Biomedicine & Pharmacotherapy 117 (2019) 109122

Contents lists available at ScienceDirect

Biomedicine & Pharmacotherapy

journal homepage: www.elsevier.com/locate/biopha

Review

Current mechanistic insights into the role of infection in systemic lupus T

erythematosus
⁎
Qingjun Pan ,1, Zejian Liu1, Shuzhen Liao1, Lin Ye, Xing Lu, Xiaoqun Chen, Zhihang Li, Xinxin Li,
⁎
Yong-Zhi Xu, Huafeng Liu
Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University,
Zhanjiang, Guangdong, 524001, China

A R T I C LE I N FO A B S T R A C T

Keywords: Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by inflammation and ab-
Systemic lupus erythematosus normal production of autoantibody, but the mechanisms of the aberrant immune responses are currently un-
Infectious agents known. Recently, growing evidence has suggested that infection plays a pivotal role in SLE. Here, we investigate
Mechanism the role of infectious agents (e.g., Epstein-Barr virus, parvovirus B19, human T-lymphotropic virus type 1,
Causative association
human immunodeficiency virus type 1, and endogenous retroviruses) in the pathogenesis of SLE. More im-
Protective association
portantly, we explore the known mechanisms underlying the involvement of infectious agents in the patho-
genesis of SLE, including molecular mimicry, epitope spreading, superantigen production, bystander activation,
persistent viral infection, altered apoptosis, clearance deficiency, and epigenetic alterations (e.g., DNA methy-
lation and microRNAs). However, some infectious agents (e.g., malaria parasites, hepatitis B virus, Toxoplasma
gondii, and Helicobacter pylori) may exert protective effects on SLE. Therefore, the relationship between infection
and SLE is multifaceted and multidirectional, including causative and/or protective associations, which warrant
further investigation in the future.

1. Introduction development of autoimmune diseases, which have been widely studied

Systemic lupus erythematosus (SLE), a chronic systemic auto-
immune disease, is characterized by inflammation and abnormal pro-
duction of autoantibody affecting multiple organs throughout the body.
However, the mechanisms underlying the aberrant immune responses
remain not well known [1]. In the past several decades, infection has
been increasingly recognized as a possible trigger of SLE. More recently,
accumulating evidence has indicated that infection and SLE are tightly
linked, with a multifaceted and multidirectional relationship [2–7].
In this review, we investigated the involvement of infectious agents
in the pathogenesis of SLE. More importantly, the currently understood
mechanisms underlying the involvement of infectious agents in SLE are
summarized.
2. Infectious agents and the mechanisms of their involvement in
SLE pathogenesis
Infectious agents, such as viruses, bacteria, parasites, and fungi, are
associated with the abnormal production of autoantibodies and the
in human and experimental animal models [8–11], particularly with
respect to the pathogenesis of SLE [6,12]. The predominant pathogens
known to be associated with SLE include Epstein-Barr virus (EBV),
parvovirus B19 virus, exogenous retroviruses (e.g., human T-lympho-
tropic virus type 1 [HTLV-1] and human immunodeficiency virus type 1
[HIV-1]), and endogenous retroviruses (ERVs) [5–7,12–19]. Other in-
fectious agents that may trigger SLE but their involvement in SLE pa-
thogenesis is less understood, including viruses such as transfusion-
transmitted virus (TTV) and cytomegalovirus (CMV), and bacteria such
as vibrio cholera and group A streptococcus (GAS) [3,6,20–25]. Only
one or two cases of some pathogens, including hepatitis C virus (HCV),
C-type oncornavirus, parainfluenza type 1, rubella virus, and measles,
has been reported in of the involvement of SLE pathogenesis
[3,6,26,27]. The definite, probable, and possible influences of these
infectious agents on SLE are summarized in Table 1.
Among SLE etiologies, infectious agents have been suggested to play
pivotal roles in individuals genetically predisposition; these pathogens
induce aberrant innate and adaptive immunity, leading to a loss of
tolerance toward autoantigens. The potential mechanisms of infectious

⁎
Corresponding authors at: No. 57, South of People's Avenue, Xiashan, Zhanjiang, Guangdong, 524001, China.
E-mail addresses: stillwater2004@126.com (Q. Pan), hf-liu@263.net (H. Liu).
1
These authors contributed equally to this work.

https://doi.org/10.1016/j.biopha.2019.109122
Received 23 April 2019; Received in revised form 5 June 2019; Accepted 12 June 2019
0753-3322/ © 2019 The Authors. Published by Elsevier Masson SAS. This is an open access article under the CC BY license
(http://creativecommons.org/licenses/BY/4.0/).
Q. Pan, et al. Biomedicine & Pharmacotherapy 117 (2019) 109122

Table 1
Infectious agents involved in the pathogenesis of SLE.
Definite Probable Possible

Viruses: Viruses: Viruses:

Epstein-Barr virus (EBV) Cytomegalovirus (CMV) Hepatitis C virus (HCV)
Parvovirus B19 virus Transfusion-transmitted virus (TTV) C-type oncornavirus
Exogenous retroviruses:HIV-1 Bacteria Measles
HTLV-1 Group A streptococcus (GAS) Parainfluenza type 1
Endogenous retroviruses (ERVs) Vibrio cholerae Rubella virus

Note: HIV-1, Human immunodeficiency virus type 1; HTLV-1, Human T-lymphotropic viruses type 1.

Fig. 1. The potential mechanisms of infectious agents in the pathogenesis of SLE. (APC, antigen-presenting cells; TCR, T cell receptors; MHC, major histocompat-
ibility complex).

agents in the pathogenesis of SLE are discussed in detail below (Fig. 1).
2.1. Molecular mimicry
Molecular mimicry by infectious agents can activate autoreactive T
cells via exogenous antigens with sequence or structural similarities to
autoantigens, consequently disordering the immune system and leading
to autoimmune responses [2,10,16,17,28,29]. However, studies also
showed that molecular mimicry did not account for T cell activation in
autoimmune diseases. Molecular mimicry may be mistakenly identified
when a single T cell has dual T cell receptors (TCR) that can react with
exogenous antigens and autoantigens. Nonetheless, this mechanism
may provide a better understanding of the cross-reactivity [7,30,31].
2.2. Epitope spreading
The adaptive immune system recognizes epitopes of the initial an-
tigens in the early immune response. However, over time, T and B cells
may respond to other epitopes. This process, known as epitope
spreading, is pivotal to promote the efficiency and breadth of the im-
mune response to infectious agents and tumors. When infectious agents
trigger or initiate SLE, epitope spreading, which can progress among
multiple epitopes on a single antigen or from one antigenic molecule to
another, facilitates the presentation of autoantigens through antigen-
presenting cells (APCs) and induces the activation of autoreactive
lymphocytes and the production of antibodies [16,28,32–34].
2.3. Superantigen production
Superantigens, produced by a variety of viruses and bacteria, can
bind to the variable domains of the T cell receptor beta chain and many
major histocompatibility complex (MHC) class II molecules. Because
superantigens lack of the antigenic specificity, this process leads to the
activation of many T lymphocytes with different antigenic specificities,
resulting in the development of autoimmune reactions [3,6,9,10].
2.4. Bystander activation
Bystander activation occurs when APCs are significantly activated
by the main virulence factors of infectious agents, which can potentially
activate pre-primed autoreactive T cells by increasing the production of
cytokines. The bystander activation of autoreactive immune T cells can

2
Q. Pan, et al.
Fig. 2. The potential protective mechanisms of infectious agents in SLE. (Treg
cells, regulatory T-cells; TLR, Toll-like receptor).
subsequently induce autoimmune diseases. In addition to bystander
activation of autoreactive T cells, APCs can activate virus-specific T
cells, which might initiate bystander activation through identifying
virus-infected cells and releasing cytotoxic granules and cytokines, such
as TNF, lymphotoxin (LT), and nitric oxide (NO), possibly causing by-
stander T cells to kill uninfected neighboring cells and activate auto-
immune responses [2,3,6,9,10,31].
2.5. Persistent viral infection
Persistent viral infection may result in autoimmunity by constantly
stimulating the immune system. At the same time, lymphotropic viruses
might stimulate the development of polyclonal lymphocytes, increase
the production of antibodies and circulating immune complexes, and
eventually damage self-tissues [3,6,9,28].
2.6. Altered apoptosis and clearance deficiency
Cell apoptosis induced by infection can trigger autoreactive Th17
cells to promote autoinflammation and autoantibody generation. In
addition, insufficient clearance of infectious agents and apoptotic cells
due to genetic defects of the immune system such as complement de-
ficiency may lead to accumulation of nuclear material [35]. These non-
ingested nuclear materials may provide survival signals for autoreactive
B cells, resulting in the production of antibodies against nuclear
structures and immunological dysfunction [3].
3
Biomedicine & Pharmacotherapy 117 (2019) 109122
2.7. Epigenetic factors
MicroRNAs are a novel class of endogenous, non-coding small RNAs
with a length of about 19–25 nucleotides. MicroRNAs negatively reg-
ulate gene expression through degrading or inhibiting post-transcrip-
tional mRNA translation. In the immune system, the biological func-
tions of microRNAs mainly include regulation of the differentiation of
immune cells and innate and adaptive responses. Dysregulation of
microRNAs may result in autoimmune diseases, including SLE. Indeed,
many pathogens can induce changes in the expression of particular
microRNAs [36,37]. Regulation of innate immune responses by mi-
croRNAs may prompt increased production of inflammatory cytokines;
for example, microRNAs abnormally activate type I IFN signaling in-
volved in SLE [38]. Further, abnormal microRNAs may impair adaptive
immunity, causing B and T cell dysfunction. Abnormal T cell function,
such as Treg instability, loss of Treg suppressor function, and lympho-
cyte accumulation, can induce loss of tolerance and the development of
autoimmunity. Abnormal B cell function involves impaired IgG class-
switch and an inadequate germinal center response, which provokes the
production of antibodies [39,40]. Moreover, altered microRNA levels
may indirectly or directly inhibit DNA methyltransferases (DNMTs),
leading to DNA hypomethylation and upregulation of autoimmunity-
associated genes (e.g., CD70, CD11a, and CD40 L), all of which are
involved in the pathogenesis of SLE [38]. Other recent studies de-
monstrated that bacterial and viral DNA are hypomethylated, which
may induce autoimmune responses by activation of Toll-like receptor 9
(TLR-9) signaling, overexpression of type 1 INF genes, and activation of
polyclonal B cells and autoantibodies [41,42].
3. The possible protective effects of infectious agents in SLE
Accumulating evidence suggests that infection can induce auto-
immune diseases. However, the relationships between infection and
autoimmune diseases are multifaceted and multidirectional, including
causative and/or protective associations [43]. Thus far, numerous
epidemiological studies and animal experimental studies have shown
that infectious agents, primarily protozoa, may prevent autoimmunity
or even abrogate an ongoing autoimmune process, depending on the
unique interaction between the microorganism and host [2]. The hy-
giene hypothesis, which was developed based on the concomitant in-
crease in autoimmune diseases and decrease in infections due to the
improvement of hygiene and sanitation in western countries, proposes
that infections may play protective roles in autoimmune diseases [44].
In general, autoimmune protection can be achieved by blocking antigen
presentation or antigen competition.
The potential protective mechanisms of infectious agents involve
the following: firstly, antigenic competition leads to a decrease in the
response to autoantigens; secondly, the suppression of host immune
response to self- or non-self molecules by irritating subgroups of Treg
cells; thirdly, TLR signaling directly or indirectly regulates immune
suppression of Treg cells (Fig. 2) [3,4,6,9,10,45].
So far, some reports have confirmed that infectious agents may play
a protective role in SLE. Continued infection with lactate dehy-
drogenase virus significantly reduced antibodies against nuclear an-
tigen and DNA in lupus mice, delaying the progression of nephritis
[46,47]. Malaria infection attenuates lupus nephritis in lupus mice by
reducing kidney oxidative stress and increasing the antioxidant defense
system [48,49]. Data from lupus animal studies indicated that FcγRIIb
deficiency prevents animals from infection, but increases susceptibility
to autoimmune diseases [50]. Some researchers have also used lupus
mice infected with live Plasmodium chabaudi (P. chabaudi) to improve
histopathological changes kidney tissue [51]. Toxoplasma infection can
delay the development of autoimmune nephropathy in lupus-suscep-
tible mice by altering mouse autoantibodies [52,53]. Parasitic worms
may protect kidney pathology by secreting glycoproteins to reduce
antinuclear antibody production and immune complex deposition or
Q. Pan, et al.
altering the cytokine microenvironment [54,55]. Studies have also
found that the worm derivative phosphocholine (PC) acts as an im-
munomodulatory molecule to significantly decrease proteinuria levels,
diminish proinflammatory cytokines, increase anti-inflammatory cyto-
kines, and significantly amplify CD4+CD25+FOXP3+ Treg cell through
multiple mechanisms [56]. Epidemiological studies have revealed that
Helicobacter pylori (H. pylori) serum reactivity is associated with SLE
development in African American women, but recent studies have
shown that topical H. pylori gastritis can induce systemic inflammatory
response and promote lupus progression in some lupus patients
[57–59]. Therefore, the existing evidence still does not fully support the
role of H. pylori in the development of SLE. Epidemiological studies
from different regions have also shown that hepatitis B virus (HBV)
infection rate in patients with SLE is lower than that in non-SLE control
group, suggesting that HBV may have protective effects on SLE, but the
specific mechanism has not been studied in depth [60,61].
In summary, since there are still many unknowns about the pro-
tective pathogens, proving their protective effects remains challenging
and need working hard on its in-depth exploration. As research of this
nature continues, novel insights into the protective effects of infectious
agents on SLE may be gained.
4. Conclusion and future perspective
Identifying the infections involved in the development of SLE could
provide insight into practicable measures to reduce trigger exposure
and prevent flares as well as the design of treatment strategies for high-
risk groups, all of which will benefit patients with SLE. Recent dis-
coveries related to the mechanisms of infection in SLE implicated mo-
lecular mimicry, epitope spreading, superantigen production, bystander
activation, persistent viral infection, altered apoptosis, clearance defi-
ciency, and epigenetic alterations (e.g., DNA methylation and
microRNAs), etc. However, the relationship between infection and SLE
is multifaceted and multidirectional, including causative and/or pro-
tective associations, which warrant further investigation in the future.
Funding acknowledgment
The work was supported by Natural Science Foundation of
Guangdong Province, China (grant number 2015A030313526), Medical
Scientific Research Foundation of Guangdong Province, China (grant
number A2014481).
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