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Neuropsychiatric lupus and infectious triggers

G Zandman-Goddard, Y Berkun, O Barzilai, M Boaz, M Ram, JM Anaya and Y Shoenfeld
Lupus 2008; 17; 380
DOI: 10.1177/0961203308090017

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http://lup.sagepub.com/cgi/content/abstract/17/5/380

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 Lupus (2008) 17, 380–384
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REVIEW

Neuropsychiatric lupus and infectious triggers

G Zandman-Goddard1,2*, Y Berkun2,3*, O Barzilai2,4, M Boaz2,5, M Ram2,4, JM Anaya6 and Y Shoenfeld2,4,7
1Department of Medicine C, Wolfson Medical Center, Holon, Israel; 2Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel; 3Pediatric
Department, Safra Childrens Hospital, Sheba Medical Center, Tel Hashomer, Israel; 4Department of Medicine B, Center for Autoimmune Diseases,
Sheba Medical Center, Tel Hashomer, Israel; 5Epidemiology Unit, Wolfson Medical Center, Holon, Israel; 6Cellular Biology and Immunogenetics
Unit, CIB-Universitario del Rosaria, Medellin, Columbia; and 7Incumbent of Laura Schwartz-Kipp Chair in Autoimmunity, Tel-Aviv University,
Tel Aviv, Israel

Infections can act as environmental triggers inducing or promoting systemic lupus erythematosus
(SLE) in genetically predisposed individuals. The aim of the present study was to compare the titres
of antibodies (Abs) to infectious agents with neuropsychiatric (NPSLE) clinical manifestations. The
sera of 260 individuals (120 patients with SLE and 140 geographic controls) were evaluated for the
titres of Epstein bar virus (EBV), cytomegalovirus (CMV), toxoplasma, rubella and syphilis Abs
using the BioPlex 2200 Multiplexed Immunoassay method (BioRad) and by the ELISA method for
Helicobacter pylori and Hepatitis B core Ag. All BioPlex 2200 kits used were in developmental
stages. Data analysis was performed using SPSS 9.0 statistical analysis software (SPSS Inc., Chi-
cago, IL, USA, 1999). Correlation analysis indicated that rubella IgM Ab titres were marginally,
positively associated with psychosis (P = 0.09). No other associations were detected between the 17
infectious Abs and five NP manifestations. When the positivity cut-off for anti-rubella IgM Abs
was set at three standard deviations above normal, three positive subjects were identified: one
patient with psychosis and one with depression, for a total NPSLE prevalence of 33.3%. On the
contrary, the prevalence of NPSLE in the remaining subjects was 6.5%. Marginally significant
correlations between elevated titres of rubella IgM Ab with psychosis and depression were found.
Although this nearly 5-fold increase is not statistically significant, it appears that in a larger sample
size, significance would be reached. This is the first study reported that examined the correlation of
NPSLE manifestations with anti-infectious Abs. Lupus (2008) 17, 380–384.

Neuropsychiatric lupus (NPSLE) manifestations are research, the precise mechanisms underlying nervous
reported in as many as 70% of patients and carry a tissue injury remain poorly understood.3
poor prognosis. Although seizures and psychosis are We described 20 autoantibodies related to NPSLE,
the only NPSLE manifestations listed in the 1997 11 are brain-specific and 9 are systemic and hence
ACR criteria for the diagnosis of systemic lupus found in the setting of other organ involvement.4
erythematosus (SLE),1 the 1999 Ad Hoc committee The targeted Abs to brain-specific antigens were neu-
included 19 different central nervous system (CNS) ronal, ganglioside, synaptosomes, glia, methyl-
focal and diffuse manifestations,2 none of which are D-aspartate receptors, lymphocytotoxic, whereas the
specific for SLE. Guidelines for diagnostic criteria of Abs to systemic antigens included nuclear, cyto-
CNS lupus are yet to be established. plasmic, phospholipid and endothelial cells. Cognitive
The stipulated mechanisms of CNS involvement in impairment, psychosis and depression were associated
lupus include vascular occlusion because of secondary with many Abs.
antiphospholipid syndrome [APS], clinically present- Cognitive dysfunction was associated with seven
ing with focal disease mostly, and injury because of Abs: anti-neuronal Abs, anti-human N-methyl-
D-aspartate receptor Abs (NMDA), anti-ganglioside
pathogenic antibody (Ab), in a disrupted abnormal
blood–brain barrier (BBB) milieu leading predomi- Abs (AGA), anti-serum lymphocytoxic Abs, anti-
nantly to diffuse manifestations. Despite extensive cardiolipin (aCL) Abs, lupus anticoagulant (LAC)
and anti-Ro Abs; psychosis with eight Abs: anti-
neuronal Abs, brain-reactive Abs (BRAA), anti-
*G Zandman-Goddard and Y Berkun are first co-authors and contrib-
uted equally to this article.
microtubule–associated protein 2 Abs (MAP-2),
Correspondence to: Yehuda Shoenfeld, MD, FRCP (Head), Department
aCL, LAC, anti-ribosomal P Ab (anti-P), anti-Ro and
of Medicine “B”, Sheba Medical Center, Tel-Hashomer 52621, Israel. anti-Sm Abs; and depression with five Abs: anti-
Email: shoenfel@post.tau.ac.il NMDA Abs, AGA, ACL, anti-P Abs and anti-
© 2008 SAGE Publications Los Angeles, London, New Delhi and Singapore 10.1177/0961203308090017
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endothelial Abs (AECA). Focal manifestations were
associated with fewer Abs. Seizures were associated
with anti-neuronal Abs, BRAA, anti-MAP-2 and
aCL Abs; chorea with aCL, LAC and anti-Ro Abs;
and migraine with AGA and ACL Abs. Interestingly,
chorea and seizures were not associated with any
brain-specific Abs. None of the NPSLE manifesta-
tions were associated with anti-glial fibrillary acidic
protein Abs. Elevated titres of aCL Abs were the
most frequently reported and found in patients with
cognitive impairment, psychosis, depression, seizures,
chorea and migraine.4 No studies were found that
evaluated a specific NP manifestation with the full
panel of 20 Ab. Conversely, no Ab was investigated
in all the different NP manifestations. The results of
this study enforced the need for a comprehensive eval-
uation of an antibody panel for NP manifestations.
What is the evidence for the pathogenicity of auto-
Abs in CNS lupus? Experimental models show direct
evidence for the pathogenicity of aCL and anti-
β-2-glycoprotein I (β2-GPI) Ab and cognitive
dysfunction.5–8 More direct evidence for the patho-
genic potential of aCL was reported by intracerebro-
ventricular administration of immunoglobulins from
patients with APS that bound neuronal structures in
the hippocampus and cerebral cortex of the mouse
brain. Mice injected with this IgG performed worse
in the water maze than the controls with significant
effects attributed to aCL IgG on the overall perfor-
mance of the mice. These results support the hypothe-
sis that aCL Ab that gain access to the CNS may play
a direct role in the pathogenesis of the neurological
manifestations of APS.9
Cerebrovascular endothelial injury may be another
mechanism that increases the BBB permeability, thus
aiding the entry of pathogenic Abs into a site other-
wise protected from the potentially harmful effects of
a deviant host immune response.3
In-vitro studies and results from a variety of animal
models indicate that aCL Abs induce endothelial acti-
vation and a prothrombotic state.10 In addition, LAC
or aCL Abs have been linked with atherosclerosis,
another mechanism that contributes to CNS ischemia.
These Abs may also be involved in the pathogenesis of
NPSLE by non-ischemic mechanisms, including the
inhibition of astrocyte proliferation and the non-
specific permeabilization and depolarization of
synaptoneurosomes.11 To date, it is not clear that
whether the Abs traverse the BBB or are locally
synthesized.
Further evidence for the role of pathogenic Abs in
NPSLE evolves from a recent study that used an
immunoproteomic approach to characterize discrimi-
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Neuropsychiatric lupus and infectious triggers
G Zandman-Goddard et al.
381
nant human brain antigenic targets.12 Protein bands
targeted by serum self-IgG antibodies allowed sys-
temic autoimmune diseases to be differentiated
according to the presence and absence of neurologic
symptoms. Some protein bands were exclusively or
frequently found in sera from NPSLE patients,
whereas other protein bands were preferentially
found in sera from SLE patients without CNS
involvement. In patients with NPSLE, some antigenic
bands were never recognized and others were detected
often. This could be related to neuropathogenic or
neuroprotective events. An antigenic band that was
never detected in patients with NPSLE (p56) was
characterized and was identified as septin 7 that
plays a conserved role in cytokinesis and exocytosis,
and regulates microtubule stability through interac-
tion with the microtubule binding protein MAP-4.
The absence of an Ab response to septin 7 in patients
with NPSLE might reflect either the loss of pathogenic
Ab linked to altered brain tissue or the absence of
regulatory Ab required for the maintenance of self-
tolerance or neuroprotection. Antigenic bands
detected more commonly in NPSLE patient sera were
MAP-2B, triosephosphate and HSP 70–71. MAP-2B,
restricted to neurons, controls cytoskeletal integrity by
stabilizing microtubules and is involved in the elabo-
ration of the neuritic compartments. Antibodies
against MAP-2B may modulate neuronal plasticity.
Triosephosphate isomerase is a highly conserved gly-
colytic enzyme that is present in all cells and is highly
expressed in brain tissues. Antibodies to MAP-2B
have been reported in patients with diffuse manifesta-
tions including psychosis and seizures.4 For the first
time, an association between NPSLE and anti-
Hsp70–71 Ab was reported. Hsp70 over-expression
in brain tissues has also been associated with neuro-
protective effects after cerebral injury.
Infections can act as environmental triggers induc-
ing or promoting SLE in genetically predisposed indi-
viduals. Infection and stress may lead to disruption of
the BBB.3 By exposing mice to lipopolysaccharide
(inducing an experimental infection), immunization
with anti-NR2 Abs led to deposition in the hippocam-
pal region responsible for memory.13,14
Briefly, there are five main mechanisms by which
such an infection can lead to an autoimmune disease.
The first is molecular mimicry, where the infecting
agent may incorporate an epitope that is structurally
similar to that of a self-antigen. The second is a phe-
nomenon known as ‘epitope spreading’, where an
exaggerated local activation of antigen-presenting
cells because an inflammatory state may cause over-
processing and over-presentation of antigens that may
Lupus
 Neuropsychiatric lupus and infectious triggers
G Zandman-Goddard et al.
382
cause the priming of large numbers of T cells with
broad specificities, thus encouraging the development
of the autoimmune disease. The third refers to poly-
clonal activation, a mechanism where an infection of
B cells results in B-cell proliferation, enhanced anti-
body production, and the generation of circulating
immune complexes, which may cause damage to
self-tissues. Bystander activation, the fourth mecha-
nism, describes a situation where enhanced cytokine
production induces the expansion of autoreactive T
cells whose previous number was insufficient to pro-
duce an overt disease. Finally, viral and bacterial
super-antigens possess the ability to bind to the vari-
able domain of the T-cell receptor β-chain along with
the ability to bind to a wide variety of major histocom-
patibility complex class 2 molecules, thereby allowing
them to bind to a wide variety of T cells, irrespective of
their specificity, and to induce an autoimmune
reaction.15 The aims of the present study were to
investigate the prevalence and levels of antibodies to
bacterial, viral and parasitic agents in SLE patients
compared with a healthy control group, and to deter-
mine the relationship between this antibodies and
NPSLE clinical manifestations.
Methods and patients
All samples were tested using the Bio-Rad BioPlex
2200 (Bio-Rad Laboratories, Hercules, California,
USA). The BioPlex 2200 is a fully automated
random-access analyzer built on a synthesis of multi-
plex, magnetic beads and flow cytometry technolo-
gies. At the core of the technology are 25 different
populations of 8-m magnetic beads, which are dyed
with two fluorophores for classification purposes.
Each bead is coated with specific proteins, according
to the different assay being tested, thus representing a
different target antigen. Briefly, coloured beads coated
with different antigens were mixed together, along
with the patient sample and sample diluent and then
allowed to incubate for 20 min at 37 °C. After a wash
cycle, different isotypes of antihuman antibodies,
according to the different assay, conjugated to phyco-
erythrin (PE) were added to the dyed bead and
allowed to incubate for 10 min at 37 °C. After removal
of excess conjugate, the bead mixture was passed
through the detector that identifies the beads based
on the fluorescence of the dyes. The amount of anti-
body bound to the bead was determined by the fluo-
rescence of PE. Raw data were initially measured as
the relative fluorescence intensity and then converted
to the fluorescence ratio using a pre-dyed internal
Lupus
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standard bead, which is included in every bead set to
normalize the detector signal. A series of calibrators
were analysed along with the patient samples to con-
vert fluorescence ratios to antibody concentration
units. Two additional control beads were also
included in all incubations. A serum verification
bead and a blank bead were added to verify the addi-
tion of serum to the reaction vessel and the absence of
significant non-specific binding, respectively. ToRC
packs, both IgG and IgM, screen for antibodies
against three target analytes: Toxoplasma gondii,
Rubella and CMV. Elevated titres were determined
at a cut-off of 2 standard deviations from the normal
control group. For screening of rubella IgM, detection
of positivity at 3 standard deviations was also per-
formed. At the time the tests were preformed, all Bio-
Plex 2200 kits used were still in developmental stages
and were not commercially available. Be that as it
may, the technology had been evaluated before this
study in our previous work as well as other published
evaluations.16 All patients were recruited from one
medical centre. Clinical data from 89 patients with
SLE was available of which 47 (52.8%) harboured
CNS manifestations. Data analysis was performed
using SPSS 9.0 statistical analysis software (SPSS
Inc., Chicago, Illinois, USA, 1999).
Normality of distribution of continuous variables
was assessed using the Kolmogorov–Smirnov test
(cut off at P = 0.01). Titres of antibodies to infectious
agents were highly skewed; hence comparisons of
values by the presence of clinical symptoms were car-
ried out using the Mann–Whitney U. Associations
between antibody titres and continuous laboratory
variables were made using Spearman’s rho. All tests
are two-sided and considered significant at P < 0.05.
Results
We evaluated the prevalence and titre of antibodies to
five different infectious agents (EBV, CMV, toxo-
plasma, rubella and syphilis) using the BioPlex 2200
Multiplexed Immunoassay method (BioRad) and by
the ELISA method for Helicobacter pylori and Hepa-
titis B core Ag in the sera from 260 individuals (120
patients with SLE and 140 geographic controls).
CMV IgM Ab prevalence was increased among
patients with SLE compared with controls, whereas
elevated anti-hepatitis B and rubella IgG Abs titres
were less prevalent in the patients with SLE than in
the control group. No by-group difference was
detected for the prevalence of anti-toxoplasma, EBV,
syphilis or H. pylori Abs titres. The titres of the Toxo-

plasma IgG, CMV IgM, EBV early antigen IgG, viral
capsid antigen IgG, syphilis TPr47G and syphilis IgG
antibodies were significantly higher in patients with
SLE compared with controls. The titres of syphilis
TPr15G and anti-hepatitis B core antibodies were
higher in the controls compared with SLE patients.
Correlation analysis indicated that rubella IgM Ab
titres were marginally, positively associated with psy-
chosis (P = 0.09). No other associations were detected
between the seven infectious agents, 17 infectious anti-
bodies and five CNS clinical manifestations (head-
aches, seizures, stroke, depression and psychosis).
Although CMV IgM was positively correlated with
rubella IgG and IgM, it was not directly associated
with CNS manifestations. No correlation of any
NPSLE manifestation with anti-EBV Abs was
reported. When the positivity cut-off for anti-rubella
IgM was set at 3 standard deviations above normal,
three positive subjects were identified, of whom two
had NPSLE manifestations: one patient with psycho-
sis and one with depression, for a total NPSLE preva-
lence of 33.3%. On the contrary, the prevalence of
NPSLE in the remaining subjects was 6.5%.
Discussion
Our data supports the importance of infectious agents
(CMV, syphilis, rubella, toxoplasma and CMV) in
SLE. Furthermore, specific clinical manifestations
may be associated with infectious exposure.
In this preliminary study, we examined the correla-
tion of CNS clinical manifestations (headaches, sei-
zures, stroke, depression and psychosis) with infec-
tious agents. Among the seven infectious agents, 17
infectious antibodies and five CNS clinical manifesta-
tions (headaches, seizures, stroke, depression and psy-
chosis), marginally significant correlations between
elevated titres of rubella IgM Ab with psychosis and
depression were found. A 33.3% prevalence of CNS
manifestations in the high rubella group versus only
6.5% in the rest of the patients was found, and
although this nearly 5-fold increase is not statistically
significant, it appears that in a larger sample size, sig-
nificance would be reached. To the best of our knowl-
edge, this is the first study reported that examined the
correlation of NPSLE manifestations with various
anti-infectious Abs.
We have shown that non-autoimmune individuals
during infections mount an autoAb response.17 We
identified autoAbs in non-autoimmune individuals
during acute bacterial, viral or parasitic infections.
Sera from 88 patients with various acute infections
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Neuropsychiatric lupus and infectious triggers
G Zandman-Goddard et al.
383
along with 80 normal controls were tested by the
ELISA method for a panel of autoAbs detected in
various autoimmune diseases. In non-autoimmune
individuals with bacterial, viral, parasitic and rickett-
sial infections, elevated titres of Abs to annexin-V,
prothrombin, laminin, saccharomyces, phospholipids
and anti-nuclear antibodies were most frequently
detected. Thirty-four individuals harboured elevated
titres of at least two Abs. An autoAb burden was
detected in individuals with hepatitis A, hepatitis B,
toxoplasma and Q-fever infections.
In a previous study by us examining the prevalence
of CMV and EBV infectious antibodies in an array of
autoimmune diseases, a significantly higher preva-
lence of elevated titres of CMV IgM Ab were found
in SLE patients compared with controls.18 By investi-
gating the NP manifestations in this group of patients,
no correlation was found with exposure to CMV or
EBV infections.
There are no reports in the literature dealing with
rubella, hepatitis B virus, EBV or CMV and the trig-
gering of NPSLE. Recent research has provided con-
vincing evidence that EBV infection may play a major
role not only in molecular mimicry but also in aberra-
tions of B cells and apoptosis leading to a state of
perpetual heightened immune response in SLE.19
Possibly, common viral agents such as EBV are
protective for CNS lupus, whereas they may be detri-
mental for other organ involvement; or, a second-hit
infection is required for NP manifestations to occur.
There are many questions to be answered. Could
the time period from infection to the occurrence of
the manifestation be important? We know that auto-
Abs are present many years before clinical diagnosis
of autoimmune diseases.20 This hypotheses is less
likely because NP symptoms seem to appear early in
disease as reported by some.21 However, we would
need to follow patients over time to evaluate the devel-
opment of other manifestations. Another possibility is
that CNS lupus is not related to the common viral
agents that were tested here. In addition, in this pre-
liminary study, only five CNS manifestations were
evaluated.
In summary, NPSLE is a spectrum of non-specific
diffuse and focal manifestations that mechanistically
may be related to pathogenic (or pathoprotective)
Abs. One possible source of pathogenic antibodies
may be exposure to infectious insults. In this prelimi-
nary report, we propose that certain infections agents
may induce in the genetically predisposed individual
not only the development of lupus but also possibly
the clinical pattern of disease. Further investigation
into this theory is warranted.
Lupus
 Neuropsychiatric lupus and infectious triggers
G Zandman-Goddard et al.
384
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