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Interplay of Infections, Autoimmunity, and Immunosuppression

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Article in International Reviews Of Immunology · January 2014

DOI: 10.3109/08830185.2013.863305 · Source: PubMed
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International Reviews of Immunology, Early Online:1–34, 2014
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ISSN: 0883-0185 print / 1563-5244 online
DOI: 10.3109/08830185.2013.863305
ORIGINAL ARTICLE
Interplay of Infections, Autoimmunity,

and Immunosuppression in Systemic Lupus
Erythematosus
Tiffany Caza, Zachary Oaks, and Andras Perl

Int Rev Immunol Downloaded from informahealthcare.com by Nyu Medical Center on 02/04/14
Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
Infectious agents are considered to be crucial environmental factor in the etiopathogenesis of

systemic lupus erythematosus (SLE). Infections may serve as initial trigger to the development of
autoimmunity and carry an overall greater risk of morbidity and mortality than the general pop-
ulation. Initial presentation of SLE can mimic infections, and in turn infections can mimic disease
flares in established SLE. Infections due to predisposition by commonly used immunosuppressive
therapies are a significant cause of morbidity and mortality. In this review, viral, bacterial, fun-
gal, and parasitic infections that contribute to the etiology of SLE, potentially mimic or precipitate
For personal use only.
flares, create diagnostic dilemmas, complicate treatment, or protect against disease, are discussed.
Infection risks of current immunosuppressive therapies used in the treatment of SLE are outlined.
Strategies to prevent infection, including vaccines, prophylactic antibiotic therapies, toll-like re-
ceptor antagonism, and antioxidant treatment that may decrease disease burden and improve
quality of life in lupus patients will be discussed.
Keywords: autophagy, bystander activation, endogenous retrovirus, immunosuppression, in-
fections, molecular mimicry, systemic lupus erythematosus, vaccinations
INTRODUCTION
Systemic lupus erythematosus (SLE) is an autoimmune disease of complex etiology,
involving genetic, epigenetic, and environmental factors and characterized by dereg-
ulation of the innate and adaptive immune systems, production of autoantibodies,
and tissue damage resulting from chronic inflammation [1]. Genetic factors contribute
to SLE pathogenesis, evidenced by epidemiological studies which identified a higher
concordance rate of disease in monozygotic twins (24–69%), compared to dizygotic
twins (2–5%)[2]. As not all siblings from affected monozygotic twins develop disease,
environmental factors must play a role in lupus pathogenesis.
Infectious agents were identified as an environmental factor implicated in the ini-
tiation and potentiation of autoimmunity in SLE. Genome-wide association studies of
SLE patients identified genes upregulated in antiviral immune responses, including
those implicated in toll-like receptor (TLR) signaling and regulation of type I inter-
feron production [3, 4]. Environmental triggers in the setting of genetic susceptibility
and epigenetic modifications results in aberrations of the innate and adaptive immune
Accepted 1 November 2013.

Address correspondence to Dr. Andras Perl, Departments of Medicine, Microbiology and
Immunology, and Biochemistry and Molecular Biology, 8299 Weiskotten Hall, Upstate Medical
University, 750 East Adams Street, Syracuse, NY 13210, USA. E-mail: perla@upstate.edu

 T. Caza et al.
responses, affecting antigen presentation, immune cell apoptosis, signaling of T and

B lymphocytes, and impaired clearance of immune complexes [5].
SLE disease flares and infections have overlapping clinical features, complicating
diagnosis and treatment. Low-grade fever or pulmonary infiltrates in a SLE patient
could represent manifestations of active disease, such as pleuritis or pneumonitis, or
be due to infection [6]. Increasing the dose of corticosteroid therapy will resolve fever
due to disease flare, but not infection [7]. Such maneuvers are risky, however, as im-
munosuppression worsens underlying infections. It is important to rule out infection
prior to treatment of lupus flare, due to use of immunosuppressive agents to control
disease activity.
An increased titer of anti-dsDNA antibodies or hypocomplementemia (low C3 and
C4 levels) suggests active disease and SLE flare, however, patients may have underlying
infection coincident with active disease [8]. Leukocytosis and positive cultures could
indicate infection [8], however, it is more common for lupus patients with infection
to present with leucopenia [9]. In a study of 124 patients with SLE, 74.2% exhibited
white blood cell (WBC) count abnormalities with leukopenia (defined as <4000
leukocytes/μl), lymphopenia (defined as <1500 lymphocytes/μl), or neutropenia
(defined as <2500 neutrophils/μl) during infection [9]. Lymphocytopenia is a hema-
tologic abnormality in the American College of Rheumatology diagnostic criteria for
SLE [10], and represents an important risk factor for the development of infections.
Symptoms of infection can be subtle in lupus patients, especially those receiving
corticosteroids or cytotoxic medications. Use of immunosuppressives greatly broad-
ens the differential diagnosis for possible infectious causes. Linking autoimmunity to
infections can be challenging, as there may be a long time between the causal infec-
tion and development of symptoms. Furthermore, serologic evidence of the infection
may no longer exist at the onset of autoimmunity [8]. This follows the “hit and run” hy-
pothesis, where an autoimmune response is a byproduct of a microbial infection that
is no longer present when the autoimmunity becomes clinically apparent [11].
Disease Burden due to Infections in SLE Patients

Infections are a major cause of morbidity and mortality in SLE patients. Despite great
improvements in reducing mortality in SLE, the mortality due to infections in lupus
patients remains unchanged, constituting the cause of death in 1 out of 3 SLE patients
[6]. Lupus disease activity, measured objectively by the systemic lupus erythematosus
disease activity index (SLEDAI), is an important risk factor for infection [12–15]. In-
creased SLEDAI is associated with increased rates of hospitalization, prolonged length
of stay, and increased rates of nosocomial infections [16]. Prior to the use of corticos-
teroids and cytotoxic agents for management of lupus flare, infection rates remained
elevated in SLE patients when compared to age-matched controls [6], suggesting that
SLE patients have an intrinsic increased susceptibility to infection.
Serious infection is a major cause of intensive care unit (ICU) admission in SLE
patients [17]. In SLE patients admitted to the ICU, infection occurred concurrently
with disease flare in a majority of patients. Lupus patients admitted to the ICU due
to infection had an increased mortality rate when compared to noninfectious causes
[17]. Bacteremia is common, identified in 17% of SLE inpatients [16] and afflict-
ing up to 47% at some point in their lives [18]. Bacteremia is associated with poor
outcomes, increased length of hospital stay, with increased mortality [16]. The average
5-year survival of SLE patients from time of diagnosis is 92%, while in patients with
bacteremia it is only 67% at 1 year [16]. Sepsis can cause lupus nephritis to progress
to end-stage renal disease, accelerating the disease course [6].
In a prospective cohort study, 32% SLE outpatients developed infections over
2 years. In those who developed infection, 35% were major infections that required
International Reviews of Immunology

Infection and SLE 
hospital admission and administration of intravenous (IV) antibiotics, with

community-acquired pneumonia and bacteremia being the most common indi-
cations for admission [12]. SLE patients hospitalized with infections have worse
outcomes and are at increased risk of acquiring secondary nosocomial infections
[19]. A delay in antimicrobial therapy of greater than 24 hours increased the mortality
of hospitalized SLE patients 12-fold [20], therefore, early identification and treatment
of infections are essential.
Increased Susceptibility to Infection in SLE Patients

Multiple factors contribute to increased risk of infection in lupus patients. Genetic
factors include mannose-binding lectin deficiency [21] and C1q deficiency [22].
Congenital deficiency of C1q, the first component of the classical complement
pathway, is associated with SLE [22]. Acquired C1q deficiency is more common, due
to autoantibodies against C1q [22]. Deficiencies in early complement components

predispose to SLE, including C1, C2, and C4. Reduced levels of other components,
including C1s, C1 inhibitor, C3, C3b, and the C5–C8 membrane attack complex
[23–25] or CR1 complement receptors are also associated with SLE and poor clear-
ance of bacterial infections [26]. Acquired hypocomplementemia is more common
than genetic complement deficiencies, due to immune-complex-mediated depletion
with less available for immune defense [23]. Five percent of SLE patients have func-
tional asplenia or hyposplenia [27], which increases susceptibility to infections with
encapsulated bacteria, including pneumococci and Salmonella [28].
Patients with chronic granulomatous disease (CGD), a primary immunodeficiency
syndrome characterized by defective ROS production in phagocytic cells due to de-

ficiency in NADPH oxidase, are at increased risk for developing SLE [29]. Consistent
with this, NADPH oxidase deficiency in lupus-prone MRL/lpr mice exacerbated dis-
ease development, with increased production of autoantibodies, splenomegaly, and
worsened nephritis, suggesting that NADPH oxidase is protective against SLE [30].
NADPH-oxidase deficient CD4+ T cells from CGD patients are directed towards Th17
specification, promoting inflammation. Additionally, CGD patients have recurrent in-
fections with catalase-positive bacteria and fungi, which could further promote au-
toimmune responses [29].
Numerous defects in the innate immune system predispose to infections in SLE pa-
tients [31]. The innate immune system is able to generate an immune response against
a broad range of microbial pathogens through recognition of pathogen-associated
molecular patterns (PAMPs) by pattern-recognition receptors (PRRs), including TLRs,
NOD-like receptors, and C-type lectin receptors. Binding of microbial components
from bacteria, viruses, or fungi to PRRs activates innate immune responses, increasing
antigen-presenting cell (APC) function, resulting in activation of T and B lymphocytes
[32]. TLRs that recognize microbial nucleic acid components, including TLR3 that rec-
ognizes dsRNA, TLR7 recognizing ssRNA, and TLR9 recognizing dsDNA and CpG mo-
tifs of bacterial DNA, are over-expressed in SLE at sites of target organ damage and
contribute to pathogenesis [33]. TLR9 ligation by viral DNA or self-DNA peptide com-
plexes stimulates plasmacytoid dendritic cells (pDCs) which produce IFN-α [34–35].
pDC activation results in activation of both Th1 and Th2 cells [36], representing a key
link in innate and adaptive immune responses [36].
Type I IFNs produced by pDCs activate neutrophils [37]. SLE patients have in-
creased production of low-density granulocytes, immature forms of neutrophils, due
to increased bone marrow release in response to IFNα and increased neutrophil
death [31]. IFNα can also trigger differentiation of peripheral blood monocytes into
pDCs, further amplifying this feedback loop. IFNα was identified as the serum factor
that triggers healthy monocytes to mature into DCs when exposed to SLE serum
Copyright
C Informa Healthcare USA, Inc.
 T. Caza et al.
[38]. Increased IFNα in SLE and overexpression of IFN-associated genes creates an

“interferon signature” of SLE monocytes and lymphocytes, the cell types responsi-
ble for increased IFNα production [39]. This signature occurs in >95% of children
and >70% of adults with SLE, and positively correlates with disease activity and
nephritis [39, 40]. Corticosteroids, which potently suppress SLE disease activity, block
interferon-related gene expression and cause pDC depletion, suggesting the IFN
signature contributes to lupus pathogenesis [41]. Polymorphisms of IRF-5 linked to
SLE susceptibility stimulate expression of IFNα-targeted genes upon TLR7 triggering
during a viral infection [42]. It is possible that a latent or chronic virus is a persistent
stimulus triggering elevated IFNα production in SLE [5].
Related to the IFN signature, a granulopoiesis gene expression signature also exists
in SLE [39]. The death of immature neutrophils represents a major source of nuclear
autoantigens for antibody generation in SLE. Lupus neutrophils primed by IFNα
have increased death, resulting in release of neutrophil extracellular traps (NETs)[43].

NETs contain antimicrobial peptides and function to bind and eliminate bacteria,
fungi, and parasites to limit infection. NETs are cleared promptly by nuclease deoxyri-
bonuclease I (DNAse I)[44]. SLE patients have deficient DNAse I production [45], with
reduced ability to clear NETs [46], especially in patients with nephritis [43]. Immune
complexes, antineutrophil cytoplasmic antibodies, and defensins produced in SLE
patients stimulate neutrophils to release NETs [47]. NETs activate T lymphocytes [48],
which are already primed in SLE patients [49]. N-acetylcysteine (NAC), an antioxidant
compound shown to suppress disease activity in SLE [50, 51], was found to block NET
formation [52].
TLR triggering with interferon production is not the sole mechanism for viral-
induced immune responses [53]. Microbial triggering of mitochondrial antiviral sig-
naling protein (MAVS) induces innate immune responses by non-TLR dependent
mechanisms [54]. A single-nucleotide polymorphism C79F within MAVS, an adaptor
protein that transduces signaling from the viral sensor retinoic acid-inducible gene-1
(RIG-1) in response to self-DNA, was identified in SLE patients [55]. RIG-1 regulates in-
nate immune responses, apoptosis, cytokine signaling, and IFN production [56]. The
C79F MAVS mutation correlates with disease activity in SLE [55] and could increase
risk of infections due to poor antiviral responses.
Deregulation of the adaptive immune system further contributes to poor response
to infections in SLE patients. B and T cells have increased activation with reduced
numbers in SLE [57]. B cells from SLE patients exhibit polyclonal activation with en-
hanced antibody generation [49]. Immunoglobulin G (IgG) production by plasma
cells is skewed with an overall increase in immunoglobulins, but reduced IgG2-
subclass immunoglobulins, which are protective against encapsulated bacteria [6]. IL-
10-producing B cells are increased in SLE patients, which suppress cellular immunity
[58]. CD8+ T cells from SLE patients have reduced cytolytic function [59], which results
in unabated expansion of autoreactive B cells with persistent CD4+ T cell-mediated
polyclonal B cell activation [60]. SLE CD4+ T cells have a bias for Th2 and Th17 specifi-
cation [61], with reduced Th1 cells [62], resulting in less protection against viruses and
intracellular bacteria. Patients also have reduced generation and suppressor activity
of regulatory T cells (Tregs), promoting inflammation [63].
Activation of the mechanistic target of rapamycin (mTOR) in SLE T cells [64] is likely
responsible for reduced T cell specification to the Treg lineage, as mTOR expression
promotes generation of effector T cells over Treg lineage commitment [65]. mTOR pro-
motes Th1 and Th2 differentiation of naı̈ve CD4+ T cells [66]. Subset specification by
mTOR is through directing T cell metabolism by regulating oxidative phosphorylation
within mitochondria [67] and through negative regulation of autophagy [68] [69].

Infection and SLE 
Defects in autophagy in lupus patients can increase infection burden due to poor
clearance of pathogens. Autophagy is a homeostatic process with an important role
in immune defense through removal of pathogens to protect cells from intracellular
bacteria and viruses. It also implicated in numerous immune cell functions, includ-
ing T cell development, T cell activation, and antigen presentation [70]. Autophagy is
also activated by viruses through dsRNA-activated protein kinase, which inhibits viral
replication and limits infection [71].
Altered induction of autophagy was identified in SLE patients as well as in murine
models [72]. Reduced autophagy in lupus [73] may account for defective clearance
of intracellular bacteria and persistence of viral infections. T cells from SLE patients
are resistant to induction of autophagy, secondary to mTOR activation and presence
of autoantibodies within sera [73]. Mutations of ATG5 that inhibit early steps in au-
tophagy were identified in SLE patients [74], while restoration of autophagy through
mTOR blockade with rapamycin reduced disease activity [75]. Multiple SLE therapies
modulate autophagy [76], suggesting that autophagy defects are pathogenic.
Infection Risk of Lupus Therapeutics

Chronic use of glucocorticoids and immunosuppressive agents used in the treatment
of SLE increases infection risk. Most SLE patients require immunosuppressive agents
for disease control, and in >80%, treatment is prolonged for long periods [77].
Medications approved by the Food and Drug Administration (FDA) for the treatment
of SLE include corticosteroids (prednisone and intralesional triamcinolone), as-
pirin, hydroxychloroquine, and belimumab [78]. In addition to these FDA-approved
medications, cytotoxic agents, including cyclophosphamide (CYC), mycophenolate

mofetil, azathioprine (AZA), and methotrexate (MTX), as well as anti-CD20 mono-
clonal antibody rituximab were found to be efficacious in the treatment of lupus flares
[79–82]. NAC and rapamycin are also beneficial in SLE through inhibition of mTOR
[50, 75]. Lupus therapeutics, their mechanisms of action, efficacy, and associated
infections are described later and summarized in Table 1.
Glucocorticoids
Glucocorticoids are the dominant therapy in management of SLE flare, with a majority
of patients continuing treatment with low doses of 7.5 mg or less indefinitely to main-
tain disease quiescence [83]. Glucocorticoids suppress immune responses and impact
almost all immune cell types through transcriptional regulation of gene targets and in-
hibition of cellular proliferative responses through NF-κB repression [84]. Prolonged
use of glucocorticoids greatly increases the risk of infection in patients with rheumatic
disease by 2 to 2.5-fold [85, 86]. Glucocorticoid use reduces cellular immunity, increas-
ing host susceptibility to bacterial, fungal, parasitic, and viral infections [87]. Infection
risk is related to the maximum daily dose of steroid and the cumulative length of ther-
apy [28]. Use of prednisone for greater than 3 weeks or of a dose greater than 16 mg/day
is associated with opportunistic infections [88]. Patients receiving >50 mg/day had a
fourfold increased risk [89], related to inhibition of T cell mediated immune responses
[89], as CD4+ and CD8+ T cells apoptose upon glucocorticoid exposure [90]. When
glucocorticoids are required, use of the lowest possible dose to achieve a clinical re-
sponse for the shortest duration of time will reduce infection risk [88].
Cyclophosphamide
CYC is a cytotoxic drug, an alkylating agent, effective in the management of severe lu-
pus nephritis. It is associated with bone marrow suppression which can lead to oppor-
tunistic infections due to leucopenia [91] occurring in one-third of patients [92]. There
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
TABLE 1. Infections related to lupus therapeutics.
Drug Mechanism Reported infection types Cells affected FDA approved for SLE
Glucocorticoids Inhibition of NF-κB Viral, Bacterial, Fungal, All immune cell types, Yes-prednisone and
Parasitic nonspecific inhibition triamcinolone acetonide
for discoid lupus
CYC DNA alkylation Herpes zoster, All immune cell types, No
opportunistic nonspecific inhibition
Mycophenolate mofetil Inhibition of IMPDH/purine synthesis Herpes zoster B and T cells No
Azathioprine Inhibits Amidophosphoribosyltransferase and Herpes zoster B and T cells No
incorporates into DNA and RNA
Methotrexate Anti-folate through DHFR and inhibits purine JC Virus B and T cells No
synthesis via thymidylate synthase
Rituximab Antagonizes CD20 Streptococcus B cells No
intermedius, PJP, S. typhi
Rapamycin Binds FKBP12 and inhibits mTOR and IL-2 Encephalomyocarditis B and T cells No
driven activation of T & B cells virus and poliovirus, but
none described in SLE
Belimumab Antagonizes BAFF CMV and acinetobacteria B cells Yes
Hydroxychloroquine Sulfate Increases lysosomal pH, blocks TLR 7 & 9 of HPV APCs and pDCs Yes
pDCs
Aspirin Inhibits COX 1 & 2, blocks NF-κB and None Neutrophils, platelets Yes
subsequent NET formation
N-acetylcysteine Reducing agent and GSH precursor None Nonspecific reducing No
agent
Infection and SLE 
is no difference in the rate of infections using IV or oral CYC preparations, however,

the subsequent use of oral after IV CYC increased the infection rate 2.3-fold [93]. The
risk of infection is dose-dependent, with 16% infection rate on low-dose therapy com-
pared to 38% receiving high-dose therapy [79]. There was a high incidence of herpes
zoster (HZ) infection on CYC therapy (47–60%) with twice the incidence on high-dose
treatment [79, 94]. In a trial comparing use of CYC with prednisone, compared to pred-
nisone only, there was a markedly increased rate of serious infections with combina-
tion therapy than with prednisone alone (45% versus 12%)[93]. In a direct comparison
study of CYC to mycophenolate mofetil (MMF) for treatment of nephritis, CYC therapy
was associated with an increased rate of severe infections and hospitalizations [92]. In
this study, 83% patients on CYC developed infection, and 6 were life-threatening [92].
Although CYC is effective, it should be used with caution due to its high infection risk
and considered in patients who do not respond to first-line therapy with MMF.
Mycophenolate Mofetil
Mycophenolate mofetil (MMF) is an immunosuppressant agent that inhibits purine
synthesis through noncompetitive inhibition of inosine monophosphate dehydroge-
nase. It is well-tolerated and used post-transplant to prevent rejection in solid organ
transplant recipients [95]. MMF is indicated for maintainence therapy of severe SLE,
found to be superior to CYC [92], and resulted in fewer flares than AZA treatment
[80]. MMF is steroid sparing, reducing corticosteroid dose by >50%[96]. MMF car-
ries a reduced risk of infections (39%) and leukopenia (<2%)[95], and reduces the risk
of chronic renal failure or death in patients with nephritis by twofold [96]. In a meta-
analysis of randomized controlled clinical trials of MMF, the risk of serious infections
was 4%, approximately half were associated with concurrent CYC use [95]. However,
5–10% of patients treated with MMF for maintainence therapy develop HZ [94]. Due
to increased efficacy and reduced risk of infection, MMF is first line therapy of lupus
nephritis [92].
Azathioprine
Azathioprine is a purine synthesis inhibitor used for maintainence immunosuppres-
sion in lupus nephritis. It carries a lower risk of infections than CYC [97, 98]. In a study
of 223 patients, AZA use was not associated with an increased risk of bacterial, viral,
or opportunistic infections [99], except in leukopenic patients. AZA-associated bone
marrow suppression causes leukopenia in a minority of patients (<4%) [80]. HZ was
most common in patients with bone marrow suppression [94]. Despite the low infec-
tion risk, AZA is not first line therapy for severe SLE or nephritis. When compared to
MMF, AZA has an increased rate of treatment failures, increased renal flare rate, and
was not found to be steroid-sparing [80].
Methotrexate
MTX is a cytotoxic compound that functions through inhibition of dihydrofolate re-
ductase, used in the treatment of rheumatoid arthritis, psoriasis, and SLE [100]. MTX
is steroid-sparing [101] and reduces skin and joint manifestations of SLE by 57–70%
[100]. However, it is strongly immunosuppressive, with and overall infection risk of
20% and opportunistic infections present in patients without leucopenia [102]. Oppor-
tunistic infections reported with MTX include Pneumocystis jerovecii, Mycobacterium
tuberculosis (TB), Listeria, Nocardia, HZ, varicella zoster virus (VZV), CMV, HSV, HBV,
JC virus, Aspergillus, and Histoplasma [102, 103].
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 T. Caza et al.
Rituximab
Rituximab is a chimeric antibody against CD20 surface antigen on B cells used for B
cell depletion in hematologic malignancies. Rituximab used off-label for SLE in 188
patients had a 91% response rate [104]. B cell depletion by rituximab reduces autoan-
tibody generation, however long-lived plasma cells persist [82]. Patients with nephritis
had the most clinical improvement with reduced SLEDAI, anti-dsDNA titers, and re-
duced B and T cell infiltration into the renal interstitium [104]. Rituximab interferes
with humoral immunity, increasing the risk of infections. Nineteen percent of SLE pa-
tients treated with rituximab had infections, including skin infections, urinary tract
infections, bacterial sepsis, pneumonia, endocarditis, and gastroenteritis [104]. Re-
ported organisms include Streptococcus spp., Pseudomonas aeruginosa, Salmonella
typhii, VZV, and JC virus [104–107]. As SLE patients are at increased risk of endocardi-
tis during bacteremic episodes, including those without a prior history, it has been
proposed that antibiotic prophylaxis be given during rituximab treatment to reduce

risk of infection [105].
Belimumab
Belimumab, the first biological treatment approved for SLE, is a human monoclonal
antibody that targets B-lymphocyte stimulator (BAFF). In a phase III, randomized,
placebo-controlled trial of 867 patients, there was no increased rate of infections (67%
from 10 mg/kg high-dose group compared to 64% placebo) [108, 109]. Additionally,
there was a lower rate of serious infections, severe infections, and infections requiring
hospital admission compared to placebo. A recent case report identified a patient hos-
pitalized with infection while being treated with prednisone, MTX, MMF, or AZA, who
had disease remission while on Belimumab [110]. Belimumab may be a good choice
to control disease in patients with repeated infections, as it is less immunosuppressive
than corticosteroids or cytotoxic drugs [110].
Rapamycin
Rapamycin is a FDA-approved immunosuppressant for use in renal transplant recipi-
ents, currently under investigation in a prospective clinical study for treatment of SLE
(clinicaltrials.gov NCT00779194). Rapamycin inhibits IL-2 dependent activation of T
and B lymphocytes through inhibition of mTOR [111, 112]. Rapamycin also reduces
IFNα production by pDCs and induces immune tolerance by expansion of Tregs [113].
Rapamycin is steroid-sparing and reduces disease activity in patients with SLE [75]. No
infectious complications of rapamycin treatment of SLE have been reported to date,
although it may hold promise of reducing overall risk of infections due to its steroid-
sparing effects.
N-acetylcysteine (NAC)
Use of the antioxidant NAC shows promise as an adjunctive treatment in SLE and
reduces infections. Overproduction of reactive oxygen species (ROS) occurs in SLE
lymphocytes secondary to mitochondrial dysfunction and contributes to inflamma-
tory damage [114]. NAC is a potent antioxidant, which can be consumed directly by
ROS or serve as a substrate for glutathione production [50]. In a small double-blind,
placebo-controlled clinical trial, NAC treatment reduced disease activity with re-
duction in the SLEDAI and British Isles Lupus Assessment Group indices, anti-DNA
antibody titers, and fatigue assessment scale scores, while increasing Tregs through
inhibition of mTOR [50]. Unlike immunosuppressive therapies that increase infection
risk, NAC treatment is protective against a wide variety of infections. NAC was shown
to reduce S. pneumoniae and H. influenzae infections in patients with chronic
bronchitis [115], bacteremia in patients with indwelling catheters [116], influenza

Infection and SLE 
disease duration [117], and is used adjunctively with antibiotics in HIV patients for
prophylaxis of opportunistic infections [118].
Mechanisms Through Which Infectious Agents May Trigger Autoimmunity

There are multiple mechanisms through which pathogens elicit autoimmune re-
sponses (Figure 1).
Molecular mimicry occurs when nonself peptides, mainly of microbial origin, share
sequence homology with self-peptides, eliciting cross-reactive recognition between
foreign and self-antigens, leading to activation of autoreactive T cells [5]. Molecular
mimicry arises due to the flexibility in T cell receptor recognition for antigens, which
allows recognition of a multitude of pathogen-derived proteins, but has redundancy.
Redundancy can lead to induction of autoimmune responses by microbial antigens.
Viral peptides cross-reactive with self-proteins provide a continuous antigen source
for formation of autoantibodies [119].

APCs that are activated by microbial products stimulate activation and expansion of
T and B cells via bystander activation of heterologous T cells. The heightened inflam-
matory response results in tissue damage [5]. Necrotic and apoptotic debris are phago-
cytosed, processed, and presented by APCs, which promote activation of dendritic
cells. As dendritic cells produce B lymphocyte stimulated (BLyS), this in turn activates
FIGURE 1. Microbes initiate autoimmune responses. Molecular mimicry of microbial components

with self-peptides results in activation of autoreactive lymphocytes and subsequent cytokine and
antibody production against self-antigens. Intramolecular or intermolecular epitope spreading am-
plifies this response. Viral or bacterial superantigens nonspecifically activate T cells, further pro-
moting inflammation.
Copyright
 T. Caza et al.
B cells. Dendritic cells and monocytes also over-produce nitric oxide (NO) that elicits
further bystander T-cell activation by positive feedback. T cells from patients with au-
toimmune diseases, including SLE, rheumatoid arthritis (RA), and multiple sclerosis
(MS) are more susceptible to bystander activation. This is due to impaired B cell toler-
ance and reduced co-stimulation requirements [120–122]. Lupus lymphocytes have a
lower activation threshold than alloreactive lymphocytes with greater cell frequencies
of activation. This is due to aggregation of lipid rafts on T cell surfaces, which make
up the domains through which signaling at the immunological synapse occurs [123].
Superantigens produced by microbes provide broad bystander activation, as they are
able to cross-link MHC II molecules on APCs, activating a large group of CD4+ T cells
expressing a given vβ domain [124]. Superantigens initiate T cell proliferation and am-
plify ongoing immune responses [124], but do not precipitate autoimmunity [5].
Epitope spreading is another process through which pathogens elicit autoimmu-
nity. In the context of inflammation, cross-reactive immune responses from molecu-

lar mimicry can spread to different portions of the same protein (intramolecular) or to
a different protein (intermolecular)[125]. Epitope spreading activates a repertoire of
T lymphocytes with broader specificities, which can be helpful to limit infection, but
can exacerbate autoimmunity. These mechanisms of autoimmunity often do not occur
in isolation; all may be present during an autoimmune response. Molecular mimicry
stimulates a population of autoreactive T cells, which can expand through bystander
activation, and be amplified by epitope spreading and/or superantigen-mediated T
cell activation, perpetuating auto-inflammatory responses [5]. Infectious agents pro-
vide antigenic sources to support autoreactive effector and memory cells [5], as well
as influence immunoregulatory networks.

Multiple viruses, bacteria, fungi, and parasitic infections have been shown to com-
plicate lupus disease activity or precipitate flare (Table 2 & Figure 2). Pathogens im-
plicated in induction of autoimmunity or precipitation of disease flare are described
later.
DNA Viruses
Herpes simplex virus (HSV, human herpesvirus 1 and 2)
Human herpesviruses are double-stranded, linear DNA viruses that maintain life-
long latency. HSV-1 and HSV-2 are ubiquitous herpesviruses maintaining latency
within nerve ganglia [126]. Severe, life-threatening manifestations of disseminated
HSV infection (usually HSV-1) rarely occur, but have been reported in SLE patients
on high-dose immunosuppressive therapy. HSV-1 was reported to cause encephalitis
and retinitis in SLE [127] and can trigger latent antiphospholipid syndrome [128].
Esophagitis, common in patients with AIDS and malignancies, can occur in immuno-
suppressed SLE patients, which can mimic or be complicated by lupus enteritis [129].
HSV reactivation from facial nerve ganglia can cause tracheobronchitis, pneumoni-
tis, or pneumonia [126]. Acyclovir, which blocks viral replication by inhibition of
thymidine kinase, is the recommended treatment for HSV in SLE patients [126].
Varicella zoster virus (VZV, human herpesvirus-3)

SLE patients are at increased risk of reactivation of VZV. Young patients with SLE
have higher rates of VZV reactivation than immunocompetent elderly individuals
over 80 years of age, including patients with low disease activity [130]. Additionally,
SLE patients have poor viral clearance due to reduced lymphocyte proliferation in
response to VZV antigens when compared to healthy controls from defects in CD4+
T cell-mediated immune responses [131].

TABLE 2. Infectious agents identified to trigger SLE onset or disease flare.

DNA viruses RNA viruses ERVs Gram + bacteria Gram − bacteria Fungi Parasites
TTV HCV HRES-1/Rab4A Streptococcus spp. E. coli Candida alibicans Strongyloides stercoralis
Parvovirus B19 Paramyxovirus HRES-1/p28 S. aureus P. aeruginosa Cryptococcus neoformans Leishmania spp.
EBV HTLV-1 HERV-K L. monocytogenes Neisseria spp. Aspergillus fumigatus Toxoplasma gondii
CMV HIV-1 HERV clone 4–1 Mycobacteria Salmonella spp. (not typhi) Pneumocystis jerovecii Schistosoma mansoni
VZV Oncorna virus Nocardia spp. Legionella pneumophilia Histoplasmosis Trichinella spiralis
HSV Enterococcus spp. Borrelia burgdorferi Coccidioides immitis Litomosoides sigmodontis
HPV Helicobacter pylori Mucormycoses Heligmosomoides polygyrus
HBV Klebsiella pneumoniae Fasciola hepatica

 T. Caza et al.
FIGURE 2. Innate and adaptive immune defects contribute to poor pathogen clearance with per-
sistence of infections in SLE. Lupus neutrophils exhibit reduced phagocytic capacity and reduced
production of ROS, resulting in poor microbial clearance. ANCAs, IFN, and ICs stimulate neu-
trophils to release NETs. NET clearance is defective in SLE, resulting in persistence of microbial
DNA, which becomes oxidized and immunogenic. Microbial DNA stimulates TLRs present on
membranes or endosomal compartments. TLR7 or 9 activation stimulates IFN production in pDCs
via activation of IRF 5 or 7. IFN can activate autoreactive lymphocytes, which are in a primed state in
SLE patients with lipid raft preclustering, reduced costimulation requirements, increased NO pro-
duction, mTOR activation, and EBV infection. EBV promotes polyclonal B cell activation and stim-
ulates production of autoantibodies by molecular mimicry with EBNA-1. KSHV stimulates B cell
differentiation into antibody-producing plasma cells by stimulating production of IL-6. IL-6 and
mTOR activation stimulates naı̈ve T cells to become effector T cells, reducing generation of T regs,
which promote tolerance. Most treatments in SLE work through inhibition of T and B lymphocytes,
which reduces cellular and humoral immune responses, predisposing to infection.
Epstein–Barr virus (EBV, human herpesvirus-4)

EBV is directly implicated in autoimmunity in SLE and is the environmental factor
most closely linked to lupus pathogenesis [132]. EBV causes polyclonal activation of
B cells and stimulates antibody production [133]. EBV infection maintains latency
in long-lived memory B cells, a population with apoptotic resistance in SLE [134].
Molecular mimicry of EBV nuclear antigen-1 (EBNA-1) may stimulate autoimmunity,
as epitopes cross-react with components of the human spliceosome. Autoantibodies
against spliceosome components occur in over 40% of SLE patients, including RNP,
Ro, Sm B/B’, and Sm D1 [132, 135]. Injection of an EBNA-1 peptide in animals re-
sults in antibody production to Sm D1 in addition to EBNA-1[136]. Transgenic ex-
pression of the EBNA-1 protein in mice elicited formation of anti-dsDNA antibodies
in addition to anti-Sm antibodies [137]. The initial epitope for autoantibody genera-
tion in SLE is thought to be 60 kDa antigen Ro, cross-reactive with EBNA-1[132]. Rab-
bits injected with Ro or EBNA-1 developed a lupus-like phenotype, with hematologic

Infection and SLE 
abnormalities and nephritis [132]. Molecular mimicry of self-components with EBNA-

1 of EBV was linked to early onset of disease, with a high titer of anti-EBNA-1 antibodies
in the pediatric population [135].
Epidemiological data supports a connection between EBV infection and SLE. In-
fectious mononucleosis from EBV infection resembles a SLE flare and results in pro-
duction of antinuclear antibody (ANA), anti-Sm antibodies, thrombocytopenia, and
proteinuria [138]. Although EBV is ubiquitous, its prevalence is higher in SLE, with
99–99.5% SLE patients seropositive compared to 70–95% in the general population
[139, 140].
Activation of B cells during flares can trigger EBV reactivation [141]. SLE patients
have a 10-fold increase in EBV-infected B cells compared to controls [142]. EBV-
infected SLE patients have a viral load of EBV DNA transcripts up to 40 times higher
than controls [143]. Both lytic and latent EBV genes are immunogenic and promote
polyclonal B cell activation [138]. Increased EBV viral load in SLE is due to defective
cytotoxic T cell immunity, as anti-EBV-specific CTL had reduced cytotoxicity and cy-
tokine production [141]. EBV frequently reactivates, as SLE patients produce high titers
of antibody against EBV membrane antigen, involved in viral neutralization and fre-
quent exposure to infectious virions [144].
Cytomegalovirus (CMV, human herpesvirus-5)

CMV is a DNA virus associated with immunosuppression and autoimmunity. Symp-
tomatic acute CMV infection among SLE patients is related to lymphocytopenia [6]
and reactivation can be triggered by disease flare. Case reports identified a temporal
relation between acute CMV infection and SLE flare [145] or disease onset [146]. Ac-
tivation of the immune system stimulates CMV viral replication from latency within
macrophages through a TNFα-dependent mechanism [147]. Immunosuppressed SLE
CMV+ patients are at risk for disseminated disease [148].
Kaposi’s sarcoma associated herpesvirus (KSHV, human herpesvirus-8)

SLE patients have a 10-fold increase in KSHV DNA transcripts and anti-KSHV
antibodies compared to controls [149]. The infection rate in SLE patients is approx-
imately 10%, compared to <1% of controls [149]. High-dose immunosuppression
predisposes to KSHV infection in SLE patients, similarly to HIV+ patients with low
CD4+ T cell counts [150]. KSHV maintains life-long latency with maintenance of
virally-infected cells by expression of Bcl-2 family proteins, protecting infected
cells from apoptosis [151]. KSHV promotes inflammation through enhancing IL-6
production, over-produced in SLE [152, 153]. IL-6 induces differentiation of naı̈ve
B cells into antibody-producing plasma cells and naı̈ve T cells into T effector cells,
which contribute to autoimmunity [153].
Torque teno virus

Torque teno virus (TTV), previously known as transfusion-transmitted virus, is
a single stranded circular DNA virus with increased prevalence in SLE patients
when compared to controls [154]. TTV DNA was identified in 57% of SLE patients
tested [154]. TTV may promote autoimmunity through molecular mimicry with
endogenous retroviral component HRES-1/p28[154]. Coinfection with TTV and EBV
with molecular mimicry of HRES-1/p28 epitopes can result in epitope spreading to
include self-antigens, including spliceosome component U1 snRNP and nucleosome
components [154].
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 T. Caza et al.
Parvovirus B19
Parvovirus B19 is a single-stranded, linear DNA virus associated with SLE onset and
flare [155]. Acute Parvovirus B19 infection can present with lupus-like manifestations,
including skin rash, malaise, polyarthritis, myalgias, lymphadenopathy, hematologic
abnormalities, and vasculitis [155, 156]. In late Parvovirus B19 infection, autoantibod-
ies are generated, including ANA, anti-DNA, anti-SSA/SSB, anti-phospholipid anti-
bodies, and transient production of RF [157].
Human papilloma virus (HPV)

HPV is a double-stranded DNA, nonenveloped virus that infects mucosal surfaces and
is implicated in carcinogenesis. SLE patients have the similar rates of HPV infection as
healthy controls, but worse outcomes [158]. HPV infected SLE patients are at a higher
risk for developing cervical cancer. SLE patients are 2–7 times more likely to have ab-
normal cervical cytology than controls, including low and high-grade squamous in-
traepithelial lesions [159]. SLE patients are more likely to be infected with high-risk
HPV strains [159]. Upon priming with HPV peptides, SLE T cells produce less IL-2 and
have reduced cytotoxicity of virally infected cells [160]. Due to increased risk of HPV
sequelae in SLE patients, annual Papanicolaou smears with HPV genotyping is recom-
mended for screening, as well as vaccination of girls 9–26 years [159].
RNA Viruses
Hepatitis C Virus (HCV)
HCV is a small single-stranded, positive-sense, enveloped RNA virus with increased

prevalence in SLE patients than controls, 11% versus <1%[161]. HCV infection is as-
sociated with production of autoantibodies, including ANA (41%), RF (38%), and an-
ticardiolipin (27%), which promote autoimmunity [162]. Patients with HCV infection
have increased levels of BAFF [163], which stimulates B cell activation and autoan-
tibody formation. BAFF over-expression contributes to SLE, as its inhibition reduces
disease activity [108]. Laboratory and extrahepatic clinical features of chronic HCV in-
fection mimic SLE, including hypocomplementemia, myalgias, and arthralgias [161].
IFN treatment for treatment of HCV infection has also been associated with develop-
ment of SLE [39, 164].
Paramyxoviruses
Paramyxoviruses are single-stranded, negative sense RNA viruses. Increased pro-
duction of antibodies to paramyxoviruses, including parainfluenza virus type I
and measles virus, were identified in SLE patients [165]. Increased antibody titers
could represent chronic viral infection, an over-active immune system, or molecular
mimicry to antigens shared by the host cell and viral proteins [8]. Lymphocytes from
SLE patients exhibit reduced lymphocyte proliferation to measles and parainfluenza
type 1, 2, or 3 antigens [166], which could represent impaired clearance of infection
due to defects in cell-mediated immunity.
Exogenous retroviruses (HTLV-1, HIV-1)

Retroviruses are ssRNA viruses that utilize reverse transcriptase to produce dsDNA
from RNA to incorporate into the host genome. Antibodies to gag and env retroviral
components have been reported in patients with SLE [167], suggesting a possible
role of retroviruses in pathogenesis of SLE. Therefore, associations with common
retroviruses, human T lymphotrophic virus (HTLV) and human immunodeficiency
virus (HIV) were sought in SLE. No definitive association exists between HTLV-1
infection and SLE [168]. Unlike in SLE, CD4+ T cells from HTLV-1-related leukemias

Infection and SLE 
are predominantly Tregs [169], a population deficient in lupus [63]. It is unlikely that
HTLV-1 is an etiologic factor in SLE, however, an endogenous retrovirus (ERV) with
sequence similarity to HTLV-1, HTLV-1 related endogenous sequence-1 (HRES-1), is
implicated in SLE etiopathogenesis [170].
Overlap syndromes of HIV infection and SLE are exceedingly rare. Co-existence of
HIV infection and SLE is greater than seven times lower that predicted, when extrapo-
lating to the HIV infection rate of the general population [171]. Worsening of HIV infec-
tion, with resultant increased viral load and CD4+ T cell depletion, has been associated
with SLE remission [172]. Control of HIV infection with highly-active anti-retroviral
therapy can cause rebound SLE flare [173] or immune reconstitution inflammatory
syndrome [174]. Conversely, control of SLE disease activity with CYC was reported to
increase HIV viral load [173]. Depletion of CD4+ T cells, which produce cytokines, pro-
vide B cell help, and promote nephritis in SLE [175], could explain why HIV-infected
SLE patients have lower lupus disease activity. HIV infection in DCs and their subse-
quent depletion results in reduced IFNα production, which could contribute to the
protection against SLE. HIV patients who are long-term non-progressors maintain
control of infection through upregulation of interferon production with increased ter-
minal differentiation of pDCs [176].
Case reports identified HIV infection with autoimmune manifestations of pol-
yarthritis, anemia, leukopenia, thrombocytopenia, vasculitis, and polymyositis [177].
Additionally, 12% of HIV+ patients express ANAs, often without an underlying
rheumatic disease [178]. Despite immunologic changes that protect against lupus, HIV
infection depletes Tregs, which exacerbates autoimmunity [179]. HIV gene products,
Nef and Tat, cause a Th2 lineage specification, which accelerates apoptosis via in-
creased FasL expression, leading to depletion of CD4+ T cells [8]. This Th2-cytokine
shift and accelerated apoptosis of CD4+ T cells is enhanced by oxidative stress [180].
Indeed, immune activation in HIV+ patients has been shown to trigger metabolic
disorders. Increased viral load correlated with risk of metabolic syndrome, while
antiretroviral therapy was protective[181]. A similar Th2-predominant cytokine pro-
file, accelerated apoptosis with lymphocytopenia, deregulated metabolism, and influ-
ences of oxidative stress seen in HIV+ patients are present in lupus CD4+ T cells[177].
Endogenous retroviruses (ERVs)

ERVs represent a connection between lupus susceptibility genetics and infectious
viruses [167]. ERVs contribute to SLE pathogenesis by directly encoding autoanti-
gens, by immune dysregulation due to insertional mutagenesis or regulation of cellu-
lar genes, and by eliciting autoimmune responses by molecular mimicry with the host
genome or epitope spreading to self-antigens [167]. Since ERVs are incorporated into
the genome, they are considered as self, and should not provoke immune responses.
However, ERVs can trigger breakdown of tolerance via molecular mimicry and epitope
spreading [119]. Exogenous viruses can act as helper viruses, promoting ERV expres-
sion. Helper viruses, such as EBV, can be synergistic with human ERVs (HERVs) in ini-
tiating autoimmune responses. EBV can transactivate HERV-K18 in B cells, promoting
its superantigen activity, resulting in activation of both the B cells it infects and the
CD4+ T cells stimulated as a result [182]. HERV-K is expressed in a number of autoim-
mune diseases and SLE patients produce the highest titers antibodies against HERV-K
components [183].
ERVs are defective proviruses that make up 8% of the human genome [119] and
have been implicated in regulating outcomes of infection and promoting autoimmune
responses. They have a similar genetic structure as exogenous retroviruses, with gag,
pol, and env genes between two long terminal repeats (LTRs), with transcription reg-
ulated by promoter and enhancer elements within the LTRs [167]. HERVs are mostly
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 T. Caza et al.
replication-defective through mutations accumulated over time [119] and do not pro-
duce infectious viral particles.
Expression of ERVs influences the outcomes of exogenous infections through mul-
tiple mechanisms. They provide genes that can recombine with exogenous viruses, in-
cluding retroviruses. ERVs can encode immunoregulatory proteins or interrupt gene
sequences leading to interference of virion assembly. ERVs can compete for cellular
receptors and block pathogen entry. Additionally, their interaction with the immune
system can regulate responses against pathogens [167]. ERVs were identified as ge-
netic factors contributing to pathogenesis in murine models of SLE, which are pre-
disposed to develop disease with aging. In five different lupus-prone murine models,
ERV expression was identified within thymi, the site of positive and negative selection
of T lymphocytes [184]. MRL/lpr lupus-prone mice develop autoimmunity due to ERV
disruption of the Fas receptor, resulting in loss of function and defective apoptosis of
lymphocytes leading to massive lymphadenopathy [185].

Accumulation of ERV-derived DNA stimulates IFN production and production of
ANA, contributing to SLE pathogenesis [167]. This is negatively regulated by 3’-5’ re-
pair exonuclease Trex1, which limits the amount of ERV DNA accumulating within
cells [186]. Trex1 deficiency results in an autoimmune phenotype in mice [187] and
is associated with Aicardi-Goutiere’s syndrome and Chilblain lupus in humans [188,
189]. In Trex1 deficiency, ssDNA accumulates outside the nucleus, where it becomes
immunostimulatory through inappropriate activation of TLR9 [186].
HRES-1 is expressed in T cells of SLE patients. It has two active open reading frames,
encoding HRES-1/p28, a 28 kDa nuclear antigen cross-reactive with antiviral antibod-
ies, and HRES-1/Rab4, a 24 kDa early endosomal trafficking protein found to regulate
CD4 expression within CD4+ T lymphocytes [190]. Polymorphic haplotypes of HRES-1
can predispose to SLE [183]. HRES-1 contains 6 haplotypes, one of which is associated
with nephritis [170, 191]. Methylation patterns of HERVs can also result in differences
in expression. HRES-1/Rab4 expression in SLE T lymphocytes enhances recycling and
lysosomal degradation of immunological synapse (IS) components, CD4 and CD3ζ ,
which influences CD4+ T cell activation [64]. HRES-1/Rab4 was found to interact with
dynamin-related protein 1 (Drp1)[192], a mitochondrial fission initiator required for
IS formation to meet the immediate high energy demands of T cell activation [193].
HRES-1/Rab4 overexpression in SLE T cells resulted in Drp1 depletion [192], which
may enhance mitochondrial dysfunction in lupus. HRES-1/Rab4 overexpression in
CD4+ T cells decreases CD4 expression and reduces infectivity of CD4+ T cells by
HIV-1, demonstrating an interaction between an endogenous and exogenous retro-
virus [194]. Feedback between HRES-1/Rab4 and HIV-1 exists, as HIV-1 Tat is capable
of enhancing transcription of HRES-1/Rab4 via transactivation of its LTR [194].
Bacterial infections
Bacteria are the most common cause of infection complicating SLE disease activity
and flare, making up 80% of infections in SLE patients [28]. Bacterial infections in
SLE patients, as in the general population, can be community-acquired or nosoco-
mial. The most common bacteria responsible for community-acquired infections in
SLE outpatients include Streptococcus spp., S. aureus, and E. coli, P. aeruginosa is a
common nosocomial infection in SLE patients [6, 28]. Patients with functional hypos-
plenia/asplenia are at risk of repeated infections with S. pneumoniae and Neisseria
spp. [195, 196]. Functional asplenia in SLE is sometimes reversible with control of dis-
ease activity, due to immune-complex mediated blockade of the reticuloendothelial
system [197]. However, lupus patients in a hypercoagulable state due to antiphospho-
lipid antibody production are at risk for autosplenectomy, resulting in life-long risk of
bacterial infections [198]. Patients with neutrophil phagocytic defects are susceptible

Infection and SLE 
to infections with Listeria, TB, Legionella, and Salmonella with a prolonged course due
to deficient clearance of intracellular pathogens [18]. Patients exposed to high-dose
prednisone of >50 mg/day and patients on hemodialysis are at increased risk for Lis-
teria infections. Up to 20% of bacteremic patients have complications of osteomyelitis
or septic arthritis due to Salmonella, with a high rate of recurrence [18]. This is due
to dysfunction of the reticuloendothelial system, resulting in reduced elimination of
bacteria, chronic carrier states, or reactivation of infection [16]. Impaired neutrophil
function seen in patients of increased age, with nephritis, or concurrent infections in-
creases risk of Salmonellosis. SLE patients on corticosteroids are at increased risk of
opportunistic infections with Nocardia, which can mimic disease flare [199, 200]. No-
cardia infections in SLE patients can be disseminated, or limited to the skin, eye, lung,
or CNS [199, 201–203]. CNS involvement carries a high mortality of 35%[199]. In re-
gions endemic for TB infection, the infection rate is >10% in SLE patients, with miliary
disease common (67%) in patients on immunosuppressive therapies [204]. Cumula-

tive glucocorticoid dose and SLE disease activity were the most common associations
related to infection risk [204].
Fungal infections
SLE patients have increased susceptibility to invasive fungal infections compared to
patients with other conditions on similar doses of immunosuppressive therapies [87].
Disseminated fungal infections in SLE patients have a 50–70% mortality risk [87, 205,
206]. Disseminated fungal infections result from inappropriate cytokine responses,
asplenia, neutropenia, and complement deficiency [87, 207]. Risk factors for oppor-
tunistic invasive fungal infections in SLE patients include high SLEDAI, organ failure
requiring mechanical ventilation or dialysis, use of glucocorticoid or mycophenolate
mofetil, and CRP > 10 mg/dL [87].
Candida albicans is the most common fungal pathogen in SLE patients, causing
pharyngitis, esophagitis, cellulitis, and urinary tract and vaginal infections [208]. In
SLE patients with pre-existing vasculitis, Candida albicans infection can trigger se-
vere leukocytoclastic vasculitis [209]. Cryptococcus neoformans was reported to cause
meningitis in immunosuppressed SLE patients [210]. Cryptococcal infection can pre-
cede the onset of SLE [211] or occur concurrently[212, 213]. Cryptococcal infection
concominant with lupus cerebritis is associated with meningitis and sixth cranial
nerve palsies [214]. Aspergillus fumigatus infections were reported in SLE, with skin,
lung, peritoneal, and CNS involvement [215–218]. Pneumocystis jerovecii pneumonia
(PJP) can occur in SLE patients without immunosuppressive therapy [219]. SLE pa-
tients who developed PJP had lymphocytopenia, lower CD4+ T cell counts, higher
disease activity, higher incidence of nephritis (86% versus 12%), and interstitial fibro-
sis [219]. PCP has a higher mortality rate in patients in patients with SLE (20%) than
reported in HIV/AIDS [219]. Thus, antibiotic prophylaxis is recommended for lym-
phopenic patients [220].
SLE patients with a history of travel to endemic regions are at risk of histoplasmosis
[221]. Histoplasma infections in SLE patients can present disseminated or with dis-
ease flare, with isolated lung, liver, bone marrow, or ovarian involvement [221, 222].
Coccidioides immitis infection was reported in SLE patients with travel to endemic ar-
eas [87]. Mucormycoses are rare, yet disseminated Mucor infections in SLE patients
has a high mortality rate of 88% [223]. Manifestations can mimic flare, with hypocom-
plementemia, nephrotic syndrome, uremia, or leucopenia [223].
Fungi can also trigger autoimmune responses. Twenty-six peptides derived from
various fungal species were identified with sequence homology with p70 and p80
subunits of Ku antigen, responsible for maintaining genome organization into hete-
rochromatin and euchromatin domains [224, 224, 224, 225]. Autoantibodies against
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 T. Caza et al.
Ku were identified in SLE patients and represent an antigen-driven response to the Ku

complex which could lead to aberrant transcriptional regulation [225] secondary to
fungal infection [224].
Parasitic infections
Strongyloides stercoralis is a nematode endemic in subtropical regions [226], iden-
tified to exacerbate SLE. Acute infection mimics SLE flare with vasculitis and pul-
monary hemorrhage [227]. Hyperinfection syndrome can be induced by immunosup-
pression from corticosteroids in SLE patients [227, 228, 229] and carries a high mortal-
ity rate. Visceral leishmaniasis from infection with Leishmania parasites can present
with symptoms similar to SLE flare, with pancytopenia and autoantibody production
[230]. Disseminated infection can mimic autoimmune hepatitis and primary biliary
cirrhosis [231], therefore, caution should be taken prior to initiating immunosuppres-
sive therapy in patients from endemic regions [220, 230].

Plasmodium infections are less common in patients with SLE, as the inflamma-
tory environment protects against malaria. In Africans residing in malaria-endemic
regions, there is a 6 to eightfold increase in prevalence of SLE. SLE patients with-
out a history of malaria produce ssDNA antibodies reactive against plasmodial anti-
gens. ANA and anti-ssDNA antibodies present in sera from SLE patients can inhibit
growth of plasmodia parasites [232]. A loss of function polymorphism in Fcγ RIIB, an
inhibitory immunoglobulin receptor on B cells, dendritic cells, and macrophages, has
been identified with increased incidence in East African and Southeast Asian patients
with SLE (25%) compared to Caucasians (10%)[233]. This receptor contains an im-
munoreceptor tyrosine-based inhibitory motif that suppresses phagocytosis, prolifer-

ative responses, and cytokine production. This mutation confers susceptibility to SLE
by 70%, but is protective against malaria by 44% [233]. Studies with Fcγ RIIB-deficient
or TLR7-transgenic mice, which spontaneously develop SLE, are protected from death
due to cerebral malaria [234]. Maintainence of this polymorphism could be due to se-
lective pressure to improve survival from malaria [233]. Two polymorphisms within
the nitric oxide synthase 2 (NOS2) gene, which is responsible for production of ni-
tric oxide (NO) by macrophages during infection or inflammation, have increased fre-
quency in SLE and provide protection from malaria [235]. Although SLE immune cells
overproduce NO [114], these polymorphisms were not found to be pathogenic [236].
Protective infections in SLE

Some infectious agents, including Toxoplasma gondii, Helicobacter pylori, and
helminths, inhibit autoimmune responses [8]. Infection with T. gondii, an obligate in-
tracellular parasite, is protective against SLE. In lupus-prone mice, T. gondii infection
prior to disease onset reduced development of lupus nephritis and prolonged lifes-
pan [237]. There are few case reports of toxoplasmosis in SLE. Toxoplasmosis is often
asymptomatic, but can mimic a SLE flare [238]. A high index of suspicion for infection
is necessary, as fatal CNS toxoplasmosis has been reported in SLE patients [239].
Epidemiological studies have identified an increase in incidence autoimmune
diseases in populations with low rates of H. pylori infection [240]. A negative associ-
ation exists between H. pylori and SLE, with fewer SLE patients infected compared
to controls [241]. H. pylori infection is protective through downregulation of the
host immune response. Recognition of H. pylori antigens by PRRs results in a net
anti-inflammatory response, through stimulating B cell production of cytokine IL-10,
with resultant induction of naı̈ve CD4+ T cells into Tregs [242].
Areas where helminth infections are endemic have reduced rates of autoimmune
diseases, including SLE and type I diabetes [243]. This observation is consistent with
the hygiene hypothesis [244], which suggests that parasites exert important influences

Infection and SLE 
on immune responses, as the incidence of autoimmune diseases has increased since

sanitation, chlorination of water, and antibiotic use became customary [245]. Dis-
ease prevention by helminth-induced immunoregulation was identified in animal au-
toimmune models of type I diabetes mellitus, experimental allergic encephalomyeli-
tis, Graves’ disease, and collagen-induced arthritis [243]. Schistosomes were found to
suppress immune responses through inducing development of IL-10-producing reg-
ulatory B cells (Bregs). Bregs produce immunoregulatory cytokines IL-10 and TGF-
β, which suppress activation of effector T cells (CD4+ , CD8+ , NKT cells) and induce
Foxp3+ Tregs [246]. Breg numbers decrease after schistosome clearance [246]. Due to
this shift in immune response, it is probable that helminth infections are protective
against SLE [243]. At this time, no clinical trials have explored use of helminths in SLE,
however, helminth therapies are under investigation in MS [247].
Prevention of infection in lupus patients

Early identification of infections precipitating or coinciding with disease flare is essen-
tial, as a delay in antimicrobial therapy results in worse outcomes in SLE patients with
infections. Procalcitonin (PCT) has a good negative predictive value for bacterial infec-
tion in SLE patients with active disease, with a value <0.17 ng/mL ruling out infection
complicating SLE flare [248]. In SLE patients with quiescent disease, an increase in the
CRP level is a preferred over PCT [12].
Empiric therapy should be initiated for suspected bacterial infection, covering the
most common and most deadly pathogens. Empiric antibiotic therapy in SLE patients
with suspected bacteremia should include coverage of community-acquired causes
(E. coli, S. aureus, Salmonella), as well as nosocomial causes (Pseudomonas, Kleb-

siella, Acinetobacter), as they are associated with reduced survival and poor long-term
outcomes [16]. Recurrent bacteremia in SLE patients is due to the same species as a
previous episode >50% of the time [16].
Polyclonal activation of B cells in lupus patients can cause confusion in the diag-
nosis of infections. False positive serologies for Treponema pallidum [249], Borrelia
burgdorferi [250], Toxoplasma gondii [251], and HIV [171] were reported in SLE pa-
tients. Screening for chronic infections in SLE patients should be done upon initial
diagnosis of SLE and upon initiation of immunosuppressive therapy. Testing for HPV,
HBV, HCV, and HIV should be included [220]. In patients who have traveled to a re-
gion with endemic Strongyloides infection, including Central Africa, Vietnam, Cambo-
dia, Laos, Brazil, or Central America, serology for Strongyloides can be included [220].
Results of testing should be interpreted with caution, as SLE patients produce higher
titers of antibodies against microbes than healthy controls. This can be a response to a
true infection, reactivation from latency, or nonspecific antibodies related to immune
system activation [252].
Vaccinations are critical to reduce the incidence of severe and life-threatening
infections, however, microbial products, adjuvants, preservatives, or stabilizers in
vaccines have the potential to induce autoimmune responses. SLE patients are more
likely to develop new immune responses towards self-antigens and increased autoan-
tibody titers or disease flares following vaccinations. Adjuvants within vaccines boost
immunogenicity of microbial components through activation of the innate immune
system, which were temporally linked to onset of SLE. A newly defined autoim-
mune disorder linked to adjuvant-containing vaccines, autoimmune/inflammatory
syndrome induced by adjuvants (ASIA), mimics SLE without fulfilling sufficient
criteria for diagnosis [253]. Aluminum hydroxide-based adjuvants complexed to
desacyl-4 -monophosphoryl lipid A, present in vaccines against HPV and HBV were
linked to autoimmunity, with 362 reported events from a total of approximately 68,000
recipients [254]. Vaccinations may be less efficacious in SLE patients, as they have
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 T. Caza et al.
reduced primary and secondary immune responses upon antigenic challenge [255],
in part due to immunosuppressive therapy [256]. Live vaccines are contraindicated
in SLE patients with active disease or on high-dose immunosuppressive therapy as
they can result in infection [255]. Recommended vaccinations in adult SLE patients
include influenza, pneumococcal, HZ, HPV, and HBV [220], discussed later and in
Table 3.
Yearly influenza vaccination (trivalent-inactivated) is recommended for all SLE pa-
tients, however, they may experience less protection. Adequate vaccine responses to
influenza A and B, defined by fourfold increases in antibody titers, occurred in 39–41%
of SLE patients compared to 71–94% controls [257], despite an increased proportion of
SLE patients vaccinated in the previous year. Patients with inadequate responses had
higher ANA titers, IFN-α production, and number of ACR criteria for SLE (>6). This
cohort was more likely to have nephritis or CNS involvement, to be taking prednisone,
and to have hematologic criteria for SLE than responders [258]. Up to 6 weeks follow-
ing vaccination, low responders had an increased rate of flare, increased ANA, and
new-onset anti-SSB/La or anti-cardiolipin antibodies [257, 258]. Long-lasting effects
are uncommon, as at 12 weeks post-vaccination, there was no increase in autoanti-
body titers. Vaccination may be contraindicated during disease flare, as patients are
less likely to develop a protective response [259].
The 23-valent pneumococcal polysaccharide vaccine is recommended in all SLE
patients, as there is an increased risk of invasive pneumococcal infections, especially
in patients with hyposplenia [195]. Patients with high disease activity or using high-
dose corticosteroids were more likely to have inadequate vaccination responses [260],
however other treatments had no effect [261]. The response rate of SLE patients to
pneumococcal vaccination is only 47% [262]. Poor responders can be vaccinated up
to every 6 years as needed [262]. Vaccination is safe in SLE patients, as in a study of 73
patients who received pneumococcal polysaccharide vaccine alone [263] or with si-
multaneous tetanus toxoid, H. influenzae, and pneumococcal vaccination, there were
no disease flares in a 3 month period following immunization [262].
Zostavax is a live-attenuated vaccine to prevent HZ in patients previously exposed
to VZV. SLE patients have increased incidence of HZ [264], but lower vaccination rates
[130]. This is due to guidelines by the Advisory Committee on Immunization Practice
recommending that patients on immunosuppressive therapies, including prednisone
>20 mg/day, mycophenolate mofetil, or high-dose methotrexate or azathioprine not
receive live attenuated vaccines [265]. One month free of immunosuppressive therapy
is recommended prior to vaccination [265], however, drug holidays place patients at
an unacceptable risk of worsening disease activity and organ damage [130]. Zostavax
has been shown to be safe and efficacious in other populations who are immunosup-
pressed, including elderly individuals and patients with hematologic malignancies,
with a 40–51% reduction in HZ [266, 267]. The vaccine is thought to be safe, as it does
not introduce new virus into a naı̈ve population, as seropositivity to VZV is confirmed
prior to vaccination in immunosuppressed individuals. Additionally, the Oka vaccine
strain is susceptible to antivirals if infection were to occur [130]. Lupus patients with
quiescent or low disease activity may benefit from Zostavax immunization, but caution
should be taken by confirming prior infection with varicella-specific IgG and delaying
vaccination in patients with moderate to severe disease activity and/or on high doses
of corticosteroids [130].
The Gardasil vaccination is a quadrivalent recombinant vaccine against HPV types
6, 11, 16, and 18 [268]. Nine cases of new-onset SLE in patients or disease flare have
been reported two to four months following Gardasil vaccination [269]. There are case
reports of a temporal association of SLE onset or flare following Gardasil [269]. Since
SLE patients are at increased risk of high-grade squamous intraepithelial lesions and

TABLE 3. Vaccination responses in SLE patients.

Vaccine Response in SLE Risk factors for vaccine failure Outcomes
HPV (Gardasil) 74%, 76%, 92%, 76% for types 6, 11, 16, 18 Mycophenolate mofetil with prednisone results in Reduced seroconversion for some HPV
at 7 months (type 6 & 11 are reduced seroconversion for HPV6 and HPV18. serotypes, no reported increase of flares,
significantly lower than controls). Ongoing flares reduce vaccine efficacy. temporal association with new onset SLE.
Safe in SLE
HBV 80% in children, 93% in adult with SLE Immunosuppression, active disease Temporal association with new onset SLE,
compared to 100% in healthy controls. slower response to vaccines than controls,
safe in SLE .
Influenza 39–41% Elevated ANA, increased IFNα production, >6 Increased flare risk, elevated ANA, new SSB/La
ACR criteria, CNS/kidney involvement, taking and cardiolipin antibodies
prednisone, hematological manifestations of
SLE, active flare
HZ/VZV (Zostavax) Decreased incidence of HZ >50% No previous exposure to VZV, immunosuppression Flare risk if immunosuppression is halted
Pneumococcus 47% High disease activity, high-dose corticosteroids No reported flares
Tdap 46% Reduced humoral response with lower titer of Reduced serocoversion, but safe in SLE
anti-tetanus antibodies
HIB 56–88% Humoral responses adequate in a majority of Disease activity unaffected by vaccination.
patients. Post-splenectomy patients may require
booster
Safe in SLE

 T. Caza et al.
cervical cancer due to HPV infection, the benefits of vaccination outweigh risk of dis-
ease flare [159].
HBV immunization is recommended in a three-dose series. SLE patients have re-
duced seroconversion, with adequate responses in 80% of children [270] and 93% of
adults, compared to 100% of controls [271]. Ten cases of new-onset SLE occurring
within 2 months of HBV vaccination were reported, in which joint (100%), skin (80%),
neurological (80%), and pulmonary (70%) manifestations were the most common.
There is no direct evidence that the vaccine triggered disease development in these
patients, only a temporal association exists. HBV vaccine is safe in patients with SLE,
with the rate of disease flare following vaccine unchanged from the flare rate of the
previous year [271].
Other vaccinations required in SLE patients and all adults include tetanus toxoid in
combination with diphtheria (Td) with a one time acellular pertussis booster (Tdap)
for all adults. SLE patients have reduced seroconversion rates (46% of recipients) and
reduced antibody titers when compared to healthy controls [262]. H. influenzae B vac-
cination also yields a poor seroconversion rate (56–88%) in SLE patients with reduced
titers [262].
TLR antagonists, including quinine antimalarial drugs, reduce incidence of infec-
tions. Use of antimalarial drugs, including chloroquine and hydroxychloroquine, were
shown to reduce mortality in lupus [272]. Antimalarials exert their therapeutic effects
through inhibition of TLR7 and TLR9 activation by blocking endosomal acidification
[273]. There is a strong inverse correlation between the use of antimalarial drugs and
infections [15]. SLE patients taking antimalarials are 16 times less likely to develop
a major infection [15]. The mechanism of antimicrobial activity of antimalarials is

through increasing the pH within phagosomes and lysosomes to reduce viability of
intracellular bacteria and pH-dependent iron deprivation. Antimalarial drugs inhibit
the growth of numerous microbial pathogens [274]. Additionally, abrupt discontinu-
ation of antimalarials in SLE patients can precipitate infection, with two case reports
of PJP [275]. Lupus patients who receive antimalarial drugs are more likely to be of
younger age, less likely to have nephritis or leukopenia, and are less likely to be taking
immunosuppressive agents, including mycophenolate mofetil[15]. However, SLE pa-
tients who require more potent medications (corticosteroids or cytotoxic drugs) may
still benefit from antimalarials, as they reduce infection rate, mortality, and have few
side effects.
Antibiotic prophylaxis has been considered in SLE patients with lymphocytope-
nia at risk for opportunistic infections, particularly PJP [276]. Prophylaxis against P.
jerovecii is indicated in SLE patients with CD4+ T cell count <250/μl, an absolute lym-
phocyte count <750/μl, interstitial pulmonary fibrosis, high SLEDAI, severe nephritis,
or with chronic use of prednisone ≥20 mg/day [219]. Antibiotic prophylaxis to prevent
bacterial endocarditis is recommended prior to invasive dental procedures, as 1–4%
of SLE patients develop endocarditis, a rate higher than patients with prosthetic heart
valves [277].
CONCLUSIONS
Multiple infectious agents precipitate disease flare and exacerbate autoimmunity,
changing the natural history of disease and worsening outcomes in lupus patients.
Intrinsic immune aberrations and use of immunosuppressive therapies increase
susceptibility and mask classic symptoms of infection, leading to increased complica-
tions. Early recognition, treatment, and prevention of infections are crucial to reduce
disease burden in lupus patients. Prophylactic therapies to prevent opportunistic in-
fection may be considered in patients with lymphocytopenia, although no established

Infection and SLE 
guidelines are currently available. Judicious use of immunosuppressive therapies to

maintain disease quiescence using the lowest possible doses for the shortest required
duration should be considered, as well as the use of adjunctive therapies such as NAC
and hydroxychloroquine to concurrently reduce infection risk and disease activity in
SLE.
Declaration of Interest
The authors report no conflicts of interest. The authors alone are responsible for the
content and writing of the article.
ABBREVIATIONS
ANA antinuclear antibody
APC antigen-presenting cell

ASIA autoimmune/inflammatory syndrome induced by adjuvants
AZA azathioprine
BAFF B cell activating factor
CGD chronic granulomatous disease
CMV cytomegalovirus
CNS central nervous system
CRP C-reactive protein
DNase-I deoxyribonuclease-I
Drp1 dynamin-related protein-1
EBNA-1 Epstein-Barr virus nuclear antigen-1

EBV Epstein–Barr virus
ELISA enzyme-linked immunosorbent assay
Env envelope
ERV endogenous retrovirus
Gag group-specific antigen
HBV Hepatitis B virus
HCV Hepatitis C virus
HERV human endogenous retrovirus
HHV human herpesvirus
HIV human immunodeficiency virus
HPV human papilloma virus
HRES-1 HTLV-related endogenous sequence-1
HSCT hepatopoietic stem cell transplant
HSV herpes simplex virus
HZ Herpes zoster
ICU intensive care unit
IFNα interferon-α
Ig immunoglobulin
IL interleukin
IMPDH inosine monophosphate dehydrogenase
IV intravenous
LTR long terminal repeat
MAVS mitochondrial antiviral signaling protein
MHC major histocompatibility complex
MMF mycophenolate mofetil
MS multiple sclerosis
mTOR mammalian target of rapamycin
MRL/lpr murine model of spontaneous SLE
Copyright
 T. Caza et al.
NAC N-acetylcysteine
NET neutrophil extracellular trap
NETosis Modality of cell death via neutrophil extracellular trap release
NO nitric oxide
NOD nucleotide binding oligomerization domain
(NZB × NZW) F1 new Zealand Black × New Zealand White F1 progeny, a murine
model of spontaneous
PAMP pathogen-associated molecular pattern
PCR polymerase chain reaction
PCT procalcitonin
pDC plasmacytoid dendritic cell
PKR dsDNA-activated protein kinase R
Pol polymerase
PRR pattern recognition receptor

RA rheumatoid arthritis
RIG-1 retinoic acid inducible gene-1
ROS reactive oxygen species
SLE systemic lupus erythematosus
SLEDAI systemic lupus erythematosus disease activity index
STAT signal transducer and activator of transcription
Tat trans-activator of transcription
TB Mycobacterium tuberculosis
TGF-β tumor growth factor-β
T helper CD4+ T cell
Th
TLR toll-like receptor
TNF tumor necrosis factor
Trex1 3 -repair exonuclease-1
Td tetanus and diphtheria vaccine
Tdap tetanus, diphtheria, and acellular pertussis
TTV torque teno virus
Treg regulatory T cell CD4+ CD25+ Foxp3+ T cell
VZV varicella zoster virus
WBC white blood count
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Interplay of Infections, Autoimmunity, and Immunosuppression

Article in International Reviews Of Immunology · January 2014

Tiffany Nicole Caza Zachary Oaks

Metabolic control of autoimmunity View project

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Interplay of Infections, Autoimmunity,

Tiﬀany Caza, Zachary Oaks, and Andras Perl

Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA

Infectious agents are considered to be crucial environmental factor in the etiopathogenesis of

Accepted 1 November 2013.

responses, affecting antigen presentation, immune cell apoptosis, signaling of T and

Disease Burden due to Infections in SLE Patients

International Reviews of Immunology

hospital admission and administration of intravenous (IV) antibiotics, with

Increased Susceptibility to Infection in SLE Patients

to autoantibodies against C1q [22]. Deficiencies in early complement components

syndrome characterized by defective ROS production in phagocytic cells due to de-

[38]. Increased IFNα in SLE and overexpression of IFN-associated genes creates an

have increased death, resulting in release of neutrophil extracellular traps (NETs)[43].

International Reviews of Immunology

Infection Risk of Lupus Therapeutics

medications, cytotoxic agents, including cyclophosphamide (CYC), mycophenolate

is no difference in the rate of infections using IV or oral CYC preparations, however,

proposed that antibiotic prophylaxis be given during rituximab treatment to reduce

International Reviews of Immunology

Mechanisms Through Which Infectious Agents May Trigger Autoimmunity

for formation of autoantibodies [119].

FIGURE 1. Microbes initiate autoimmune responses. Molecular mimicry of microbial components

nity. In the context of inflammation, cross-reactive immune responses from molecu-

as influence immunoregulatory networks.

Varicella zoster virus (VZV, human herpesvirus-3)

International Reviews of Immunology

TABLE 2. Infectious agents identified to trigger SLE onset or disease flare.

Epstein–Barr virus (EBV, human herpesvirus-4)

International Reviews of Immunology

abnormalities and nephritis [132]. Molecular mimicry of self-components with EBNA-

Cytomegalovirus (CMV, human herpesvirus-5)

Kaposi’s sarcoma associated herpesvirus (KSHV, human herpesvirus-8)

Torque teno virus

Human papilloma virus (HPV)

HCV is a small single-stranded, positive-sense, enveloped RNA virus with increased

Exogenous retroviruses (HTLV-1, HIV-1)

International Reviews of Immunology

Endogenous retroviruses (ERVs)

lymphocytes leading to massive lymphadenopathy [185].

International Reviews of Immunology

disease common (67%) in patients on immunosuppressive therapies [204]. Cumula-

Ku were identified in SLE patients and represent an antigen-driven response to the Ku

sive therapy in patients from endemic regions [220, 230].

munoreceptor tyrosine-based inhibitory motif that suppresses phagocytosis, prolifer-

Protective infections in SLE

International Reviews of Immunology

on immune responses, as the incidence of autoimmune diseases has increased since

Prevention of infection in lupus patients

(E. coli, S. aureus, Salmonella), as well as nosocomial causes (Pseudomonas, Kleb-

International Reviews of Immunology

TABLE 3. Vaccination responses in SLE patients.