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REVIEW

CURRENT
OPINION Infections: a double-edge sword in autoimmunity
Oded Shamriz a and Yehuda Shoenfeld b,c

Purpose of review
Infections play a role in the pathogenesis of autoimmune diseases (AID). Several bacterial and viral
pathogens play a double role, as both inducers and inhibitors of AID. In this review, we will present current
evidence and discuss different aspects of this notion.
Recent findings
Infectors that both inhibit and induce AID include Helicobacter pylori, Klebsiella pneumoniae, hepatitis B
virus, group B Coxsackieviruses, Epstein–Barr virus and Lymphocytic choriomeningitis virus. Numerous
AIDs are affected by infections, including polyarteritis nodosa, inflammatory bowel disease, and type 1
diabetes. Some pathogens, such as group B Coxsackieviruses, may induce and inhibit the development of
the same AID. This reveals a complex role of infections in autoimmunity pathogenesis.
Summary
Elucidating the exact role of each pathogen on each specific AID is important, as this will enable
evaluating the manipulation of these infections in the treatment of AID.
Keywords
autoimmune diseases, group B Coxsackieviruses, Helicobacter pylori, hepatitis B virus, infections

INTRODUCTION current evidence and discuss different aspects of

The microbiome is believed to play a role in the
pathogenesis of autoimmune diseases (AIDs).
Changes in the composition and diversity of oral,
skin, and gut microbiota were demonstrated to
induce various AID, including inflammatory bowel
diseases (IBD), diabetes mellitus type 1 (T1D), rheu-
matoid arthritis (RA), and multiple sclerosis (MS)
&
[1 ]. Moreover, various factors, such as nutrition,
genetics, hormones, and age, affect both the
immune system and the microbiome, thus creating
bacterial and viral infectors that induce and protect
from AID.
MECHANISMS FOR INFECTION ROLE IN
AUTOIMMUNITY PATHOGENESIS
AIDs have a multifactorial etiology, including
&
genetic, hormonal and environmental causes [5 ].
Thus, infections are not single players in the patho-
genesis of autoimmunity and often affect genetic or
&

a close inter-relationship between the two [2 ].

&
It is therefore reasonable to assume that infec-
tions will also play a role in the pathogenesis of
autoimmunity. Indeed, several infectious agents
have been found to induce autoimmunity. The
hallmark for infection-induced AID is rheumatic
fever, which has long been identified as being trig-
gered by group A b-hemolytic Streptococcal (GAS)
&
infection [3 ]. However, infections can also prevent
AID. For example, some studies have associated
infections with Helicobacter pylori and amelioration
& Sheba Medical Center, affiliated to the Sackler Faculty of Medicine
of disease activity in IBD [4 ].
Review of the literature draws a more compli-
cated picture. It seems that some infections play a
double role: the same pathogen both induces and
inhibits different and sometimes even the same AID,
suggesting that their role in autoimmunity is not
fully understood. In this review, we will present
otherwise susceptible hosts [6 ].
Molecular mimicry is one mechanism to explain
induction of AID by infectious agents. Molecular
mimicry results from structural similarities between
infectious and self-antigens that provokes the
immune system to create autoantibodies and autor-
eactive T-cells. A well established example of
a
Pediatric Division, Hadassah-Hebrew University Medical Center, Ein
Kerem, Jerusalem, bZabludowicz Center for Autoimmune Diseases,
Tel-Aviv University and cSackler Faculty of Medicine, Tel-Aviv University,
Tel Aviv, Israel
Correspondence to Oded Shamriz, MD, Hadassah Medical Organiza-
tion, POB 12000 Kiryat Hadassah, 91120, Jerusalem, Israel.
Tel: +972 52 921 2082; e-mail: oded.shamriz@mail.huji.ac.il
Curr Opin Rheumatol 2018, 30:000–000
DOI:10.1097/BOR.0000000000000490

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Infections and environmental aspects of autoimmunity

mechanism for the protective role of Bordetella per-

KEY POINTS
 AIDs have a multifactorial etiology that includes
infections.
 Several infections, such as Helicobacter pylori, CVB,
and HBV, play a role both as inducers and inhibitors
of AIDs.
 The same infector may both induces and inhibits the
development of the same AID, as in the case of CVB
and T1D.
molecular mimicry is the structural similarity
tussis in MS by using a mouse model. This included
B. pertussis-induced production of interleukin-10, an
important anti-inflammatory cytokine [10]. There-
fore, it seems that complete understanding of the
immunomodulatory effects of bacterial and viral
infections and their role in autoimmunity patho-
genesis, remains elusive.
PATHOGENS THAT INDUCE AND PREVENT
AUTOIMMUNE DISEASES
There is increasing evidence supporting the fact that
some infectious agents both induce and prevent AID
(Table 1) [18,20,21,23,24,27,29,30,32–34,35 ,38,
&&

between the M protein of GAS and cardiac myosin, &&

which results in the development of rheumatic fever
&
[7 ]. There are other mechanisms of infection-
induced autoimmunity. These consist of bystander
activation, epitope spreading, and polyclonal acti-
vation, all with extensive supporting data in the
literature [8].
On the other hand, exposure to infections can
prevent autoimmunity. The most important mech-
anism in that regard is the ‘hygiene hypothesis’ [9].
41 ,42,47,58–102]. Herein, we will elaborate on
three such pathogens.
Helicobacter pylori
H. pylori is a microaerophilic gram-negative bacte-
rium, which resides in the stomachs of approxi-
mately 50% of the world population [11]. Data
regarding the mechanisms, by which H. pylori affects
the development of AID, is summarized in Table 2
&& &

It consists of the observation that the lack of expo-
sure to different microorganisms in our environ-
ment has an immunomodulatory role and can
induce autoimmunity. Interestingly, it seems that
the hygiene hypothesis is not limited to exposure to
helminths. There are also data concerning the pro-
tective role of bacteria. For example, researchers
have suggested the hygiene hypothesis as a possible
[12,17,18,21,20,24,26,33,34,50,54 ,55 ,59,86,103].
Helicobacter pylori induces autoimmune
diseases
Different studies have implicated H. pylori infections
as inducers of several AIDs. Autoimmune gastritis is
considered by many to be a hallmark for H. pylori-
induced AID. A possible mechanism of molecular

Table 1. Evidence for induction and prevention of autoimmune diseases by the same infectious agent

Autoimmune disease
Pathogen Induction (reference) Protection [reference numbers]

Bacteria
Helicobacter pylori Beçhet disease [32,33], RA [18,27,60], SLE MS [29,30], RA [34,35 ], SSc [73–76],
&&

Klebsiella pneumoniae
[18], SjS [20,61,62], HSP [63–66], AG SLE [62,77], IBD [24,78,79], AG [80]
[67,68], AT [69–72] ITP [23,58–64], PBC
[65–67], ABD [21,68], Psoriasis [47,69–
73], Vitiligo [74,75]
Ankylosing spondylitis [81,82 ], IBD [83,84] T1Da [85]
&

Viruses
Hepatitis B virus Polyarteritis nodosa [34,86], antiphospholipid SLE [41 ,42]
&&

syndrome [38]
Group B Coxsackieviruses T1D [87–89], myocarditis [90,91] T1D [58,59]
Epstein–Barr virus MS [92 ], Graves’ disease [93 ], SSc [94 ], T1D [99,100]
&& & &

MG [95 ], SLE [96], SjS [97,98]

&&

Lymphocytic choriomeningitis virus T1D [101] T1D [102]

ABD, autoimmune bullous disease; AG, autoimmune gastritis; AT, autoimmune (Hashimoto’s) thyroiditis; HSP, Henoch–Schonlein Purpura; IBD, inflammatory
bowel disease; MG, myasthenia gravis; MS, multiple sclerosis; PBC, primary biliary cirrhosis; RA, rheumatoid arthritis; SjS, Sjögren’s syndrome; SLE, systemic
lupus erythematosus; SSc, systemic sclerosis; T1D, type 1 diabetes mellitus.
a
Klebsiella pneumoniae glycoprotein extract.

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Table 2. Suggested mechanisms for the role of infections in the pathogenesis of autoimmunity
Pathogen Autoimmune diseases
Helicobacter pylori Multiple sclerosis
Rheumatoid arthritis
Systemic sclerosis
Systemic lupus
erythematosus
Sjören’s syndrome
Inflammatory bowel
disease
Autoimmune gastritis
Immune thrombocytopenic
purpura
HBV Polyarteritis nodosa
Antiphospholipid syndrome
CVB Type 1 diabetes mellitus
Type 1 diabetes mellitus
Anti-ssDNA, anti-single-stranded DNA; autoimmune bullous diseases, include bullous pemphigoid and pemphigus vulgaris; CVB, group B Coxsackieviruses; HBV,
hepatitis B virus; HSP, heat shock protein; NA, data is not available; PD-L1, programmed cell death- ligand 1; Th, T helper cells; Tregs, regulatory T cells.
mimicry between H. pylori and H/K ATPase was
previously suggested [12]. The presence of H/K
ATPase autoantibodies in 20–30% of H. pylori-
infected patients supports that notion [13].
In patients with systemic sclerosis (SSc), severity
of skin, gastrointestinal, and musculoskeletal
involvement was demonstrated to be higher in
H. pylori-positive, as compared to H. pylori-negative
SSc patients [14]. H. pylori ’s induction of autoim-
mune bullous diseases was also demonstrated, as
higher prevalence of H. pylori antibodies was found
in bullous pemphigoid and pemphigus in compari-
son to healthy controls [15].
Immune thrombocytopenic purpura (ITP) is
another example and it is of a special interest.
H. pylori infection prevalence among ITP patients
is reported to be 58.6% [11,16]. CagA-positive
strains of H. pylori were suggested to induce ITP
[16]. Another study, found that cross-reactivity of
anti-H. pylori urease B antibodies with platelet gly-
coprotein IIIa is significant in ITP pathogenesis [17].
Furthermore, eradication of H. pylori was found in
different studies to increase platelets recovery, as
compared to H. pylori-seronegative or eradication
failure patients [16].
Different mechanisms were suggested for
H. pylori induction of AID. B1 cells activation by
H. pylori urease and production of autoantibodies,
including immunoglobulin M (IgM)-type rheuma-
toid factor, antisingle-stranded DNA (ssDNA) and
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Infections and autoimmunity Shamriz and Shoenfeld
Effect on AID Suggested mechanism [reference numbers]
Protection Downregulation of Th1/Th17 response [26]
Induction IgM rheumatoid factor autoantibody production via B1 cells
activation [18]
Induction Presence of anti-HSP65 antibodies [21]
Induction Anti-ssDNA autoantibody production via B1 cells activation [18]
Induction Auto-reactivity with HSP-60 [20]
Protection Activation of mucin 2 transcription [24]
Induction Molecular mimicry between H. pylori and H/K ATPase [12]
Induction Cross-reactivity of anti-H. pylori urease B antibodies with platelet
glycoprotein IIIa [17]
Induction Deposition of immune complexes in vessel walls [33,34,86]
Induction Cell receptors for HBV envelope include annexin V and b2-GPI
[103]
Induction CVB4-induced bystander activation [50]; dysregulation of
microRNAs that target T1D genes [54 ,55 ]
&& &
Protection Upregulation of PD-L1 in lymphocytes and inhibition of PD1-
producing autoreactive CD8þ T cells. Induction of
CD4þCD25þ Treg production [59]
antiphosphatidyl choline antibodies is one of the
suggested mechanisms [18]. Another mechanism for
H. pylori-induced autoimmunity consists of the
homology between H. pylori and heat shock proteins
(HSP) 60 and 65 [19]. This is confirmed by different
studies that reported the presence of anti-HSP60 and
anti-HSP65 antibodies in H. pylori-positive patients
with various AID, such as Sjögren’s syndrome and
SSc, respectively. [20,21]. HSP has also been linked
to inflammation related to atherosclerosis. There-
fore, molecular mimicry between HSP and H. pylori
may also play a role in atherogenesis and coronary
heart disease [22].
Helicobacter pylori protects from
autoimmune diseases
Recent data suggest that H. pylori may actually
inhibit the development of certain AIDs. H. pylori
seropositivity was found to be significantly lower in
patients with MS and IBD, than healthy individuals
[11]. A negative association between anti-H. pylori
and gastrointestinal-associated autoantibodies was
found in connective tissue disorders [23]. In IBD,
mouse models of dextran sodium sulfate-induced
chronic colitis demonstrated amelioration of clini-
cal and histopathological colitis after exposure to
H. pylori extracts. A fascinating mechanism of mucin
2 transcriptional activation was suggested by
researchers to explain the induction of IBD by
H. pylori. This process appears to be dependent on
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Infections and environmental aspects of autoimmunity
nucleotide-binding oligomerization domain-like
receptor protein 3 inflammasome and interleukin-
18 production [24].
The immunoprotective role of H. pylori was also
demonstrated in MS. In MS patients, H. pylori sero-
positivity was found to be inversely associated with
the mean expanded disability status scale score and
fulfillment of McDonald’s MRI diagnostic criteria
for MS [25]. A protective mechanism that includes
immune modulation of both T helper (Th) 1 and
Th17-related responses was suggested in an experi-
mental autoimmune encephalitis mouse models. In
one study, H. pylori infection reduced the severity of
experimental autoimmune encephalitis, as well as
antigen-specific T-cell proliferative responses, the
number of central nervous system CD4þ cells and
Th1-related cytokines, such as interferon-g and
interleukin-17 [26].
Controversies regarding the role of
Helicobacter pylori in autoimmune diseases
In some AID, H. pylori involvement is still contro-
versial. This is the case for RA and systemic lupus
erythematosus (SLE). H. pylori seropositivity preva-
lence rate in Japanese RA patients is reported to be
49.3%, lower than the control group [27]. Eradica-
tion of H. pylori in different studies resulted in
contradictory results, in regard to its effect on RA
onset, severity, and clinical course [11].
In SLE, H. pylori was suggested to have a protec-
tive role, as the prevalence rate of H. pylori seroposi-
tivity in SLE patients was found to be lower than in
healthy controls [11]. Moreover, African American
H. pylori-seropositive women were found to develop
symptoms related to SLE in an older age than their
seronegative counterparts [14]. However, antissDNA
autoantibodies production in mice exposed to
H. pylori components, as we mentioned earlier, is
supportive of H. pylori role in induction of SLE [18].
Therefore, it appears that the role of H. pylori in the
pathogenesis of autoimmunity is yet to be clearly
defined.
Hepatitis B virus
Hepatitis B virus (HBV) is a hepatotropic virus
that belongs to the hepadnaviridae family [28].
Recent studies suggest that HBV both induces and
inhibits autoimmunity (suggested mechanisms are
presented in Table 2).
Hepatitis B virus induces autoimmune
diseases
First described by Gocke et al. [29], HBV has long
been reported to induce polyarteritis nodosa (PAN)
[30]. Highest frequency of 77 per 1 000 000 is seen in
4 www.co-rheumatology.com
Alaskan Eskimos living in HBV-endemic areas [31].
Furthermore, the incidence rates of HBV-induced
PAN (HBV-PAN) were shown to decrease in devel-
oped countries, most probably due to the introduc-
tion of HBV vaccine [32].
Specific characteristics of HBV-PAN include the
presence of antineutrophil cytoplasmic antibodies
(ANCA)-negative vasculitis. HBV replication hold
was found to be associated with HBV-PAN remission
[31]. Suggested mechanisms consist of deposition of
immune complexes in vessel walls. In one study,
circulating immunoglobulin G (IgG) containing
immune complexes in HBV-PAN, as compared to
non-HBV-PAN patients were measured and found to
be lower (7185  2472 and 26 462  10 796, respec-
tively) [33]. Histologic findings of immune com-
plexes deposits consisting of HBV surface antigen
(HBsAg), immunoglobulins, b1C-globulin, and C1q
in vessel walls support that notion [34].
Treatment of HBV-PAN includes clearance of
immune complexes by plasmapheresis in combina-
tion with antiviral drugs and corticosteroids, and
was shown to achieve 80.9% remission [30]. In
contrast, immunosuppression using corticosteroids
and cyclophosphamide is recommended for a non-
&&
HBV-PAN [35 ]. Therefore, HBV-PAN is considered
to be a distinct entity with different pathogenesis
and treatment from non-HBV-PAN.
Another AID associated with HBV infection is
antiphospholipid syndrome (APS). It appears that
chronic HBV infection triggers the production of
antiphospholipid antibodies [APLA: anticardiolipin
(aCL), antib (2)-glycoprotein I (b2GPI), and lupus
anticoagulant antibodies] [28]. Suggested mecha-
nism is presented in Table 2.
One study evaluated 50 HBV patients and found
the presence of IgG aCL antibodies in 14% of the
patients [36]. In Korea, among 143 HBV patients,
aCL, b2GPI, and lupus anticoagulant antibodies
were noted in 12.6, 2.1, and 1.4% of the patients,
respectively [37]. Moreover, a meta-analysis of 20
studies confirmed the link between HBV, aCL [odds
ratio (OR) 11.22, 95% confidence interval (CI) 6.68–
18.84] and b2GPI (OR 14.07, 95% CI 3.06–64.66)
antibodies [38].
Clinical significance of APLA in chronic HBV
infection is unknown. One study has reported that
in patients with chronic HBV-induced cirrhosis or
hepatocellular carcinoma, the presence of APLA is
related to the development of portal vein thrombo-
sis [39]. However, in all the studies mentioned
above, including the meta-analysis, found no asso-
ciation between HBV-APLA and clinical manifesta-
tions of APS [36–38]. Therefore, APLA production in
chronic HBV patients does not necessarily induce
clinical APS.
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Hepatitis B virus protects from systemic
lupus erythematosus
HBV role in SLE pathogenesis has long been contro-
versial. Measurements of HBsAg in the sera and
glomerular immune complexes of SLE patients
yielded contradicting results [40].
However, current data suggest that HBV may
actually have a protective role in SLE. In a pristane-
induced lupus mouse model, HBV-infected mice
were found to have lower titers of antinuclear anti-
bodies (ANA), lower levels of interleukin-17, tumor
necrosis factor-a, and B-cell activating factor, and
higher levels of interleukin-2, interleukin-4, and
interleukin-6, than non-HBV lupus-prone mice.
Moreover, lower rates of glomerulonephritis were
noted in the HBV-infected group [41 ].
&&
Human studies provide supporting data, as well.
Lower rates of anti-HBc (HBV core) antibodies were
noted in the sera of 117 SLE patients, as compared to
healthy controls (2.5 and 10.7%, respectively;
P ¼ 0.01) [42]. Another study in China demonstrated
significantly lower rates of HBsAg in the sera of SLE
patients, as compared to the general population
(2.33 and 9.57%, respectively; P < 0.01) [43]. There-
fore, HBV role in SLE pathogenesis is still undefined
and may be inhibitory.
Group B coxsackieviruses
Group B Coxsackieviruses (CVB), a group of six
serotypes that belongs to the family of enterovi-
ruses, have extensively been studied as important
players in the pathogenesis of T1D (diabetogenesis).
Evidence supporting both induction and inhibition
of T1D by CVB was obtained from nonobese diabetic
(NOD) mouse model studies [44] (data regarding
mechanisms is presented in Table 2).
Coxsackievirus B induces type 1 diabetes
mellitus
Several environmental factors, including different
infectors, have been previously suggested to trigger
the onset of T1D. Among other infections, CVB were
marked as strong candidates [45].
Numerous epidemiological studies have associ-
ated CVB infection with T1D onset. In one study
researchers found an incidence rate of 67% of posi-
tive CVB IgM serology among children diagnosed
with T1D in the period of 1964–1984 [46]. Another
study analyzed the sera of 14 children presenting
with a new-onset T1D using PCR and found that
64% of them were positive for enteroviruses, mainly
CVB3 and CVB4 [47]. Among 183 children who
developed autoantibodies compatible with T1D,
CVB1 was found to increase risk for T1D [48].
Increased risk of T1D among CVB1-infected individ-
uals was confirmed in another study [49].
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Infections and autoimmunity Shamriz and Shoenfeld
An association between CVB infection and T1D
was also demonstrated in NOD mouse models.
Infection of T-cell receptors (TLR) transgenic NOD
mice with CVB4 has induced T1D [50]. CVB tropism
to the pancreas and development of pancreatitis was
observed in the process [51,52]. Phagocytosis of b
cells following CVB infection and participation of
antigen-presenting cells are probably required in the
autoimmune process [53]. Another study demon-
strated that knockout of the TLR3 gene protects
CVB4-infected NOD mice from developing T1D,
suggesting that TLR3 plays a major role in CVB-
induced diabetogenesis [52]. Furthermore, CVB
infection-induced dysregulation of islet microRNAs
that target T1D genes is another suggested mecha-
&& & &&
nism for T1D development [54 ,55 ,56 ]. Interest-
ingly, transfer of CVB-specific antibodies from
mothers to their offspring in NOD mouse models
has decreased the risk in the offspring for CVB
infection and also protected from T1D development
[57].
Coxsackievirus B protects from type 1
diabetes mellitus
However, it seems that CVB can also inhibit T1D
development. NOD mice aging 4–8 weeks, which
was infected with different strains of CVB have
demonstrated two to 10-fold decrease in T1D inci-
dence rate, as compared with controls. This protec-
tive feature of CVB was found to be greater in more
virulent strains [58].
Another study found that infection of pre-
diabetic NOD mice with CVB3 had immuno-
modulatory effects, which included expression of
programmed cell death-ligand 1 (PD-L1) in lympho-
cytes and inhibition of PD1-producing autoreactive
CD8þ T cells. Production of CD4þCD25þ regula-
tory T cells was also observed and provided further
protection against T1D development [59].
Specific mechanisms explaining why CVB both
induces and inhibits T1D are still unclear. Age of the
CVB-infected mice is thought to be one explanation,
as induction and inhibition of T1D development is
noted in older and younger ages, respectively [44].
Other authors suggested that the net effect of CVB
on T1D is the result of direct CVB-induced b cell
damage versus b cells sparing, the later having pro-
tective features against T1D [59]. Therefore, CVB
is a good example on how the same infector both
induces and inhibits the same AID.
CONCULSION
Different infectious agents play a double role,
as inducers and inhibitors of autoimmunity. This
contributes to the complex multifactorial etiology
www.co-rheumatology.com 5
CE: Tripti; BOR/300402; Total nos of Pages: 8;
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Infections and environmental aspects of autoimmunity
of AID. Elucidating the exact role of each pathogen
on each specific AID is important, as complete
understating of these processes is still lacking. This
will enable further studies that will examine manip-
ulation of such infections, as a possible therapeutic
modality against AID.
Acknowledgements
None.
Financial support and sponsorship
None.
Conflicts of interest
There are no conflicts of interest.
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