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.
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individual patients during a breach of tolerance. 13 West J, Fleming KM, Tata LJ, Card TR, Crooks CJ. Incidence
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the future. erythematosus in the UK, 1999–2012. Ann Rheum Dis 2014;
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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
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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-
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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-

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