INFECTION IN SYSTEMIC LUPUS

ERYTHEMATOSUS, SIMILARITIES, AND

DIFFERENCES WITH LUPUS FLARE

Oleh:
 INTRODUCTION

Inflammatory
Inflammatory reaction
reaction can
can ItIt often
often affects
affects young
young
target
target various
various organs;
organs; the
the women
women during
during
organs
organs affected
affected and
and disease
disease Systemic childbearing
childbearing periods;
periods;
activity
activity are
are considerably
considerably Lupus can
can also
also occur
occur atat any
any
different
different between
between
individuals
Erythematosus age
age in
in children,
children,
individuals and
and changes
changes the
the aged,
aged, and
and males
males
as
as time
time progresses
progresses (SLE)

AA heterogeneous
heterogeneous autoimmune
autoimmune disease
disease characterized
characterized by
by pathogenic
pathogenic auto-
auto-
antibodies
antibodies and
and uncontrolled
uncontrolled inflammatory
inflammatory response
response
 INTRODUCTION

Systemic Symptom
Symptom manifestations
manifestations :: skin
skin
SLE
SLE management
management should
should be
be
Lupus rash
rash (butterfly-shaped
(butterfly-shaped malar
malar
sensitive
sensitive toward
toward such
such rash),
rash), oral
oral ulcer,
ulcer, arthritis,
arthritis,
changes
changes and
and adjust
adjust Erythematosus hemolytic
hemolytic anemia,
anemia, and
and
medications
medications accordingly
accordingly (SLE) nephritis
nephritis
 INTRODUCTION
whether
whether both
both diseases
diseases are
are
affected
affected by
by each
each other
other

There have been

some long-
standing questions
about infection
and SLE which
which pathogens
pathogens cause
cause SLE
SLE or
or
are
are vulnerable
vulnerable to
to SLE
SLE

how
how infection
infection and
and lupus
lupus flare
flare can
can be
be discriminated
discriminated
ifif patients
patients with
with lupus
lupus present
present fevers.
fevers.
 INTRODUCTION

ItIt is
is currently
currently evident
evident that
that
infection
infection affects
affects the
the development
development
of
of SLE,
SLE, and and infection
infection occurrence
occurrence
and
and prevention
prevention are are also
also influenced
influenced
by
by SLE
SLE (Fig.
(Fig. 1).
1).
 INFECTION
INFECTION AS
AS AA TRIGGERING
TRIGGERING FACTOR
FACTOR FOR
FOR SLE
SLE

Viral
Viral Infection
Infection
Epstein-Barr
Epstein-Barr virus
virus (EBV)
(EBV) // human
human herpesvirus
herpesvirus 44
aa ubiquitous
ubiquitous virus
virus that
that
infects
infects about
about 95%
95% ofof the
the worlds
worlds population
population
Known
Known toto occur
occur during
during childhood
childhood without
without any
any symptoms
symptoms
ItIt causes
causes infectious
infectious mononucleosis
mononucleosis in in adults
adults (skin
(skin rash,
rash, arthralgia,
arthralgia, renal
renal
disorders,
disorders, cytopenia,
cytopenia, pharyngitis,
pharyngitis, and
and lymphadenopathy)
lymphadenopathy)

Many
Many studies
studies EBV
EBV infection
infection is
is related
related to
to systemic
systemic autoimmunity
autoimmunity
SLE
SLE patients
patients had
had higher
higher titers
titers of
of anti-EBV
anti-EBV antibodies
antibodies
prevalence
prevalence of
of EBV
EBV infection
infection in
in patients
patients with
with SLE
SLE was
was higher
higher than
than in
in the
the
healthy
healthy population
population

EBV
EBV infection
infection BB cells
cells resistant
resistant to
to apoptosis
apoptosis

produce
produce more
more IFNs
IFNs that
that are
are pivotal
pivotal pro-
pro-
TT cells
cells inflammatory
inflammatory cytokines
cytokines for
for systemic
systemic autoimmunity
autoimmunity
INFECTION
INFECTION AS
AS AA TRIGGERING
TRIGGERING FACTOR
FACTOR FOR
FOR SLE
SLE

Viral
Viral Infection
Infection (EBV)
(EBV)
Components
Components of of the
the EBV
EBV protein,
protein, including
including Epstein-Barr
Epstein-Barr nuclear
nuclear antigen-1,
antigen-1,
showed
showed similarity
similarity to
to autoantigens
autoantigens in in SLE molecular
SLE molecular mimicry
mimicry as
as aa
potential
potential mechanism
mechanism of of antibody
antibody cross-reactivity
cross-reactivity and
and disease
disease pathogenesis
pathogenesis

Human
Human endogenous
endogenous retroviruses
retroviruses (HERVs)
(HERVs)
Its
Its endogenous
endogenous retroviral
retroviral sequence
sequence (ERS)
(ERS) encodes
encodes self-antigens
self-antigens that
that
contribute
contribute toward
toward immunological
immunological tolerance
tolerance breakdown
breakdown

Several
Several haplotypes
haplotypes of
of human
human ERS
ERS (human
(human HRES-1)
HRES-1) were
were revealed
revealed to
to
affect
affect the
the development
development ofof SLE
SLE

HERV-E
HERV-E 4-1
4-1 mRNA
mRNA expression
expression was
was higher
higher than
than healthy
healthy controls
controls and
and
correlated
correlated with
with disease
disease activity
activity in
in SLE,
SLE, and
and SLE
SLE CD4+
CD4+ TT cells
cells had
had
decreased
decreased methylation
methylation levels
levels of
of the
the long
long terminal
terminal repeats
repeats inin HERV-E
HERV-E
4-1
4-1
INFECTION
INFECTION AS
AS AA TRIGGERING
TRIGGERING FACTOR
FACTOR FOR
FOR SLE
SLE

Viral
Viral Infection
Infection (Parvovirus
(Parvovirus B19)
B19)
ItIt is
is generally
generally asymptomatic
asymptomatic or or self-limited;
self-limited; butbut can
can present
present aa systemic
systemic
immune
immune response
response mimicking
mimicking SLESLE flare,
flare, including
including arthritis
arthritis and
and skin
skin rash
rash [20].
[20].
Parvovirus
Parvovirus B19B19 infection
infection induces
induces TT cell
cell activation
activation through
through molecular
molecular
mimicry,
mimicry, leading
leading toto tissue
tissue damage
damage andand cell
cell necrosis
necrosis
Ku80,
Ku80, aa lupus
lupus autoantigen
autoantigen that
that consists
consists of of nuclear
nuclear DNA-binding
DNA-binding proteins,
proteins,
functions
functions asas aa specific
specific B19
B19 capsid-binding
capsid-binding surface
surface protein
protein
INFECTION
INFECTION AS
AS AA TRIGGERING
TRIGGERING FACTOR
FACTOR FOR
FOR SLE
SLE

Viral
Viral Infection
Infection (Cytomegalovirus)
(Cytomegalovirus)
The
The correlation
correlation between
between CMV
CMV infection
infection and
and SLE
SLE development
development hashas been
been
controversial
controversial
Nevertheless,
Nevertheless, inin recent
recent studies,
studies, the
the detection
detection ofof specific
specific human
human CMV
CMV
strains
strains and
and CMV
CMV antibodies
antibodies were
were higher
higher in
in patients
patients with
with SLE
SLE than
than in
in healthy
healthy
controls
controls
 INFECTION
INFECTION AS
AS AA TRIGGERING
TRIGGERING FACTOR
FACTOR FOR
FOR SLE
SLE

Bacterial
Bacterial products
products binds TLRS
Bacterial
Bacterial Infection
Infection TLRS or
or other
other
(pathogen-associated
(pathogen-associated receptors
receptors on
on APCs,
APCs, BB
molecular
molecular patterns)
patterns) cells,
cells, and
and TT cells
cells
Bacterial
Bacterial
lipopolysaccharide/
lipopolysaccharide/ activate
activate immune
immune cells
cells
nucleic
nucleic acid-
acid- innate
innate immunity
immunity
to
to produce
produce proinflam-
proinflam-
containing
containing immune
immune activation
activation
matory
matory cytokines
cytokines
complexes
complexes

Engage
Engage and
and stimulate plasmacytoid
plasmacytoid
deteriorate
deteriorate the
the TLR
TLR ligands
ligands dendritic
dendritic cells
cells
immune
immune system
system
release
release antibodies
antibodies produce
produce IFN
IFN

The
The release
release of
of cholera
cholera toxin
toxin BB by
by Vibrio
Vibrio cholera
cholera was
was revealed
revealed to
to produce
produce
autoantibodies
autoantibodies and
and promote
promote glomerulonephritis
glomerulonephritis inin lupus-prone
lupus-prone mice
mice by
by enhancing
enhancing
lipid
lipid raft
raft aggregation
aggregation in
in TT cells
cells
 INFECTION
INFECTION AS
AS AA PROTECTOR
PROTECTOR AGAINST
AGAINST SLE
SLE

Hygiene Hypothesis
Infection by certain parasites or bacteria has been known to confer
protection against autoimmune or allergic diseases

was
was introduced
introduced because
because the
the prevalence
prevalence of
of allergic
allergic and
and autoimmune
autoimmune
diseases
diseases showed
showed aa steep
steep increase
increase over
over the
the past
past few
few decades;
decades;

Background
Background studies
studies have
have not
not been
been conducted
conducted until
until now.
now.
 INFECTION
INFECTION AS
AS AA PROTECTOR
PROTECTOR AGAINST
AGAINST SLE
SLE

Before the hygiene

hypothesis was
introduced, the Malarial
Malarial infection
infection (Plasmodium
(Plasmodium falciparum)
falciparum) was
was
shown
shown to
to confer
confer protection
protection against
against the
the
protective role of
development
development ofof SLE
SLE
infection against because
because the
the gene
gene related
related to
to malaria
malaria
autoimmune disease protection
protection is
is an
an SLE-susceptible
SLE-susceptible gene
gene
development has
been investigated
 INFECTION
INFECTION AS
AS AA PROTECTOR
PROTECTOR AGAINST
AGAINST SLE
SLE

Toxoplasma
Toxoplasma gondii
gondii infection
infection had
had aa protective
protective role
role in
in preventing
preventing the
the
development
development of
of autoimmune
autoimmune renal
renal disorder
disorder in
in lupus-prone
lupus-prone mice
mice

AA glycoprotein
glycoprotein secreted
secreted by
by parasitic
parasitic helminths
helminths prevented
prevented
nephritis
nephritis in
in lupus
lupus mice
mice model
model via
via reduction
reduction of
of antinuclear
antinuclear antibody
antibody
(ANA)
(ANA) production
production andand immune
immune complex
complex deposition
deposition

Helicobacter
Helicobacter pylori
pylori seronegativity
seronegativity was
was associated
associated with
with the
the
development
development ofof SLE
SLE in
in African-American
African-American women
women

In
In some
some studies,
studies, the
the prevalence
prevalence of
of hepatitis
hepatitis BB virus
virus (HBV)
(HBV) infection
infection in
in
patients
patients with
with SLE
SLE was
was lower
lower than
than that
that in
in non-SLE
non-SLE controls
controls
 INFECTION
INFECTION AS
AS AA PROTECTOR
PROTECTOR AGAINST
AGAINST SLE
SLE

The Intricate Mechanim

promotion
promotion of
of T-helper
T-helper 22 (Th2)
(Th2)

inhibition
inhibition of
of Th1/Th17
Th1/Th17 differentiation
differentiation

amplication
amplication of
of T-regulatory
T-regulatory (Treg)
(Treg) and
and B-regulatory
B-regulatory (Breg)
(Breg)
cells
cells and
and type
type 22 macrophages
macrophages

orientation
orientation of
of dendritic
dendritic cells
cells toward
toward aa tolerogenic
tolerogenic
phenotype
phenotype

downregulation
downregulation of
of type
type 22 innate
innate lymphoid
lymphoid cells
cells

modulation
modulation of
of gut
gut microbiota
microbiota
 INFECTION
INFECTION AS
AS AA VULNERABLE
VULNERABLE POINT
POINT IN
IN SLE
SLE

Infection is common in SLE

Half
Half of
of the
the patients
patients with
with SLE
SLE experience
experience severe
severe
infection,
infection, and
and >20%
>20% of
of hospitalizations
hospitalizations occur
occur
from
from infections
infections

ItIt accounts
accounts for
for 25%
25% to
to 50%
50% of
of Defense
Defense mechanisms
mechanisms against
against bacteria,
bacteria, viruses,
viruses, or
or
overall
overall mortality
mortality fungi
fungi become
become impaired
impaired in
in SLE
SLE
 INFECTION
INFECTION AS
AS AA VULNERABLE
VULNERABLE POINT
POINT IN
IN SLE
SLE

Predisposition
Predisposition to
to infection
infection

Decreased
Decreased phagocytosis
phagocytosis Defective
Defective chemotaxis
chemotaxis

Reduced
Reduced production
production of
of interleukin
interleukin 88 (IL-8)
(IL-8) Membrane
Membrane recognition
recognition
and
and IL12
IL12 by
by polymorph
polymorph nuclear
nuclear cells
cells
Attachment
Attachment to
to microorganisms
microorganisms
Complement
Complement deficiency
deficiency
 INFECTION
INFECTION AS
AS AA VULNERABLE
VULNERABLE POINT
POINT IN
IN SLE
SLE
BACTERIAL
BACTERIAL INFECTION
INFECTION

Commonly
Commonly reported
reported inin SLE
SLE and
and affect
affect diverse
diverse organs,
organs, including
including the
the
respiratory
respiratory tract,
tract, urinary
urinary tract,
tract, and
and skin
skin

Streptococcus
Streptococcus pneumonia
pneumonia common
common causecause of
of respiratory
respiratory infection
infection
Staphylococcus
Staphylococcus aureus skin,
aureus skin, soft
soft tissue,
tissue, bone,
bone, and
and joint
joint infections
infections
and
and bacteremia
bacteremia
Escherichia
Escherichia coli the
coli the most
most common
common cause
cause of
of urinary
urinary tract
tract infection;
infection;
Klebsilla
Klebsilla and
and Pseudomonas
Pseudomonas spp.
spp. also
also cause
cause urinary
urinary tract
tract infections.
infections.

VIRAL
VIRAL INFECTION
INFECTION

Varicella-zoster
Varicella-zoster virus
virus (VZV)
(VZV) isis the
the most
most frequent
frequent in in SLE
SLE patients,
patients, and
and can
can
develop
develop into
into herpes
herpes zoster
zoster
The
The concomitant
concomitant use
use of
of corticosteroids
corticosteroids and
and immunosuppressive
immunosuppressive agents
agents
agents
agents are
are regarded
regarded as
as triggering
triggering factors
factors for
for VZV
VZV infection
infection
More
More frequent
frequent among
among patients
patients with
with no
no or
or low
low SLE
SLE disease
disease activity
activity
INFECTION
INFECTION AS
AS AA VULNERABLE
VULNERABLE POINT
POINT IN
IN SLE
SLE

VIRAL
VIRAL INFECTION
INFECTION

Cytomegalovirus
Cytomegalovirus (CMV) (CMV) infection
infection can
can be
be presented
presented as
as CMV
CMV
retinitis,
retinitis, CMV
CMV colitis,
colitis, oror CMV
CMV pneumonitis
pneumonitis in
in patients
patients with
with SLE,
SLE,
and
and may
may result
result in
in aa systemic
systemic inflammation
inflammation mimicking
mimicking SLE
SLE

The
The prevalence
prevalence ofof abnormal
abnormal squamous
squamous epithelial
epithelial lesions
lesions was
was
increased
increased in
in patients
patients with
with SLE
SLE with
with HPV
HPV infection
infection
 INFECTION
INFECTION AS
AS AA VULNERABLE
VULNERABLE POINT
POINT IN
IN SLE
SLE

anti-double-stranded
anti-double-stranded corticosteroids
corticosteroids treatment
treatment atat aa prednisolone
prednisolone
DNA
DNA (dsDNA)
(dsDNA) titer
titer equivalent
equivalent dose
dose of
of 7.5
7.5 to
to 10
10 mg/day
mg/day
The risk factors
low
low complement
complement for infection in high-dose
high-dose regimen
regimen of
of
levels
levels patients with SLE cyclophosphamide
cyclophosphamide
are disease
nephritis
nephritis and
and activity corticosteroid
corticosteroid pulse
pulse
leucopenia
leucopenia therapy
therapy
 INFECTION
INFECTION AS
AS AA VULNERABLE
VULNERABLE POINT
POINT IN
IN SLE
SLE

Several studies showed that most infections, Score

Score that
that
from mild to severe, can be associated with the assesses
assesses the
the
Systemic Lupus Erythematosus Disease Activity current
current disease
disease
Index (SLEDAI) activity
activity of
of SLE
SLE

CYCLOPHOSPHAMIDE
an
an alkylating
alkylating agent
agent used
used in
in severe
severe manifestations
manifestations ofof SLE
SLE (lupus
(lupus nephritis
nephritis and
and
mesenteric
mesenteric vasculitis)
vasculitis)
strongly
strongly suppress
suppress the
the immune
immune system
system
aa higher
higher dose
dose was
was associated
associated with
with aa higher
higher prevalence
prevalence ofof infection
infection and
and
leucopenia
leucopenia after
after cyclophosphamide
cyclophosphamide therapy
therapy also
also affects
affects infection
infection
 INFECTION
INFECTION AS
AS AA VULNERABLE
VULNERABLE POINT
POINT IN
IN SLE
SLE

TUBERCULOSIS
TUBERCULOSIS

AA serious
serious infection
infection that
that results
results in
in pulmonary
pulmonary damage
damage in
in SLE,
SLE, and
and its
its risk
risk and
and
prevalence
prevalence are
are much
much higher
higher in
in SLE
SLE when
when combined
combined with
with aa defective
defective immune
immune
system
system and
and use
use of
of immunosuppressive
immunosuppressive drugsdrugs

Before
Before starting
starting any
any potent
potent immunosuppressive
immunosuppressive therapy,
therapy, screening
screening for
for latent
latent TB
TB
should
should be be performed
performed in in an
an endemic
endemic area
area
IfIf aa result
result is
is positive,
positive, treatment
treatment for
for latent
latent TB
TB would
would be
be needed
needed
(IGRA)
(IGRA) has has aa critical
critical role
role in
in screening
screening latent
latent TB
TB

Arthritis,
Arthritis, pleuritis,
pleuritis,
Use vasculitis,
vasculitis, nephritis
nephritis
Use of
of
glucocorticoids
Factors that
glucocorticoids
associated with organic
organic brain
brain
previous
previous TB in SLE syndrome
syndrome
TB
TB patients
duration
duration of
of SLE
SLE
 DIFFERENTIATION
DIFFERENTIATION BETWEEN
BETWEEN INFECTION
INFECTION AND
AND
LUPUS
LUPUS FLARE
FLARE UP
UP DURING
DURING FEVER
FEVER

Differentiation
Differentiation isis important
important because
because
Fever is a typical symptom
each
each of
of the
the different
different cause
cause of
of fever,
fever,
not only of infection but requires
requires directly
directly opposite
opposite treatment
treatment
also of SLE flare up from
from each
each other.
other.

Infection-related Fever Flare-up Fever

need
need antimicrobial
antimicrobial agents
agents needimmunosuppressive
needimmunosuppressive therapy
therapy
developed
developed from
from aa definite
definite origin
origin including
including steroids
steroids
arthritis
arthritis and
and skin
skin rash
rash are
are presented
presented
DIFFERENTIATION
DIFFERENTIATION BETWEEN
BETWEEN INFECTION
INFECTION AND
AND
LUPUS
LUPUS FLARE
FLARE UP
UP DURING
DURING FEVER
FEVER

Overall,
Overall, CRP
CRP is
is the
the most
most critical
critical marker
marker in
in
differentiating
differentiating between
between infection
infection and
and disease
disease flare
flare up
up in
in SLE.
SLE.

In
In aa recent
recent study,
study, fever
fever duration,
duration, anti-dsDNA
anti-dsDNA anti-body
anti-body titers,
titers, and
and CRP
CRP
were
were regarded
regarded as
as the
the most
most reliable
reliable markers
markers toto distinguish
distinguish between
between
infection
infection and
and SLE
SLE activity.
activity.
 INFECTION
INFECTION AS
AS AA TARGET
TARGET OF
OF VACCINE
VACCINE IN
IN SLE
SLE

Vaccination
Vaccination is
is considered
considered anan essential
essential method
method to to prevent
prevent infections
infections or
or reduce
reduce
complications
complications inin SLE,
SLE, although
although the
the clinical
clinical effects
effects are
are not
not prominent
prominent

According to the European League Against Rheumatism

recommendations for vaccination in adult patients with
autoimmune inflammatory diseases
Vaccination
Vaccination status
status needs
needs to to be
be determined
determined during
during the
the initial
initial
investigation,
investigation, and
and itit includes
includes ::
Haemophilus
Haemophilus influenzae
influenzae bb
hepatitis
hepatitis AA virus,
virus,
HBV,
HBV,
HPV,
HPV,
influenza,
influenza,
Neisseria
Neisseria meningitidis,
meningitidis,
rubella
rubella for
for women
women of of childbearing
childbearing age,
age,
S.
S. pneumonia,
pneumonia, andand
tetanus
tetanus toxoid
toxoid
INFECTION
INFECTION AS
AS AA TARGET
TARGET OF
OF VACCINE
VACCINE IN
IN SLE
SLE

Vaccinations
Vaccinations should
should be
be administered
administered during
during
stable
stable disease
disease and
and before
before BB cell
cell depletion
depletion therapy
therapy

vaccines
vaccines are
are thought
thought to
to trigger
trigger immune
immune system
system activation
activation
because
because they
they stimulate
stimulate an
an antigen-specific
antigen-specific immune
immune response
response
similarly
similarly to
to the
the molecular
molecular mimicry
mimicry described
described previously
previously

Their
Their causality
causality was
was not
not clearly
clearly identified,
identified, but
but the
the temporal
temporal connection
connection
of
of vaccination
vaccination with
with symptom
symptom development
development was was consistent
consistent

But
But the
the safety
safety of
of vaccines
vaccines in
in patients
patients with
with SLE
SLE has
has been
been
demonstrated;
demonstrated; aa recent
recent case-control
case-control study
study showed
showed that
that
immunization
immunization is
is not
not associated
associated with
with SLE
SLE development
development
INFECTION
INFECTION AS
AS AA TARGET
TARGET OF
OF VACCINE
VACCINE IN
IN SLE
SLE

Vaccination Recommendation
Vaccinations
Vaccinations against
against diseases
diseases including
including HBV,
HBV, HPV,
HPV,
pneumococcal,
pneumococcal, and and influenza
influenza are
are recommended
recommended forfor patients
patients
with
with SLE
SLE in
in remission
remission period
period

An
An inactive
inactive live
live vaccine
vaccine such
such as
as zoster
zoster vaccine
vaccine should
should be
be
avoided
avoided when
when thethe patients
patients are
are on
on immunosuppressive
immunosuppressive drugs
drugs
such
such as
as cyclophosphamide,
cyclophosphamide, methotrexate,
methotrexate, and
and corticosteroids
corticosteroids
(over
(over 20
20 mg/day
mg/day of of prednisolone
prednisolone or
or equivalent).
equivalent).
 CONCLUSION

Among the environmental factors causing or aggravating SLE, infection

is most well described; however, how it works or who is vulnerable to it
remains unclear.

Currently, several viruses including EBV, parvovirus B19,

and retrovirus may contribute to SLE development.

In addition, certain pathogens such as T. gondii, Plasmodium, and H.

pylori may play a role in preventing autoimmune inflammation.
 CONCLUSION

It is evident that patients with SLE are vulnerable to infection because

of the nature of the disease and symptom management practices that
suppress ones immunity.

When patients with SLE present fevers, SLE-related manifestations and

disease activity markers indicate an SLE flare up, and increased CRP and
leukocyte count suggest a combined infection.

Despite its concerns in SLE, vaccination is indispensable for patients

with this disease.
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