmune diseases through genome- and CNC homolog 2 (BACH2) is a transcription
wide association studies (GWAS), the results have repressor that belongs to the basic-region leucine
failed to have major predictive value. Of interest, zipper family and binds to Maf recognition ele-
however, the strongest component for genetic ments (MAREs). It has critical roles in both
bias in human autoimmunity still remains the acquired and innate immunity, including
MHC [27, 28]. immunoglobulin class-switch recombination [35],
somatic hypermutation of immunoglobulin-encod-
Although genomewide association studies have not ing genes, the pre-B-cell antigen receptor (pre-BCR)
led to the anticipated predictive properties, they checkpoint, development of B cells [36] and effector
have described several uncommon variants that and regulatory T cells [37], and the activation of
would not otherwise have been identified [29]. tissue macrophages. BACH2 has been identified as
Indeed, in the past 10 years, hundreds of non- a key regulator controlling the balance between
HLA loci have been reported to be associated with tolerance and immunity and is associated with loss
RA, SLE, MS, T1D, ulcerative colitis (UC), PBC, of tolerance in AITD [38], CeD [39], T1D [40],
autoimmune hepatitis and many other autoim- Crohn’s disease [41], MS [42] and vitiligo [43].
mune diseases [30]. These risk factors appear to be Other loci that are shared by several autoimmune
associated with gene products involved in both diseases include TNFRSF14, IL-12RB2, pseu-
innate and adaptive immune responses. But, more douridylate synthase 10 (PUS10), signal trans-
importantly, this has led to the idea that the ducer and activator of transcription 4 (STAT4),
occurrence of multiple autoimmune diseases cytotoxic T lymphocyte-associated protein 4
within one individual as well as an increased risk (CTLA4), CD80, IL-12B, thymocyte selection asso-
for developing an autoimmune disease in a family ciated (THEMIS), chemokine C-C motif receptor 6
member can be explained [31]. This concept is (CCR6), RNA-binding motif protein 17 (RBM17),
illustrated by the protein tyrosine phosphatase RAD51B, suppressor of cytokine signalling 1
nonreceptor type 22 (PTPN22) gene [32, 33], (SOCS1), IKAROS family zinc finger 3 (IKZF3),
expressed by hematopoietic cells. PTPN22 has a tyrosine kinase 2 (TYK2), intercellular adhesion
dual role and is critically involved in the regulation molecule 3 (ICAM3), runt-related transcription fac-
of immune cell signalling. In the adaptive immune tor 1 (RUNX1) and mitogen-activated protein kinase
system, PTPN22 inhibits T-cell activation by 1 (MAPK1). The presence of these loci supports the
restricting signalling downstream of the T-cell optimistic hypothesis that ‘one cure for many
receptor. By contrast, in the innate immune sys- diseases’ may be possible [44].
tem, PTPN22 selectively promotes myeloid cell type
I interferon production by enhancing signalling The concordance rate of autoimmune disease in
downstream of pattern recognition receptors. monozygotic twins ranges from 12% to 67% [45],
PTPN22, a classical shared autoimmunity gene, suggesting that factors other than genetic suscepti-
has been found in patients with many autoimmune bility may coexist. Clearly, there are requirements
disorders, including T1D, RA, SLE, Graves’ disease for environmental interactions, which are discussed
and Crohn’s disease. below. However, there is increasing focus on the
likelihood that autoimmunity is at least partially
There are several other loci that illustrate the modulated by epigenetic mechanisms, including
overlap and the predisposition to autoimmunity DNA methylation. Numerous examples of epigenetic
within families. These include IRF5-TNPO3 encod- changes in DNA have been associated with loss of
ing interferon regulatory factor 5 and transportin 3. tolerance, including insulin DNA hypermethylation
This gene is involved in the accumulation of lym- in T1D [46], hypomethylation of peptidylarginine
phocytes within lymphoid organs and the failure to deaminase 2 (PAD2) [47] and Src homology region 2
delete autoreactive native T cells. This gene also domain-containing phosphatase-1 (SHP-1) [48] in
has a role in the Toll-like receptor (TLR) signalling MS, methylation of the CD40L promoter in PBC [49],
histone modification (global acetylation of histones K+-ATPase a chain have been found in human
H3 and H4) in active CD4 T cells in SLE [50], histone gastric autoimmunity [67].
deacetylase (HDAC) inhibitors in RA [51], acetyla-
tion of histone H4 in aquaporin 5 (AQP5) gene Any discussion of molecular mimicry and loss of
promoter in SS [52] and microRNA (e.g. miR-21) tolerance must also include the concept of epitope
signalling in T1D, MS, SLE, SS, UC and psoriasis spreading, that is a diversification of epitope speci-
[53–55]. Epigenetic or stochastic events may ficity from a dominant epitope to subdominant
become a critical bridge in understanding genetic (cryptic) epitopes [68]. The switch from dominant
and environmental interactions that lead to autoim- to cryptic epitopes begins with the initial mimicry to
munity; this emerging concept will require consid- the dominant epitope, followed by protein process-
erable research effort, in particular with regard to ing and antigen presentation, resulting in responses
mechanisms of action [56]. directed at neo-epitopes [69]. Epitope spreading in
autoimmunity was first noted in experimental
autoimmune encephalomyelitis (induced by prim-
The environmental influence of autoimmunity
ing mice with myelin antigens), stimulating the
The identification of specific environmental factors production/expression of myelin basic protein, pro-
has critical importance for understanding individ- teolipid protein, myelin oligodendrocyte glycopro-
ual susceptibility, but there are very few agents tein and myelin peptides [70]. A number of other
that clearly have a role and identification of generic mechanisms have been proposed, including bystan-
risk factors remains elusive. These environmental der activation [71], viral persistence and polyclonal
factors include nutrition, the microbiota, infectious activation, which have the potential to induce/
processes and xenobiotics, such as tobacco smoke, modulate postinfection autoimmunity [72]
pharmaceutical agents, hormones, ultraviolet (Table 3). Although there is no direct evidence that
light, silica solvents, heavy metals, vaccines and it fulfils Koch’s postulates, EBV has been reported to
collagen/silicone implants [57–59]. be a cofactor in numerous autoimmune diseases,
including SLE, SS, RA [73], MS [74] and PBC [75].
Infectious agents have long been the most well- The majority of such studies are difficult to interpret,
studied environmental factors [60]. The best exam- and it is possible that EBV serves as a generic
ple of a relation between infection and immunity is polyclonal activator that amplifies underlying
acute rheumatic fever, which occurs following autoimmunity.
exposure in genetically susceptible hosts to Strep-
tococcus pyogenes [61]. The mechanism of autoim- Numerous other infectious agents have been sug-
munity in acute rheumatic fever is thought to be gested but not proved to have a role, including
‘molecular mimicry’ between the bacterial M pro- bacteria (Gram negative and positive), other viruses
tein and human lysoganglioside that leads to loss (herpes simplex virus, mouse mammary tumour
of immunological tolerance and the development of virus and cytomegalovirus), parasites (try-
cardiac reactive T cells [62]. The term ‘molecular panosomes and Ascaridia galli) and fungi (Saccha-
mimicry’ was first coined by Damian in 1964, who romyces cerevisiae) [2, 76]. Perhaps more important
suggested that selected antigenic determinants of than the presence of specific agents is the suggestion
microorganisms could potentially resemble host that predisposition to autoimmunity may be influ-
epitopes and were therefore capable of eliciting an enced by the microflora. This concept has been
autoimmune response [63, 64]. Multiple examples termed the ‘hygiene hypothesis’ and was first sug-
of molecular mimicry in infectious agents have gested by Strachan in 1989 [77]. It was suggested
been identified, but it is not always clear whether that the increase in autoimmune diseases observed
or not such mimicry is clinically significant. How- in the Western world was due in part to a decline in
ever, it should be noted that similarities have been infectious disease exposure and subsequent
reported between the Epstein–Barr virus (EBV) improved hygiene. This hypothesis applies to almost
peptide PPPGRRP and the PPPGMRPP peptide of all autoimmune diseases and has become particu-
Sm in EBV-infected SLE patients [65]; similarly, larly attractive in T1D and in inflammatory bowel
sequence homology between myelin basic protein disease. Early supporting evidence was based on
and HHV6-encoded U24, and cross-reactive T cells retrospective epidemiological studies [72].
have been reported in patients with MS [66], and
nine Helicobacter pylori proteins, each harbouring The relationships between the microbiota, host
a T-cell epitope, cross-reactive with the gastric H+, immune responses and autoimmunity have
Table 3 Proposed mechanisms for infection-related autoimmunity
Mechanisms Infections Diseases References

Molecular mimicry: Sequence Streptococcus pyogenes Acute rheumatic [61]
similarities between (bacterial M protein) fever (ARF)
pathogen-derived peptides Escherichia coli (PDC- PBC [2]
and self-peptides E2212–226, PDC-E2212–226), Pseudomonas
aeruginosa (PDC-E2159–167)
Helicobacter pylori (H+, Gastric autoimmunity, [67]
K -ATPase a chain)
+
SS, PBC
EBV (PPPGRRP peptide) SLE, [65]
HHV6 (U24) MS [66]
Cytomegalovirus; T1D [216–218]
Enteroviruses;
Rotavirus
Epitope spreading: Changes HCV (polypeptide AIH (type 2) [219]
from primary epitope precursor)
to other epitopes EBV (Epstein–Barr virus SLE, MS, RA [220–222]
nuclear antigen-1)
Cytomegalovirus SLE [223]
infection
Bystander activation: Measles virus MS [224],
Activation of pre-existing EBV MS [217]
autoreactive immune cells
Viral persistence and EBV MS, SLE, RA, SS, PBC, MS [73–75]
polyclonal activation: Enterovirus T1D [225]
Constant presence of viral
antigen driving the immune
response or epitope spreading
PDC-E2, the E2 subunit of the pyruvate dehydrogenase complex; EBV, Epstein–Barr virus; HHV6, human herpes virus 6;
ARF, acute rheumatic fever.
become a subject of intense interest, particularly givalis [83] and Prevotella nigrescens [84]) and
as microbes are located at the host–environment intestinal (Bacteroidetes and Bifidobacterium) [85,
interface, for example the skin, gastrointestinal 86] microbiota have been correlated with the onset
tract, genital tract and respiratory mucosal barrier. and course of disease. Recent data have demon-
With improved methods, including sophisticated strated that changes in the colonization of
sequencing and high-throughput technology, it segmented filamentous bacteria influence autoim-
has been demonstrated that changes in the micro- munity even into adult life [87] (Fig. 4).
biota even in normal hosts are pivotal to normal
immune development and homoeostasis. Of inter- The best example of the importance of noninfec-
est, available data suggest that changes in the gut tious environmental agents is the relationship
microbiome precede the onset of T1D and are also between gluten ingestion and CeD [88]. However,
associated with the progression of disease [78]. perhaps of more interest is the appearance of
From a microbiological perspective, changes in autoimmune diseases following exposure to many
Firmicutes [79, 80] and Bacteroidetes [81, 82] in common pharmaceutical agents, for example the
the upper small bowel mucosal and faecal flora many drugs that induce lupus. This subject has
have been detected particularly in coeliac disease. been extensively reviewed elsewhere, but it should
Interestingly, in RA, the oral (Porphyromonas gin- be emphasized that such lupus-like syndromes
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 neo-
epitopes. 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. Of interest to the clinician is the relationship
However, there remains the possibility that the between vitamin D levels and the immune response.
autoimmune disease may persist in some patients It has long been known that vitamin D is a natural
and it is very difficult if not impossible to identify a immune modulator [91], in addition to its role in
specific trigger in such individuals by epidemiolog- modulation of calcium metabolism, cellular growth,
ical analysis. There is, however, considerable data proliferation and apoptosis [92]. Epidemiological
to suggest that chemical modifications can lead to studies have demonstrated that reduced levels of
loss of tolerance in two other diseases. First, in vitamin D lead to an increased risk for loss of
PBC, modification of mitochondrial antigens by tolerance. In fact, reduced levels of vitamin D have
food additives, in particular 2-octynoic acid, may now been demonstrated in multiple human autoim-
lead to the development of the hallmark antimito- mune diseases [93]. With the large number of
chondrial antibodies [16]. Secondly, higher con- individuals living in large cities, and often indoors
sumption of dietary iodine increases the incidence with insufficient sunlight exposure, this deficiency
and severity of AITD. Iodine incorporation in thy- may be prevented by vitamin D supplementation.
roglobulin augments the antigenicity of this mole- Once again, more studies are needed.
cule by increasing the affinity of its determinants
for the T-cell receptor or the MHC-presenting Smoking is by far the most well-recognized risk
molecule [89]. A list of other suggested noninfec- factor for RA [94] as well as for SLE [95]. It might
tious agents and their mechanisms of action is contribute to disease development via several
presented in Table 4. Patients often inquire about pathways. Cigarette smoke contains several TLR-
the risks of vaccination. Vaccination is a long- stimulating compounds, including lipopolysaccha-
established and extremely important public health ride (a TLR4 agonist), which can elicit an innate
measure, and fortunately, side effects are rare. immune response. By interacting with the HLA
However, for genetically predisposed individuals, haplotype [96] and changing gene expression in the
there are rare instances of autoimmune reactions joint [97], smoking may promote the development
and autoimmune disease that have been precipi- of RA. It has also been reported that other autoim-
tated by vaccines, likely via the mechanisms of mune diseases, including PBC, SS and AITD, are
molecular mimicry. This should not, however, associated with tobacco smoke [98].
prevent the use of vaccination [90]. Less well
known is whether vaccination can exacerbate Environmental factors have also been found to
autoimmune disease and our recommendations induce changes in apoptosis [99]. Autoantigens
are to avoid vaccination during an active phase of have been demonstrated within apoptotic bodies
autoimmunity. and apoptotic cells and appear critical for the
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]
2) Increase circulating T lymphocytes
3) Augment autoreactive B cells
4) Exposure and release of autoantibodies
Ultraviolet 1) Oxidative damage to DNA and RNA SLE, RA, MS, T1D [226–228]
light 2) Induce apoptotic and necrotic cell death
3) Promote the release of TLR7
and TLR9 ligands
Iodine 1 Increase the affinity of its determinants Autoimmune thyroid [89]
for the T-cell receptor or the
MHC-presenting molecule
Hormones 1) Influence both innate and adaptive Most of the ADs (SLE, MS, RA) [229, 230]
immune responses
2) Affect signal pathway: HoxC4,
activation-induced deaminase,
miR-155, or miR-181b
Apoptosis 1) Presentation of antigens SEL, PBC, T1D, CeD, AIH [100, 102, 104–107]
2) Activate innate immunity
3) Regulate macrophage cytokine secretion
Vaccines 1) Stimulate the immune system via SLE, RA, MS, AIH, PBC [90]
pattern recognition receptors, such as
TLRs, increase the risk of initiation
or progression of ADs
Heavy metals 1) Deregulate balance of Th1 and Th2, SLE, AIH, RA, SS [227, 231]
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 in SLE [102, 103], PBC [104], T1D [105], CeD [106]
immunity and regulation of macrophage cytokine and autoimmune hepatitis [107].
secretion [100]. A classical experimental model
that illustrates these principles is lymphoprolifer-
Mechanisms of tissue destruction
ation (Lpr) and generalized lymphoproliferative
disease (gld), in which mice develop an autoim- Tissue destruction can be divided into a variety of
mune disease that resembles human SLE [101]. In effector pathways depending on the autoimmune
humans, defects in apoptosis have been reported disease. Of note, the immune system is promiscu-
ous and there is often an orchestrated response plement activation and/or antibody-dependent
that involves a multitude of diverse cell popula- cell-mediated cytotoxicity (ADCC) are the most
tions. This has made treatment of some diseases, common pathways of destruction [109]. Classical
such as SLE and SS, very difficult. The effector ADCC is mediated by natural killer cells that
mechanisms for a number of autoimmune diseases carry the receptor for the Fc portion of IgG;
are illustrated in Fig. 5. binding stimulates the release of hydrogen per-
oxide and hydroxyl radicals. Other cells, that is
The presence of autoantibodies is a common monocytes and eosinophils, can also mediate
feature of autoimmune diseases [108], and a ADCC. ADCC is a known mechanism in AITD
large number of serum antibodies are directed mediated by antithyroperoxidase antibodies [110].
against functional structures of the cell (nucleic Immune complex-mediated damage is another
acids, nuclear molecules, receptors or other func- important pathogenic mechanism; SLE is a typ-
tional cell components). They not only play a ical example of damage by immune complex. In
central role in diagnosis and classification, but RA, rheumatoid factor-IgG complexes are also a
may also be involved in tissue damage. One of the component of synovial damage. Autoantibodies
best-established pathogenic effects of autoanti- may also interact with cell surface receptors,
bodies is the cytotoxic destruction of cells by cell which can both activate (antithyroid-stimulating
surface binding and lysis. In this process, com- 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
Fas–Fas 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).
pathways (anti-acetylcholine receptor for myas- to tissue injury [113]. The paradigm of Th1/Th2
thenia gravis). Another mechanism includes bind- balance has shifted due to the increasing body of
ing to extracellular molecules (such as in the information on other CD4 subsets, including Th17
antiphospholipid antibody syndrome) where [114], Tregs [115] and T follicular helper cells (Tfh)
autoantibodies are directed against b2-glycopro- [116].
tein I in plasma [111].
PBC: a model autoimmune disease
Unlike autoantibodies, relevant (disease-associ-
ated) autoreactive T cells [112] act on the target Autoimmune disorders are a spectrum of diseases
tissue and circulate only at very low precursor ranging from those that are organ specific, in which
levels. In other words, the autoreactive T-cell antibodies and T cells react to self-antigens local-
precursor level in the target tissue is much higher, ized in a specific tissue, to organ-non-specific or
often more than 100-fold in the target organ, than systemic diseases characterized by reactivity
in the peripheral blood. Autoreactive cytotoxic T against antigens spread throughout various tis-
lymphocytes (CTL) recognize a target cell by bind- sues (Fig. 6). Numerous classifications have been
ing the T-cell receptor (TCR) to the appropriate proposed for autoimmune diseases, even for the
combination of MHC I and autoantigen-derived same autoimmune disease, and these generally
peptides. Then, a complex of MHC I and autoanti- depend upon clinical features, serology and
gen-derived peptides directly kills target cells histopathology (Table 5). The diagnostic and clin-
through different mechanisms: (i) secretion of ical classifications of a variety of autoimmune
cytotoxic granules (perforin and granzyme B) diseases have been reviewed recently [117–131].
resulting in disintegration of the cell membrane However, with the development of proteomic,
and induced apoptosis; (ii) activation of Fas–Fas genomic and metabolomics, far more sensitive
ligand, which induces apoptosis; and (iii) release of and specific methodologies will be developed in
cytokines (such as TNF-a and interferon-c), leading the future (Fig. 7).
Fig. 6 Representative organ-

specific and systemic
Table 5 Diagnosis of organ-specific and organ-non-specific autoimmune disease (for some classical autoimmune diseases)
384
Disease Known antigen Autoantibodies Target organ Pathology (or biopsy) Diagnostic criteria
Multiple sclerosis Myelin protein, (MBP, Antibodies against Central nervous Freshly demyelinated ‘plaques’ Revised 2010
MOG, PLP, MAG, lipids) myelin protein (lack system in the brain matter McDonald diagnostic
diagnostic specificity) criteria [232]
L. Wang et al.
Type 1 diabetes Glutamate decarboxylase IAA, GADA, IA-2A, Pancreas b-islets Decreased b cell mass with 2010 diagnostic
(GAD-65), insulin receptor, ZnT8A infiltration of mononuclear criteria [233]
IA-2 (ICA512), insulin cells into the islets (‘insulitis’)
Primary biliary Mitochondrial (PDC-E2) AMA Small- and Ludwig’s stage I–IV 2009 diagnostic
cirrhosis medium-sized criteria [234]
intrahepatic

bile ducts
Autoimmune Chromatin, ANA, anti-LKM-1, Liver Interface (periportal or 1999 [235] and 2008
hepatitis ribonucleoproteins, antismooth muscle perseptal) hepatitis [236] criteria
asialoglycoprotein receptor, antibody, anti-actin with a predominantly
cytochrome P4502D6 lymphoplasmacytic
(CYP2D6), F-actin necroinflammatory infiltrate
ª 2015 The Association for the Publication of the Journal of Internal Medicine
Primary sclerosing Tubulin-b isoform 5 Antineutrophil Bile ducts Typical ‘onion-skinning’ lesions 2010 diagnostic
cholangitis cytoplasmic antibody, Ludwig’s stage I–IV criteria [237]
ANA, anti-SM, anti-
endothelial cell
antibody,
anticardiolipin
antibody
Graves’ disease TSHR, sodium iodide Anti-TSHR Thyroid Thyroid follicles 2010 diagnostic
transporter autoantibodies criteria [238]
Crohn’s disease Desmin, saccharomyces Anti-TG2, antigliadin Gastrointestinal Focal (discontinuous) 2010 diagnostic
cerevisiae, Tubulin-b tract chronic inflammation, focal criteria [239]
isoform 5? crypt architectural irregularity,
transmural inflammation,
granulomas (not related to
crypt injury), increased
intra-epithelial lymphocytes,
pyloric gland metaplasia
Review: Human autoimmune diseases
Disease Known antigen Autoantibodies Target organ Pathology (or biopsy) Diagnostic criteria
Ulcerative colitis Desmin, saccharomyces ANCA, GAB Colon Diffuse inflammatory cell infiltration 2008 diagnostic
L. Wang et al.
cerevisiae, tubulin-b of the mucosa with basal criteria [240]

isoform 5? plasmacytosis, crypt architecture,
reduction of mucus-secreting
goblet cells
Coeliac Tissue transglutaminase Endomysial IgA Small intestine Intra-epithelial lymphocytosis, 1990 revised ESPGAN
disease antibodies and crypt hyperplasia, villous atrophy criteria [88, 241]
antitissue
transglutaminase
antibodies
Addison’s disease 21-hydroxylase (CYP21) ACA Adrenal glands Widespread mononuclear cell 2014 criteria [163]
infiltrate in adrenal glands
(containing lymphocytes, plasma
cells, and macrophages, during
the active phase)
Sjogren’s La phosphoprotein (La 55-B), Anti-Ro/SSA, anti-La/ Several organs (Lymphocytic sialadenitis), 2012 revised
syndrome golgin (95, 97, 160, 180) SSB, ANA (e.g. lungs, liver, lymphoepithelial lesions in ACR/SICCA
Ro52/TRIM21, kidneys, central salivary and lacrimal glands criteria [242, 243]
Ro60/TROVE2, La/SSB nervous system),
mainly salivary and
lacrimal glands
Systemic lupus Cardiolipin, carbonic anhydrase Antinuclear antibody, Several organs (heart, Nephritis compatible with lupus 2012 new SLICC
erythematosus II, collagen, RNA anti-dsDNA antibody, joints, skin, lungs, classification
polymerase I–III anti-Sm, blood vessels, liver, criteria [168, 244]
(RNP), fibronectin, golgin antiphospholipid kidneys, and
(95, 97, 160, 180), C1q, antibody nervous system)
histone H2A-H2B-DNA
Rheumatoid arthritis Rheumatoid factor, keratin, Anti-CCP synovium of joints Pathological changes in synovium 2010 ACR/EULAR
CCP, collagen, fibronectin RF-IgG, ACPA, anti- criteria [245]
Carp
ACR/SICCA, American College of Rheumatology/Sj€ ogren’s International Collaborative Clinical Alliance; SLICC, Systemic Lupus International
Collaborating Clinic; EULAR, European League Against Rheumatism.

ª 2015 The Association for the Publication of the Journal of Internal Medicine
Review: Human autoimmune diseases
385
Fig. 7 Diagnostic platform for

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

Glucocorticoid (cortisone, Suppress the whole activated 1) Increase the rates [246–248]
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 [249]
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
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 Inhibits T-cell activation (only 1) Adverse events PMID: 14614165;
(abatacept, RG2077) approved for RA, still in (infection, malignancies) 23800448
clinical trials for other ADs) 2) Acute infusion events
3) Autoimmunity
(psoriasis, vasculitis)
Azathioprine (purine Inhibits synthesis of DNA (SLE, 1) Increase risk of malignancy [251–254]
analogues) CD, MS, PBC, myasthenia 2) Bone marrow suppression
gravis, AIH, etc.) 3) Nausea and vomiting
development of novel therapeutic agents. At pre- not only for the treatment of RA, but also for SLE,
sent, ursodeoxycholic acid is the only agent psoriasis, psoriatic arthritis, inflammatory bowel
approved to treat PBC; the mechanism of action disease, MS and many others. It is beyond the scope
is not entirely understood, but it may reduce the of this review to discuss the individual agents (see
bystander inflammatory response. Liver transplan- Table 6 for a list of the more commonly used agents
tation is the final option for patients with end-stage and their side effects). It is clear that the goal for
disease and, importantly, PBC may recur following treating patients with autoimmunity is a specific
transplantation despite the absence of MHC agent that will completely reverse if not cure the
matching [142]. Finally, as with many other disease. At present, this does not exist for any
autoimmune diseases, there is considerable ongo- autoimmune disease. By contrast, it is hoped that it
ing research to identify specific activation path- would also be possible to modify the host immune
ways, the blockade of which might reduce the system to restore tolerance. Although this is possi-
inflammatory and therefore cytopathic response. ble in selected mouse models of autoimmunity, it
has not proven effective as yet in humans despite
many attempts using immunotherapy, including
New approaches to therapy
stem cell therapies. However, our understanding of
The new paradigm in the treatment of autoimmune human autoimmune disease has and continues to
diseases is the use of biological agents that modify be developed through a huge number of molecular
specific inflammatory and/or effector pathways. studies investigating not only genetic factors, but
The agents that block TNF-a were the first drugs also the role of epigenetics [143], the environment,
approved and since then drugs have been developed 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 4) Neurological disorders
IL-6 inhibitor (tocilizumab) Blocks the signal pathway 1) Infection [256]
of IL-6 (only approved for RA, 2) Gastrointestinal complaints
still in clinical trials for 3) Rash
other ADs) 4) Headache
5) Biochemical abnormalities
Ustekinumab Blocks the signal pathway 1) Increased incidence of [257]
of IL-12 nonmelanoma skin cancer
2) Headache
3) Back pain
Anti-CD20 antibody Selective B-cell depletion 1) Infusion reaction [258, 259]
(rituximab) 2) Infections (progressive
multifocal leukoencephalopathy,
Hepatitis B virus (HBV),
tuberculosis)
3) Hypogammaglobulinemia
4) Herpes zoster reactivation
AD, autoimmune disease; TNF, tumour necrosis factor; CD, Crohn’s disease; AIH, autoimmune hepatitis; RA, rheumatoid
arthritis; SLE, systemic lupus erythematosus; MS, multiple sclerosis; PBC, primary biliary cirrhosis; IBD, inflammatory
bowel disease.
been improvements in laboratory testing methods, 11 Wahren-Herlenius M, Dorner T. Immunopathogenic mecha-

including standardization of serology and develop- nisms of systemic autoimmune disease. Lancet 2013; 382:
819–31.
ment of new autoantibody tests. Further, improved
12 Milo R, Kahana E. Multiple sclerosis: geoepidemiology,
understanding of geoepidemiology has led to a genetics and the environment. Autoimmun Rev 2010; 9:
much better appreciation of what is happening to A387–94.
individual patients during a breach of tolerance. 13 West J, Fleming KM, Tata LJ, Card TR, Crooks CJ. Incidence
Autoimmunity is a challenge for all clinicians; and prevalence of celiac disease and dermatitis herpeti-
nevertheless, the prognosis for patients with these formis in the UK over two decades: population-based study.
Am J Gastroenterol 2014; 109: 757–68.
diseases has dramatically improved in the past
14 Rees F, Doherty M, Grainge M, Davenport G, Lanyon P,
decade and we anticipate further improvements in Zhang W. The incidence and prevalence of systemic lupus
the future. erythematosus in the UK, 1999–2012. Ann Rheum Dis 2014;
doi: 10.1136/annrheumdis-2014-206334.
15 Cross M, Smith E, Hoy D et al. The global burden of
Conflict of interest statement rheumatoid arthritis: estimates from the global burden of
No conflicts of interest to declare. disease 2010 study. Ann Rheum Dis 2014; 73: 1316–22.
16 Leung PS, Wang J, Naiyanetr P et al. Environment and
primary biliary cirrhosis: electrophilic drugs and the induc-
Acknowledgements tion of AMA. J Autoimmun 2013; 41: 79–86.
17 Ulmanen I, Halonen M, Ilmarinen T, Peltonen L. Monogenic
This work was supported by the National Natural autoimmune diseases – lessons of self-tolerance. Curr Opin
Science Foundation of China, grant 81470837, and Immunol 2005; 17: 609–15.
National Institutes of Health grant DK39588. We 18 Ahonen P, Myllarniemi S, Sipila I, Perheentupa J. Clinical
variation of autoimmune polyendocrinopathy-candidiasis-
thank Lei Jin and all other persons who contrib-
ectodermal dystrophy (APECED) in a series of 68 patients. N
uted to this work Engl J Med 1990; 322: 1829–36.
19 Barrera MJ, Bahamondes V, Sepulveda D et al. Sjogren’s
syndrome and the epithelial target: a comprehensive review.
J Autoimmun 2013; 42: 7–18.
References 20 Endo T, Kobayashi T. Immunization of mice with a newly
identified thyroid-stimulating hormone receptor splice vari-
1 Yu C, Gershwin ME, Chang C. Diagnostic criteria for
ant induces Graves’-like disease. J Autoimmun 2013; 43:
systemic lupus erythematosus: a critical review. J Autoim-
18–25.
mun 2014; 48–49: 10–3.
21 Nagamine K, Peterson P, Scott HS et al. Positional cloning of
2 Wang L, Wang FS, Chang C, Gershwin ME. Breach of
the APECED gene. Nat Genet 1997; 17: 393–8.
tolerance: primary biliary cirrhosis. Semin Liver Dis 2014;
22 Le Deist F, Emile JF, Rieux-Laucat F et al. Clinical,
34: 297–317.
immunological, and pathological consequences of Fas-defi-
3 Silverstein AM. Paul Ehrlich, archives and the history of
cient conditions. Lancet 1996; 348: 719–23.
immunology. Nat Immunol 2005; 6: 639.
23 Shah S, Wu E, Rao VK, Tarrant TK. Autoimmune lympho-
4 Rose NR, Witebsky E. Studies on organ specificity. V.
proliferative syndrome: an update and review of the litera-
Changes in the thyroid glands of rabbits following active
ture. Curr Allergy Asthma Rep 2014; 14: 462.
immunization with rabbit thyroid extracts. J Immunol 1956;
24 Gambineri E, Torgerson TR, Ochs HD. Immune dysregula-
76: 417–27.
tion, polyendocrinopathy, enteropathy, and X-linked inher-
5 Salinas GF, Braza F, Brouard S, Tak PP, Baeten D. The
itance (IPEX), a syndrome of systemic autoimmunity caused
role of B lymphocytes in the progression from autoimmu-
by mutations of FOXP3, a critical regulator of T-cell home-
nity to autoimmune disease. Clin Immunol 2013; 146: 34–
ostasis. Curr Opin Rheumatol 2003; 15: 430–5.
45.
25 Sakaguchi S. Naturally arising Foxp3-expressing
6 Hang LM, Nakamura RM. Current concepts and advances in
CD25+CD4+ regulatory T cells in immunological tolerance
clinical laboratory testing for autoimmune diseases. Crit Rev
to self and non-self. Nat Immunol 2005; 6: 345–52.
Clin Lab Sci 1997; 34: 275–311.
26 Sollid LM, Pos W, Wucherpfennig KW. Molecular mecha-
7 Avrameas S, Selmi C. Natural autoantibodies in the phys-
nisms for contribution of MHC molecules to autoimmune
iology and pathophysiology of the immune system. J Autoim-
diseases. Curr Opin Immunol 2014; 31: 24–30.
mun 2013; 41: 46–9.
27 Cui Y, Sheng Y, Zhang X. Genetic susceptibility to SLE:
8 Panda S, Ding JL. Natural antibodies bridge innate and
recent progress from GWAS. J Autoimmun 2013; 41: 25–33.
adaptive immunity. J Immunol 2015; 194: 13–20.
28 Lu Q. The critical importance of epigenetics in autoimmu-
9 Jacobson DL, Gange SJ, Rose NR, Graham NM. Epidemiol-
nity. J Autoimmun 2013; 41: 1–5.
ogy and estimated population burden of selected autoim-
29 Hu X, Daly M. What have we learned from six years of GWAS
mune diseases in the United States. Clin Immunol
in autoimmune diseases, and what is next? Curr Opin
Immunopathol 1997; 84: 223–43.
Immunol 2012; 24: 571–5.
10 Eaton WW, Rose NR, Kalaydjian A, Pedersen MG, Mortensen
30 Deitiker P, Atassi MZ. Non-MHC genes linked to autoim-
PB. Epidemiology of autoimmune diseases in Denmark. J
mune disease. Crit Rev Immunol 2012; 32: 193–285.
Autoimmun 2007; 29: 1–9.
31 Cho JH, Gregersen PK. Genomics and the multifactorial in patients with primary biliary cirrhosis. Hepatology 2012;
nature of human autoimmune disease. N Engl J Med 2011; 55: 153–60.
365: 1612–23. 50 Hu N, Qiu X, Luo Y et al. Abnormal histone modification
32 Stanford SM, Bottini N. PTPN22: the archetypal non-HLA patterns in lupus CD4+ T cells. J Rheumatol 2008; 35: 804–
autoimmunity gene. Nat Rev Rheumatol 2014; 10: 602–11. 10.
33 Wiede F, Ziegler A, Zehn D, Tiganis T. PTPN2 restrains CD8 51 Young DA, Lakey RL, Pennington CJ et al. Histone deacety-
(+) T cell responses after antigen cross-presentation for the lase inhibitors modulate metalloproteinase gene expression
maintenance of peripheral tolerance in mice. J Autoimmun in chondrocytes and block cartilage resorption. Arthritis Res
2014; 53: 105–14. Ther 2005; 7: R503–12.
34 Kottyan LC, Zoller EE, Bene J et al. The IRF5-TNPO3 52 Yamamura Y, Motegi K, Kani K et al. TNF-alpha inhibits
association with systemic lupus erythematosus has two aquaporin 5 expression in human salivary gland acinar cells
components that other autoimmune disorders variably via suppression of histone H4 acetylation. J Cell Mol Med
share. Hum Mol Genet 2015; 24: 582–96. 2012; 16: 1766–75.
35 Muto A, Tashiro S, Nakajima O et al. The transcriptional 53 Xu WD, Pan HF, Li JH, Ye DQ. MicroRNA-21 with therapeu-
programme of antibody class switching involves the repres- tic potential in autoimmune diseases. Expert Opin Ther
sor Bach2. Nature 2004; 429: 566–71. Targets 2013; 17: 659–65.
36 Itoh-Nakadai A, Hikota R, Muto A et al. The transcription 54 Qu Z, Li W, Fu B. MicroRNAs in autoimmune diseases.
repressors Bach2 and Bach1 promote B cell development by Biomed Res Int 2014; 2014: 527895.
repressing the myeloid program. Nat Immunol 2014; 15: 55 Pauley KM, Cha S, Chan EK. MicroRNA in autoimmunity
1171–80. and autoimmune diseases. J Autoimmun 2009; 32: 189–94.
37 Roychoudhuri R, Hirahara K, Mousavi K et al. BACH2 56 Wang Z, Zheng Y, Hou C et al. DNA methylation impairs
represses effector programs to stabilize T(reg)-mediated TLR9 induced Foxp3 expression by attenuating IRF-7 bind-
immune homeostasis. Nature 2013; 498: 506–10. ing activity in fulminant type 1 diabetes. J Autoimmun 2013;
38 Plagnol V, Howson JM, Smyth DJ et al. Genome-wide 41: 50–9.
association analysis of autoantibody positivity in type 1 57 Colafrancesco S, Perricone C, Priori R, Valesini G, Shoenfeld
diabetes cases. PLoS Genet 2011; 7: e1002216. Y. Sjogren’s syndrome: another facet of the autoimmune/
39 Dubois PC, Trynka G, Franke L et al. Multiple common inflammatory syndrome induced by adjuvants (ASIA). J
variants for celiac disease influencing immune gene expres- Autoimmun 2014; 51: 10–6.
sion. Nat Genet 2010; 42: 295–302. 58 Kivity S, Arango MT, Ehrenfeld M et al. Infection and
40 Cooper JD, Smyth DJ, Smiles AM et al. Meta-analysis of autoimmunity in Sjogren’s syndrome: a clinical study and
genome-wide association study data identifies additional comprehensive review. J Autoimmun 2014; 51: 17–22.
type 1 diabetes risk loci. Nat Genet 2008; 40: 1399–401. 59 Peng J, Narasimhan S, Marchesi JR, Benson A, Wong FS,
41 Franke A, McGovern DP, Barrett JC et al. Genome-wide Wen L. Long term effect of gut microbiota transfer on
meta-analysis increases to 71 the number of confirmed diabetes development. J Autoimmun 2014; 53: 85–94.
Crohn’s disease susceptibility loci. Nat Genet 2010; 42: 60 Bogdanos DP, Smyk DS, Invernizzi P et al. Infectome: a
1118–25. platform to trace infectious triggers of autoimmunity. Au-
42 International Multiple Sclerosis Genetics Consortium, Well- toimmun Rev 2013; 12: 726–40.
come Trust Case Control Consortium 2, Sawcer S et al. 61 Cunningham MW. Rheumatic fever, autoimmunity, and
Genetic risk and a primary role for cell-mediated immune molecular mimicry: the streptococcal connection. Int Rev
mechanisms in multiple sclerosis. Nature 2011; 476: 214– Immunol 2014; 33: 314–29.
9. 62 Guilherme L, Oshiro SE, Fae KC et al. T-cell reactivity
43 Jin Y, Birlea SA, Fain PR et al. Genome-wide association against streptococcal antigens in the periphery mir-
analyses identify 13 new susceptibility loci for generalized rors reactivity of heart-infiltrating T lymphocytes in rheu-
vitiligo. Nat Genet 2012; 44: 676–80. matic heart disease patients. Infect Immun 2001; 69:
44 Zhernakova A, Withoff S, Wijmenga C. Clinical implications 5345–51.
of shared genetics and pathogenesis in autoimmune dis- 63 Blank M, Barzilai O, Shoenfeld Y. Molecular mimicry and
eases. Nat Rev Endocrinol 2013; 9: 646–59. auto-immunity. Clin Rev Allergy Immunol 2007; 32: 111–8.
45 Quintero-Ronderos P, Montoya-Ortiz G. Epigenetics and 64 Kremer JM, Westhovens R, Leon M et al. Treatment of
autoimmune diseases. Autoimmune Dis 2012; 2012: rheumatoid arthritis by selective inhibition of T-cell activa-
593720. tion with fusion protein CTLA4Ig. N Engl J Med 2003; 349:
46 Fradin D, Le Fur S, Mille C et al. Association of the CpG 1907–15.
methylation pattern of the proximal insulin gene promoter 65 James JA, Neas BR, Moser KL et al. Systemic lupus erythe-
with type 1 diabetes. PLoS ONE 2012; 7: e36278. matosus in adults is associated with previous Epstein-Barr
47 Calabrese R, Zampieri M, Mechelli R et al. Methylation- virus exposure. Arthritis Rheum 2001; 44: 1122–6.
dependent PAD2 upregulation in multiple sclerosis periph- 66 Mirandola P, Stefan A, Brambilla E, Campadelli-Fiume G,
eral blood. Mult Scler 2012; 18: 299–304. Grimaldi LM. Absence of human herpesvirus 6 and 7 from
48 Kumagai C, Kalman B, Middleton FA, Vyshkina T, Massa PT. spinal fluid and serum of multiple sclerosis patients. Neu-
Increased promoter methylation of the immune regulatory rology 1999; 53: 1367–8.
gene SHP-1 in leukocytes of multiple sclerosis subjects. J 67 Amedei A, Bergman MP, Appelmelk BJ et al. Molecular
Neuroimmunol 2012; 246: 51–7. mimicry between Helicobacter pylori antigens and H+, K+ –
49 Lleo A, Liao J, Invernizzi P et al. Immunoglobulin M levels adenosine triphosphatase in human gastric autoimmunity.
inversely correlate with CD40 ligand promoter methylation J Exp Med 2003; 198: 1147–56.
68 Vanderlugt CL, Miller SD. Epitope spreading in immune- 87 Van Praet JT, Donovan E, Vanassche I et al. Commensal
mediated diseases: implications for immunotherapy. Nat microbiota influence systemic autoimmune responses.
Rev Immunol 2002; 2: 85–95. EMBO J 2015; 34: 466–74.
69 Lehmann PV, Targoni OS, Forsthuber TG. Shifting T-cell 88 Green PH, Cellier C. Celiac disease. N Engl J Med 2007; 357:
activation thresholds in autoimmunity and determinant 1731–43.
spreading. Immunol Rev 1998; 164: 53–61. 89 Rose NR, Bonita R, Burek CL. Iodine: an environmental
70 Lehmann PV, Forsthuber T, Miller A, Sercarz EE. Spreading trigger of thyroiditis. Autoimmun Rev 2002; 1: 97–103.
of T-cell autoimmunity to cryptic determinants of an 90 van der Laan JW, Gould S, Tanir JY, Vaccines IH, Adjuvants
autoantigen. Nature 1992; 358: 155–7. Safety Project Committee. Safety of vaccine adjuvants: focus
71 Duke RC. Self recognition by T cells. I. Bystander killing of on autoimmunity. Vaccine 2015; 33: 1507–14.
target cells bearing syngeneic MHC antigens. J Exp Med 91 Antico A, Tampoia M, Tozzoli R, Bizzaro N. Can supplemen-
1989; 170: 59–71. tation with vitamin D reduce the risk or modify the course of
72 Kivity S, Agmon-Levin N, Blank M, Shoenfeld Y. Infections autoimmune diseases? A systematic review of the literature.
and autoimmunity–friends or foes? Trends Immunol 2009; Autoimmun Rev 2012; 12: 127–36.
30: 409–14. 92 Samuel S, Sitrin MD. Vitamin D’s role in cell proliferation
73 Draborg AH, Duus K, Houen G. Epstein-Barr virus in and differentiation. Nutr Rev 2008; 66: S116–24.
systemic autoimmune diseases. Clin Dev Immunol 2013; 93 Agmon-Levin N, Theodor E, Segal RM, Shoenfeld Y. Vitamin
2013: 535738. D in systemic and organ-specific autoimmune diseases. Clin
74 Abdelrahman HS, Selim HS, Hashish MH, Sultan LI. Ep- Rev Allergy Immunol 2013; 45: 256–66.
stein-Barr virus in multiple sclerosis. J Egypt Public Health 94 Afridi HI, Kazi TG, Talpur FN, Naher S, Brabazon D. Relation-
Assoc 2014; 89: 90–5. ship between toxic metals exposure via cigarette smoking and
75 Morshed SA, Nishioka M, Saito I, Komiyama K, Moro I. rheumatoid arthritis. Clin Lab 2014; 60: 1735–45.
Increased expression of Epstein-Barr virus in primary biliary 95 Ekblom-Kullberg S, Kautiainen H, Alha P, Leirisalo-Repo M,
cirrhosis patients. Gastroenterol Jpn 1992; 27: 751–8. Miettinen A, Julkunen H. Smoking, disease activity, perma-
76 Root-Bernstein R, Fairweather D. Complexities in the rela- nent damage and dsDNA autoantibody production in
tionship between infection and autoimmunity. Curr Allergy patients with systemic lupus erythematosus. Rheumatol Int
Asthma Rep 2014; 14: 407. 2014; 34: 341–5.
77 Strachan DP. Hay fever, hygiene, and household size. BMJ 96 Klareskog L, Gregersen PK, Huizinga TW. Prevention of
1989; 299: 1259–60. autoimmune rheumatic disease: state of the art and future
78 Dunne JL, Triplett EW, Gevers D et al. The intestinal perspectives. Ann Rheum Dis 2010; 69: 2062–6.
microbiome in type 1 diabetes. Clin Exp Immunol 2014; 97 Ospelt C, Camici GG, Engler A et al. Smoking induces
177: 30–7. transcription of the heat shock protein system in the joints.
79 Olivares M, Neef A, Castillejo G et al. The HLA-DQ2 genotype Ann Rheum Dis 2014; 73: 1423–6.
selects for early intestinal microbiota composition in infants 98 Arnson Y, Shoenfeld Y, Amital H. Effects of tobacco smoke on
at high risk of developing coeliac disease. Gut 2015; 64: 406– immunity, inflammation and autoimmunity. J Autoimmun
17. 2010; 34: J258–65.
80 Nistal E, Caminero A, Herran AR et al. Differences of small 99 Mackay IR, Leskovsek NV, Rose NR. Cell damage and
intestinal bacteria populations in adults and children with/ autoimmunity: a critical appraisal. J Autoimmun 2008; 30:
without celiac disease: effect of age, gluten diet, and disease. 5–11.
Inflamm Bowel Dis 2012; 18: 649–56. 100 Lleo A, Selmi C, Invernizzi P, Podda M, Gershwin ME. The
81 Sellitto M, Bai G, Serena G et al. Proof of concept of consequences of apoptosis in autoimmunity. J Autoimmun
microbiome-metabolome analysis and delayed gluten expo- 2008; 31: 257–62.
sure on celiac disease autoimmunity in genetically at-risk 101 Cohen PL, Eisenberg RA. Lpr and gld: single gene models of
infants. PLoS ONE 2012; 7: e33387. systemic autoimmunity and lymphoproliferative disease.
82 Schippa S, Iebba V, Barbato M et al. A distinctive ‘microbial Annu Rev Immunol 1991; 9: 243–69.
signature’ in celiac pediatric patients. BMC Microbiol 2010; 102 Pieterse E, van der Vlag J. Breaking immunological toler-
10: 175. ance in systemic lupus erythematosus. Front Immunol 2014;
83 Martinez-Martinez RE, Abud-Mendoza C, Patino-Marin N, 5: 164.
Rizo-Rodriguez JC, Little JW, Loyola-Rodriguez JP. Detec- 103 Shao WH, Cohen PL. Disturbances of apoptotic cell clear-
tion of periodontal bacterial DNA in serum and synovial fluid ance in systemic lupus erythematosus. Arthritis Res Ther
in refractory rheumatoid arthritis patients. J Clin Periodontol 2011; 13: 202.
2009; 36: 1004–10. 104 Lleo A, Bowlus CL, Yang GX et al. Biliary apotopes and
84 Moen K, Brun JG, Valen M et al. Synovial inflammation in anti-mitochondrial antibodies activate innate immune
active rheumatoid arthritis and psoriatic arthritis facilitates responses in primary biliary cirrhosis. Hepatology 2010;
trapping of a variety of oral bacterial DNAs. Clin Exp 52: 987–98.
Rheumatol 2006; 24: 656–63. 105 Vives-Pi M, Rodriguez-Fernandez S, Pujol-Autonell I. How
85 Vaahtovuo J, Munukka E, Korkeamaki M, Luukkainen R, apoptotic beta-cells direct immune response to tolerance or
Toivanen P. Fecal microbiota in early rheumatoid arthritis. J to autoimmune diabetes: a review. Apoptosis 2015; 20: 263–
Rheumatol 2008; 35: 1500–5. 72.
86 Scher JU, Sczesnak A, Longman RS et al. Expansion of 106 Hoffmanova I, Sanchez D, Habova V, Andel M, Tuckova L,
intestinal Prevotella copri correlates with enhanced suscep- Tlaskalova-Hogenova H. Serological markers of enterocyte
tibility to arthritis. eLife 2013; 2: e01202. damage and apoptosis in patients with celiac disease,
autoimmune diabetes mellitus and diabetes mellitus type 2. (formerly named Churg-Strauss syndrome). J Autoimmun
Physiol Res 2014; [Epub ahead of print]. 2014; 48–49: 99–103.
107 Czaja AJ. Targeting apoptosis in autoimmune hepatitis. Dig 128 Moutsopoulos HM. Sjogren’s syndrome: a forty-year scien-
Dis Sci 2014; 59: 2890–904. tific journey. J Autoimmun 2014; 51: 1–9.
108 Damoiseaux J, Andrade LE, Fritzler MJ, Shoenfeld Y. 129 Nesher G. Polymyalgia rheumatica–diagnosis and classifi-
Autoantibodies 2015: from diagnostic biomarkers toward cation. J Autoimmun 2014; 48–49: 76–8.
prediction, prognosis and prevention. Autoimmun Rev 2015; 130 Raychaudhuri SP, Deodhar A. The classification and diag-
14: 555–63. nostic criteria of ankylosing spondylitis. J Autoimmun 2014;
109 Ohishi K, Kanoh M, Shinomiya H, Hitsumoto Y, Utsumi S. 48–49: 128–33.
Complement activation by cross-linked B cell-membrane 131 Sanchez-Manubens J, Bou R, Anton J. Diagnosis and
IgM. J Immunol 1995; 154: 3173–9. classification of Kawasaki disease. J Autoimmun 2014; 48–
110 Rodien P, Madec AM, Ruf J et al. Antibody-dependent cell- 49: 113–7.
mediated cytotoxicity in autoimmune thyroid disease: rela- 132 Lleo A, Zhang W, McDonald WH et al. Shotgun pro-
tionship to antithyroperoxidase antibodies. J Clin Endocrinol teomics: identification of unique protein profiles of apop-
Metab 1996; 81: 2595–600. totic bodies from biliary epithelial cells. Hepatology 2014;
111 Lleo A, Invernizzi P, Gao B, Podda M, Gershwin ME. Definition 60: 1314–23.
of human autoimmunity–autoantibodies versus autoim- 133 Zhang J, Zhang W, Leung PS et al. Ongoing activation of
mune disease. Autoimmun Rev 2010; 9: A259–66. autoantigen-specific B cells in primary biliary cirrhosis.
112 Hewagama A, Gorelik G, Patel D et al. Overexpression of X- Hepatology 2014; 60: 1708–16.
linked genes in T cells from women with lupus. J Autoimmun 134 Imam MH, Lindor KD. The natural history of primary biliary
2013; 41: 60–71. cirrhosis. Semin Liver Dis 2014; 34: 329–33.
113 Davidson A, Diamond B. Autoimmune diseases. N Engl J 135 Kourilovitch M, Galarza-Maldonado C, Ortiz-Prado E. Diag-
Med 2001; 345: 340–50. nosis and classification of rheumatoid arthritis. J Autoim-
114 Han L, Yang J, Wang X, Li D, Lv L, Li B. Th17 cells in mun 2014; 48–49: 26–30.
autoimmune diseases. Front Med 2015; 9: 10–9. 136 Bizzaro N. Autoantibodies as predictors of disease: the
115 Grant CR, Liberal R, Mieli-Vergani G, Vergani D, Longhi MS. clinical and experimental evidence. Autoimmun Rev 2007;
Regulatory T-cells in autoimmune diseases: challenges, 6: 325–33.
controversies and-yet-unanswered questions. Autoimmun 137 Liaskou E, Hirschfield GM, Gershwin ME. Mechanisms of
Rev 2015; 14: 105–16. tissue injury in autoimmune liver diseases. Semin Immuno-
116 Craft JE. Follicular helper T cells in immunity and systemic pathol 2014; 36: 553–68.
autoimmunity. Nat Rev Rheumatol 2012; 8: 337–47. 138 Eilat D. Introduction: mechanisms of tissue injury in autoim-
117 Berrih-Aknin S, Frenkian-Cuvelier M, Eymard B. Diagnostic mune diseases. Semin Immunopathol 2014; 36: 491–3.
and clinical classification of autoimmune myasthenia 139 Hirschfield GM, Gershwin ME. The immunobiology and
gravis. J Autoimmun 2014; 48–49: 143–8. pathophysiology of primary biliary cirrhosis. Annu Rev
118 Gomez-Puerta JA, Cervera R. Diagnosis and classification of Pathol 2013; 8: 303–30.
the antiphospholipid syndrome. J Autoimmun 2014; 48–49: 140 Shimoda S, Ishikawa F, Kamihira T et al. Autoreactive T-cell
20–5. responses in primary biliary cirrhosis are proinflammatory
119 Hajj-Ali RA, Calabrese LH. Diagnosis and classification of whereas those of controls are regulatory. Gastroenterology
central nervous system vasculitis. J Autoimmun 2014; 48– 2006; 131: 606–18.
49: 149–52. 141 Juran BD, Lazaridis KN. Environmental factors in
120 Hernandez-Rodriguez J, Alba MA, Prieto-Gonzalez S, Cid primary biliary cirrhosis. Semin Liver Dis 2014; 34: 265–
MC. Diagnosis and classification of polyarteritis nodosa. J 72.
Autoimmun 2014; 48–49: 84–9. 142 Raczynska J, Habior A, Paczek L, Foroncewicz B, Pawelas A,
121 Iaccarino L, Ghirardello A, Bettio S et al. The clinical Mucha K. Primary biliary cirrhosis in the era of liver
features, diagnosis and classification of dermatomyositis. J transplantation. Ann Transplant 2014; 19: 488–93.
Autoimmun 2014; 48–49: 122–7. 143 Zhao M, Liu S, Luo S et al. DNA methylation and mRNA
122 Karussis D. The diagnosis of multiple sclerosis and the and microRNA expression of SLE CD4+ T cells corre-
various related demyelinating syndromes: a critical review. J late with disease phenotype. J Autoimmun 2014; 54: 127–
Autoimmun 2014; 48–49: 134–42. 36.
123 Kuhn A, Landmann A. The classification and diagnosis of 144 Bogdanos DP, Smyk DS, Rigopoulou EI et al. Twin studies in
cutaneous lupus erythematosus. J Autoimmun 2014; 48– autoimmune disease: genetics, gender and environment. J
49: 14–9. Autoimmun 2012; 38: J156–69.
124 Mahroum N, Mahagna H, Amital H. Diagnosis and classifica- 145 Sawcer S, Franklin RJ, Ban M. Multiple sclerosis genetics.
tion of adult Still’s disease. J Autoimmun 2014; 48–49: 34–7. Lancet Neurol 2014; 13: 700–9.
125 Maverakis E, Patel F, Kronenberg DG et al. International 146 Maahs DM, West NA, Lawrence JM, Mayer-Davis EJ.
consensus criteria for the diagnosis of Raynaud’s phe- Epidemiology of type 1 diabetes. Endocrinol Metab Clin
nomenon. J Autoimmun 2014; 48–49: 60–5. North Am 2010; 39: 481–97.
126 Mosca M, Tani C, Vagnani S, Carli L, Bombardieri S. The 147 DIAMOND Project Group. Incidence and trends of childhood
diagnosis and classification of undifferentiated connective Type 1 diabetes worldwide 1990-1999. Diabet Med 2006;
tissue diseases. J Autoimmun 2014; 48–49: 50–2. 23: 857–66.
127 Mouthon L, Dunogue B, Guillevin L. Diagnosis and classi- 148 Kaplan MM, Gershwin ME. Primary biliary cirrhosis. N Engl
fication of eosinophilic granulomatosis with polyangiitis J Med 2005; 353: 1261–73.
149 Griffiths L, Dyson JK, Jones DE. The new epidemiology of selected cities from three Commonwealth of Independent
primary biliary cirrhosis. Semin Liver Dis 2014; 34: 318– States countries (the Russian Federation, Ukraine and
28. Kazakhstan). Lupus 2014; 23: 213–9.
150 Selmi C, Invernizzi P, Zuin M, Podda M, Gershwin ME. 171 McInnes IB, Schett G. The pathogenesis of rheumatoid
Genetics and geoepidemiology of primary biliary cirrhosis: arthritis. N Engl J Med 2011; 365: 2205–19.
following the footprints to disease etiology. Semin Liver Dis 172 Tobon GJ, Youinou P, Saraux A. The environment, geo-
2005; 25: 265–80. epidemiology, and autoimmune disease: rheumatoid arthri-
151 Feld JJ, Heathcote EJ. Epidemiology of autoimmune liver tis. J Autoimmun 2010; 35: 10–4.
disease. J Gastroenterol Hepatol 2003; 18: 1118–28. 173 Sung YK, Cho SK, Choi CB, Bae SC. Prevalence and
152 Heneghan MA, Yeoman AD, Verma S, Smith AD, Longhi MS. incidence of rheumatoid arthritis in South Korea. Rheumatol
Autoimmune hepatitis. Lancet 2013; 382: 1433–44. Int 2013; 33: 1525–32.
153 Liberal R, Grant CR, Mieli-Vergani G, Vergani D. Autoim- 174 Cree BA. Multiple sclerosis genetics. Handb Clin Neurol
mune hepatitis: a comprehensive review. J Autoimmun 2014; 122: 193–209.
2013; 41: 126–39. 175 Picascia A, Grimaldi V, Pignalosa O, De Pascale MR, Schiano
154 Francque S, Vonghia L, Ramon A, Michielsen P. Epidemiol- C, Napoli C. Epigenetic control of autoimmune diseases:
ogy and treatment of autoimmune hepatitis. Hepat Med from bench to bedside. Clin Immunol 2015; 157: 1–15.
2012; 4: 1–10. 176 Morran MP, Vonberg A, Khadra A, Pietropaolo M. Immuno-
155 Menconi F, Marcocci C, Marino M. Diagnosis and classifi- genetics of type 1 diabetes mellitus. Mol Aspects Med 2015;
cation of Graves’ disease. Autoimmun Rev 2014; 13: 398– 42: 42–60.
402. 177 Stankov K, Benc D, Draskovic D. Genetic and epigenetic
156 McLeod DS, Cooper DS. The incidence and prevalence of factors in etiology of diabetes mellitus type 1. Pediatrics
thyroid autoimmunity. Endocrine 2012; 42: 252–65. 2013; 132: 1112–22.
157 Laass MW, Roggenbuck D, Conrad K. Diagnosis and clas- 178 Stefan M, Zhang W, Concepcion E, Yi Z, Tomer Y. DNA
sification of Crohn’s disease. Autoimmun Rev 2014; 13: 467– methylation profiles in type 1 diabetes twins point to
71. strong epigenetic effects on etiology. J Autoimmun 2014;
158 Molodecky NA, Soon IS, Rabi DM et al. Increasing incidence 50: 33–7.
and prevalence of the inflammatory bowel diseases with 179 Chen H, Lan HY, Roukos DH, Cho WC. Application of
time, based on systematic review. Gastroenterology 2012; microRNAs in diabetes mellitus. J Endocrinol 2014; 222:
142: 46–54 e42; quiz e30. R1–10.
159 Ng SC. Epidemiology of inflammatory bowel disease: focus 180 Bianchi I, Carbone M, Lleo A, Invernizzi P. Genetics and
on Asia. Best Pract Res Clin Gastroenterol 2014; 28: 363–72. epigenetics of primary biliary cirrhosis. Semin Liver Dis
160 Conrad K, Roggenbuck D, Laass MW. Diagnosis and clas- 2014; 34: 255–64.
sification of ulcerative colitis. Autoimmun Rev 2014; 13: 181 Tang J, Zhou C, Zhang ZJ, Zheng SS. Association of
463–6. polymorphisms in non-classic MHC genes with susceptibil-
161 Kang JY, Kang AH, Green A, Gwee KA, Ho KY. Systematic ity to autoimmune hepatitis. Hepatobiliary Pancreat Dis Int
review: worldwide variation in the frequency of coeliac 2012; 11: 125–31.
disease and changes over time. Aliment Pharmacol Ther 182 Li K, Du Y, Jiang BL, He JF. Increased microRNA-155 and
2013; 38: 226–45. decreased microRNA-146a may promote ocular inflamma-
162 Paul SP, Spray C. Diagnosing coeliac disease in children. Br tion and proliferation in Graves’ ophthalmopathy. Med Sci
J Hosp Med 2014; 75: 268–70. Monit 2014; 20: 639–43.
163 Brandao Neto RA, de Carvalho JF. Diagnosis and classifi- 183 Wei H, Guan M, Qin Y et al. Circulating levels of miR-146a
cation of Addison’s disease (autoimmune adrenalitis). Au- and IL-17 are significantly correlated with the clinical
toimmun Rev 2014; 13: 408–11. activity of Graves’ ophthalmopathy. Endocr J 2014; 61:
164 Arlt W, Allolio B. Adrenal insufficiency. Lancet 2003; 361: 1087–92.
1881–93. 184 Cai TT, Muhali FS, Song RH et al. Genome-wide DNA
165 Alamanos Y, Tsifetaki N, Voulgari PV, Venetsanopoulou AI, methylation analysis in Graves’ disease. Genomics 2015;
Siozos C, Drosos AA. Epidemiology of primary Sjogren’s 105: 204–10.
syndrome in north-west Greece, 1982–2003. Rheumatology 185 Tomer Y. Mechanisms of autoimmune thyroid diseases: from
2006; 45: 187–91. genetics to epigenetics. Annu Rev Pathol 2014; 9: 147–56.
166 Larche MJ. A short review of the pathogenesis of Sjogren’s 186 Marino M, Latrofa F, Menconi F, Chiovato L, Vitti P. Role of
syndrome. Autoimmun Rev 2006; 5: 132–5. genetic and non-genetic factors in the etiology of Graves’
167 Liang Y, Yang Z, Qin B, Zhong R. Primary Sjogren’s disease. J Endocrinol Invest 2014; [Epub ahead of print]
syndrome and malignancy risk: a systematic review and 187 Kalla R, Ventham NT, Kennedy NA et al. MicroRNAs: new
meta-analysis. Ann Rheum Dis 2014; 73: 1151–6. players in IBD. Gut 2015; 64: 504–13.
168 Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus 188 Van Limbergen J, Wilson DC, Satsangi J. The genetics of
erythematosus. Lancet 2014; 384: 1878–88. Crohn’s disease. Annu Rev Genomics Hum Genet 2009; 10:
169 Pons-Estel GJ, Alarcon GS, Scofield L, Reinlib L, Cooper GS. 89–116.
Understanding the epidemiology and progression of sys- 189 Stokkers PC, Reitsma PH, Tytgat GN, van Deventer SJ. HLA-
temic lupus erythematosus. Semin Arthritis Rheum 2010; DR and -DQ phenotypes in inflammatory bowel disease: a
39: 257–68. meta-analysis. Gut 1999; 45: 395–401.
170 Nasonov E, Soloviev S, Davidson JE et al. The prevalence 190 Denizot J, Desrichard A, Agus A et al. Diet-induced hypoxia
and incidence of systemic lupus erythematosus (SLE) in responsive element demethylation increases CEACAM6
expression, favouring Crohn’s disease-associated Escher- 209 Zhang Y, Zhang J, Yang J et al. Meta-analysis of GWAS on
ichia coli colonisation. Gut 2015; 64: 428–37. two Chinese populations followed by replication identifies
191 Adams AT, Kennedy NA, Hansen R et al. Two-stage genome- novel genetic variants on the X chromosome associated with
wide methylation profiling in childhood-onset Crohn’s Dis- systemic lupus erythematosus. Hum Mol Genet 2015; 24:
ease implicates epigenetic alterations at the VMP1/MIR21 274–84.
and HLA loci. Inflamm Bowel Dis 2014; 20: 1784–93. 210 Deng Y, Tsao BP. Advances in lupus genetics and epigenet-
192 Lv B, Liu Z, Wang S et al. miR-29a promotes intestinal ics. Curr Opin Rheumatol 2014; 26: 482–92.
epithelial apoptosis in ulcerative colitis by down-regulating 211 Wong M, Tsao BP. Current topics in human SLE genetics.
Mcl-1. Int J Clin Exp Pathol 2014; 7: 8542–52. Springer Semin Immunopathol 2006; 28: 97–107.
193 Karatzas PS, Mantzaris GJ, Safioleas M, Gazouli M. DNA 212 Bottini N, Firestein GS. Epigenetics in rheumatoid arthritis:
methylation profile of genes involved in inflammation and a primer for rheumatologists. Curr Rheumatol Rep 2013; 15:
autoimmunity in inflammatory bowel disease. Medicine 372.
2014; 93: e309. 213 Yamamoto K, Okada Y, Suzuki A, Kochi Y. Genetics of
194 Harris RA, Nagy-Szakal D, Mir SA et al. DNA methylation- rheumatoid arthritis in Asia-present and future. Nat Rev
associated colonic mucosal immune and defense responses Rheumatol 2015; 11: 375–9.
in treatment-naive pediatric ulcerative colitis. Epigenetics 214 Diogo D, Okada Y, Plenge RM. Genome-wide association
2014; 9: 1131–7. studies to advance our understanding of critical cell types
195 Bascunan-Gamboa KA, Araya-Quezada M, Perez-Bravo F. and pathways in rheumatoid arthritis: recent findings and
MicroRNAs: an epigenetic tool to study celiac disease. Rev challenges. Curr Opin Rheumatol 2014; 26: 85–92.
Esp Enferm Dig 2014; 106: 325–33. 215 Kochi Y, Suzuki A, Yamamoto K. Genetic basis of rheuma-
196 Lundin KE, Sollid LM. Advances in coeliac disease. Curr toid arthritis: a current review. Biochem Biophys Res Com-
Opin Gastroenterol 2014; 30: 154–62. mun 2014; 452: 254–62.
197 Kaukinen K, Maki M. Coeliac disease in 2013: new insights 216 Harkonen T, Lankinen H, Davydova B, Hovi T, Roivainen M.
in dietary-gluten-induced autoimmunity. Nat Rev Gastroen- Enterovirus infection can induce immune responses that
terol Hepatol 2014; 11: 80–2. cross-react with beta-cell autoantigen tyrosine phosphatase
198 Fernandez-Jimenez N, Castellanos-Rubio A, Plaza-Izurieta L IA-2/IAR. J Med Virol 2002; 66: 340–50.
et al. Coregulation and modulation of NFkappaB-related 217 Honeyman MC, Stone NL, Falk BA, Nepom G, Harrison LC.
genes in celiac disease: uncovered aspects of gut mucosal Evidence for molecular mimicry between human T cell
inflammation. Hum Mol Genet 2014; 23: 1298–310. epitopes in rotavirus and pancreatic islet autoantigens. J
199 Bernecker C, Halim F, Haase M, Willenberg HS, Ehlers M, Immunol 2010; 184: 2204–10.
Schott M. MicroRNA expressions in PMBCs, CD4+, 218 Hiemstra HS, Schloot NC, van Veelen PA et al. Cy-
and CD8+ T-cells from patients suffering from autoimmune tomegalovirus in autoimmunity: T cell crossreactivity to
Addison’s disease. Horm Metab Res 2013; 45: 599–604. viral antigen and autoantigen glutamic acid decarboxylase.
200 Bjanesoy TE, Andreassen BK, Bratland E et al. Altered DNA Proc Natl Acad Sci USA 2001; 98: 3988–91.
methylation profile in Norwegian patients with Autoimmune 219 Hintermann E, Holdener M, Bayer M et al. Epitope spread-
Addison’s Disease. Mol Immunol 2014; 59: 208–16. ing of the anti-CYP2D6 antibody response in patients with
201 Bronstad I, Wolff AS, Lovas K, Knappskog PM, Husebye ES. autoimmune hepatitis and in the CYP2D6 mouse model. J
Genome-wide copy number variation (CNV) in patients with Autoimmun 2011; 37: 242–53.
autoimmune Addison’s disease. BMC Med Genet 2011; 12: 220 Poole BD, Scofield RH, Harley JB, James JA. Epstein-Barr
111. virus and molecular mimicry in systemic lupus erythemato-
202 Gallo A, Tandon M, Illei G, Alevizos I. Discovery and sus. Autoimmunity 2006; 39: 63–70.
validation of novel microRNAs in Sjogren’s syndrome sali- 221 Lunemann JD, Huppke P, Roberts S, Bruck W, Gartner J,
vary glands. Clin Exp Rheumatol 2014; 32: 761–2. Munz C. Broadened and elevated humoral immune response
203 Shi H, Zheng LY, Zhang P, Yu CQ. miR-146a and miR-155 to EBNA1 in pediatric multiple sclerosis. Neurology 2008;
expression in PBMCs from patients with Sjogren’s syn- 71: 1033–5.
drome. J Oral Pathol Med 2014; 43: 792–7. 222 Petersen J, Rhodes G, Roudier J, Vaughan JH. Altered
204 Konsta OD, Thabet Y, Le Dantec C et al. The contribution of immune response to glycine-rich sequences of Epstein-Barr
epigenetics in Sjogren’s Syndrome. Front Genet 2014; 5: 71. nuclear antigen-1 in patients with rheumatoid arthritis and
205 Lessard CJ, Li H, Adrianto I et al. Variants at multiple loci systemic lupus erythematosus. Arthritis Rheum 1990; 33:
implicated in both innate and adaptive immune responses 993–1000.
are associated with Sjogren’s syndrome. Nat Genet 2013; 223 Rozenblyum EV, Allen UD, Silverman ED, Levy DM.
45: 1284–92. Cytomegalovirus infection in childhood-onset systemic
206 Huang R, Yin J, Chen Y et al. The amino acid variation lupus erythematosus. Int J Clin Rheumatol 2013; 8: 137–
within the binding pocket 7 and 9 of HLA-DRB1 molecules 46.
are associated with primary Sjogren’s syndrome. J Autoim- 224 Tucker WG, Andrew Paskauskas R. The MSMV hypothesis:
mun 2015; 57: 53–9. measles virus and multiple sclerosis, etiology and treat-
207 Guerra SG, Vyse TJ, Cunninghame Graham DS. The genet- ment. Med Hypotheses 2008; 71: 682–9.
ics of lupus: a functional perspective. Arthritis Res Ther 225 Alidjinou EK, Sane F, Engelmann I, Geenen V, Hober D.
2012; 14: 211. Enterovirus persistence as a mechanism in the pathogenesis
208 Miao CG, Yang YY, He X et al. The emerging role of of type 1 diabetes. Discov Med 2014; 18: 273–82.
microRNAs in the pathogenesis of systemic lupus erythe- 226 Andrade F, Casciola-Rosen LA, Rosen A. Generation of novel
matosus. Cell Signal 2013; 25: 1828–36. covalent RNA-protein complexes in cells by ultraviolet B
irradiation: implications for autoimmunity. Arthritis Rheum Clinics classification criteria for systemic lupus erythemato-
2005; 52: 1160–70. sus. Arthritis Rheum 2012; 64: 2677–86.
227 Cooper GS, Wither J, Bernatsky S et al. Occupational and 245 Aletaha D, Neogi T, Silman AJ et al. 2010 rheumatoid
environmental exposures and risk of systemic lupus erythe- arthritis classification criteria: an American College of
matosus: silica, sunlight, solvents. Rheumatology 2010; 49: Rheumatology/European League Against Rheumatism col-
2172–80. laborative initiative. Ann Rheum Dis 2010; 69: 1580–8.
228 Caricchio R, McPhie L, Cohen PL. Ultraviolet B radiation- 246 Rau R. Glucocorticoid treatment in rheumatoid arthritis.
induced cell death: critical role of ultraviolet dose in inflam- Expert Opin Pharmacother 2014; 15: 1575–83.
mation and lupus autoantigen redistribution. J Immunol 247 Flammer JR, Rogatsky I. Minireview: glucocorticoids in
2003; 171: 5778–86. autoimmunity: unexpected targets and mechanisms. Mol
229 Incorvaia E, Sicouri L, Petersen-Mahrt SK, Schmitz KM. Endocrinol 2011; 25: 1075–86.
Hormones and AID: balancing immunity and autoimmunity. 248 Goodin DS. Glucocorticoid treatment of multiple sclerosis.
Autoimmunity 2013; 46: 128–37. Handb Clin Neurol 2014; 122: 455–64.
230 Shoenfeld Y, Tincani A, Gershwin ME. Sex gender and 249 Hashkes PJ, Becker ML, Cabral DA et al. Methotrexate: new
autoimmunity. J Autoimmun 2012; 38: J71–3. uses for an old drug. J Pediatr 2014; 164: 231–6.
231 Cojocaru M, Chicos B. The role of heavy metals in autoim- 250 Hahn BH. Belimumab for systemic lupus erythematosus. N
munity. Rom J Intern Med 2014; 52: 189–91. Engl J Med 2013; 368: 1528–35.
232 Polman CH, Reingold SC, Banwell B et al. Diagnostic criteria 251 Invernizzi P, Benedetti MD, Poli S, Monaco S. Azathio-
for multiple sclerosis: 2010 revisions to the McDonald prine in multiple sclerosis. Mini Rev Med Chem 2008; 8:
criteria. Ann Neurol 2011; 69: 292–302. 919–26.
233 American Diabetes A. Diagnosis and classification of dia- 252 Louis E, Irving P, Beaugerie L. Use of azathioprine in IBD:
betes mellitus. Diabetes Care 2010; 33(Suppl 1): S62–9. modern aspects of an old drug. Gut 2014; 63: 1695–9.
234 Lindor KD, Gershwin ME, Poupon R et al. Primary biliary 253 Sieb JP. Myasthenia gravis: an update for the clinician. Clin
cirrhosis. Hepatology 2009; 50: 291–308. Exp Immunol 2014; 175: 408–18.
235 Alvarez F, Berg PA, Bianchi FB et al. International Autoim- 254 Johnson PJ, McFarlane IG, Williams R. Azathioprine for
mune Hepatitis Group Report: review of criteria for diagno- long-term maintenance of remission in autoimmune hepati-
sis of autoimmune hepatitis. J Hepatol 1999; 31: 929–38. tis. N Engl J Med 1995; 333: 958–63.
236 Hennes EM, Zeniya M, Czaja AJ et al. Simplified criteria for 255 Willrich MA, Murray DL, Snyder MR. Tumor necrosis factor
the diagnosis of autoimmune hepatitis. Hepatology 2008; inhibitors: clinical utility in autoimmune diseases. Transl
48: 169–76. Res 2015; 165: 270–82.
237 Chapman R, Fevery J, Kalloo A et al. Diagnosis and man- 256 Song SN, Yoshizaki K. Tocilizumab for treating rheumatoid
agement of primary sclerosing cholangitis. Hepatology 2010; arthritis: an evaluation of pharmacokinetics/pharmacody-
51: 660–78. namics and clinical efficacy. Expert Opin Drug Metab Toxicol
238 Shoenfeld Y, Cervera R, Gershwin ME. Diagnostic Criteria in 2015; 11: 307–16.
Autoimmune Diseases. New Jersey: Springer Science & 257 Meng Y, Dongmei L, Yanbin P et al. Systematic review and
Business Media, 2010. meta-analysis of ustekinumab for moderate to severe pso-
239 Van Assche G, Dignass A, Panes J et al. The second riasis. Clin Exp Dermatol 2014; 39: 696–707.
European evidence-based Consensus on the diagnosis and 258 Edwards JC, Szczepanski L, Szechinski J et al. Efficacy of
management of Crohn’s disease: definitions and diagnosis. J B-cell-targeted therapy with rituximab in patients
Crohns Colitis 2010; 4: 7–27. with rheumatoid arthritis. N Engl J Med 2004; 350: 2572–
240 Stange EF, Travis SP, Vermeire S et al. European evidence-based 81.
Consensus on the diagnosis and management of ulcerative 259 Mok CC. Rituximab for the treatment of rheumatoid
colitis: definitions and diagnosis. J Crohns Colitis 2008; 2: 1–23. arthritis: an update. Drug Des Devel Ther 2014; 8: 87–
241 Revised criteria for diagnosis of coeliac disease. Report of 100.
Working Group of European Society of Paediatric Gastroen-
terology and Nutrition. Arch Dis Child 1990; 65: 909–11. Correspondence: Fu-Sheng Wang, Research Center for Biological
242 Fox RI. Sjogren’s syndrome. Lancet 2005; 366: 321–31. Therapy, Institute of Translational Hepatology, Beijing 302
243 Shiboski SC, Shiboski CH, Criswell L et al. American College Hospital, Beijing 100039, China.
of Rheumatology classification criteria for Sjogren’s syn- (fax: +8610-63879735; e-mail: [email protected]).
drome: a data-driven, expert consensus approach in the or M. Eric Gershwin, Division of Rheumatology, Allergy and
Sjogren’s International Collaborative Clinical Alliance Clinical Immunology, University of California at Davis School of
cohort. Arthritis Care Res 2012; 64: 475–87. Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA
244 Petri M, Orbai AM, Alarcon GS et al. Derivation and valida- 95616, USA.
tion of the Systemic Lupus International Collaborating (fax: 1-530-752-4669; e-mail: [email protected]).

Human Autoimmune Diseases: A Comprehensive Update: Review

Uploaded by

Copyright:

Available Formats

Human Autoimmune Diseases: A Comprehensive Update: Review

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Human Autoimmune Diseases: A Comprehensive Update: Review

Uploaded by

Copyright:

Available Formats

Review

Human autoimmune diseases: a comprehensive update

pioneering work of Paul Ehrlich early in the 20th

It is important to note however that even under the

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

Table 1 Geoepidemiology of selected human autoimmune diseases

Gender Monozygotic Incidence (per 100 000 person-years)

Fig. 3 Genetic basis of

Table 2 Genetic associations with autoimmune diseases

Disease HLA* Non-HLA loci Epigenetic aberrations References

Disease HLA* Non-HLA loci Epigenetic aberrations References

Disease HLA* Non-HLA loci Epigenetic aberrations References

Table 3 Proposed mechanisms for infection-related autoimmunity

Mechanisms Infections Diseases References

Fig. 4 Environmental factors

Table 4 Noninfectious agents and autoimmunity

Agent Mechanisms Diseases References

Fig. 6 Representative organ-

Journal of Internal Medicine, 2015, 278; 369–395

cerevisiae, tubulin-b of the mucosa with basal criteria [240]

Journal of Internal Medicine, 2015, 278; 369–395

Fig. 7 Diagnostic platform for

Table 6 Agents used to treat autoimmunity

Agents Treatment effect Side effects References

Agents Treatment effect Side effects References

been improvements in laboratory testing methods, 11 Wahren-Herlenius M, Dorner T. Immunopathogenic mecha-

You might also like