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G. Domenico Sebastiani and M. Galeazzi
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Lupus (2009) 18, 11691175
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SPECIAL ARTICLE
Infectiongenetics relationship in systemic lupus erythematosus
G Domenico Sebastiani
1
and M Galeazzi
2
1
Unita` Operativa Complessa di Reumatologia, Azienda Ospedaliera San Camillo-Forlanini, Roma, Italy; and
2
Dipartimento di Medicina Clinica e
Scienze Immunologiche-Sezione di Reumatologia, Universita` degli Studi di Siena, Italy
Genetic, environmental, and hormonal factors contribute to disease susceptibility in systemic
lupus erythematosus. Among environmental factors, infectious agents play a major role.
When considering the complex relationship between genetic predisposition and infections in
the pathogenesis of systemic lupus erythematosus, we have to consider that infectious agents
can interact with the immune system in several ways. For example, molecular mimicry, altered
apoptosis of the host cells, exposure of as yet masked antigens to the immune system by a
given microorganism, and direct viral invasion of immunocompetent cells are all mechanisms
that may give rise to dysfunction of the immune system; in addition, some genetically deter-
mined deficit of the immune system, such as complement deficiency or deficit of mannose
binding lectine, may cause insufficient clearance of infectious agents, whose persistence in the
host may determine autoimmunity. Finally, evidence has been emerging suggesting that the
production of autoantibodies, by infected B-lymphocytes, may be drawn by altered expression
of particular microRNA in these cells. In this paper, we review some of the distinct scenarios
that can account for the role of infectious agents, acting on a genetically prone host, in
determining systemic lupus erythematosus. Lupus (2009) 18, 11691175.
Key words: apoptosis; autoantibodies; autoimmunity; genetic; HLA; immunogenetic;
infection; microRNA; molecular mimicry; retrovirus; systemic lupus erythematosus; virus
Introduction
The etiopathogenesis of systemic lupus erythemato-
sus (SLE) is complex and still largely unknown.
Genetic, environmental, and hormonal factors con-
tribute to disease susceptibility.
1
The importance of
genetic factors in the pathogenesis of SLE is docu-
mented by family studies, population studies
and by studies conducted in murine models of
the disease.
2,3
Nevertheless the identication of
genes, possibly involved in the pathogenesis
of SLE, has been complicated by the fact that
SLE is a heterogeneous disease, both clinically
and immunologically.
48
With regards to this,
the concept of threshold liability has emerged
in which disease develops when a threshold of
genetic and environmental susceptibility eects is
reached.
9
When considering the complex relationship
between genetic predisposition and infections in
the pathogenesis of SLE, various aspects have to
be taken into account, as infectious agents can
interact with the immune system in several ways,
and the immune system is under the control of
genes, mainly those at the human leukocyte antigen
(HLA) locus. For example: components of a given
microorganism can elicit an immune response
cross-reacting with self-antigens (molecular mimi-
cry); some infectious agents can induce apoptosis
of the host cells, with the consequent exposure of as
yet masked antigens to the immune system; micro-
organisms can infect the cells of the immune system
directly, giving rise to dysfunction of such cells;
some genetically determined decit of the immune
system, such as complement deciency, not uncom-
mon in SLE, or decit of mannose binding lectine,
may cause insucient clearance of infectious
agents, whose persistence in the host may give rise
to autoimmunity; viruses can induce autoimmunity
by binding to chromatin of infected cells, with sub-
sequent production of anti-chromatin antibodies,
including anti-dsDNA and anti-histones anti-
bodies.
10
Finally, we can hypothesize a role for
virus-induced microRNAs in the production of
autoantibodies by infected B-lymphocytes, and
Correspondence to: Prof. Gian Domenico Sebastiani, Unita` Operativa
Complessa di Reumatologia, Azienda Ospedaliera San Camillo-
Forlanini, Circonvallazione Gianicolense n. 87, 00152 Roma, Italy.
Email: gsebastiani@scamilloforlanini.rm.it
!
The Author(s), 2009. Reprints and permissions: http://www.sagepub.co.uk/journalsPermissions.nav 10.1177/0961203309345737
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this phenomenon may be under the inuence of the
HLA system in the host. In this paper, we review
some of the distinct scenarios that can account for a
role of infectious agents, acting on a genetically
prone host, in determining SLE.
Evidences for the role of infectious agents
in SLE
Initially, ndings of virion-like tubuloreticular
structures in endothelial cells and lymphocytes as
well as the demonstration of elevated serum levels
of type I interferon (IFN) raised the possibility of a
viral etiology in lupus.
11,12
Both EpsteinBarr virus
(EBV)
13
and measles,
1416
have been suggested to
play a role in SLE in dierent ways.
Furthermore, the association of SLE with the
lack of access to piped water during childhood,
which remained statistically signicant after adjust-
ing for admixture, suggests a possible role for poor
hygiene and exposure to infection in early life.
17
Childhood infections (diarrheal illness) below
1 year and sharing a bedroom during childhood
were implicated in SLE etiology in one study. The
highest odds ratios (ORs) were for rubella and
mumps. The authors propose that a developing
immune system exposed to infection is more likely
to produce antinuclear antibodies (ANAs) which
may in turn lead to connective tissue diseases
such as SLE.
18
Retroviruses were also implicated in patients
with SLE, including HTLV-I and HIV-1.
19,20
Nevertheless, direct virus isolation attempts from
tissues of SLE patients have not been successful.
21
An alternative (retro) viral etiology, i.e. activation
of endogenous retroviral sequences (ERSs) was ini-
tially proposed by a study of the New Zealand
mouse model of SLE.
2224
More recently, expres-
sion and autoantigenicity of human ERS has been
demonstrated in patients with SLE.
2529
ERSs may lead to autoimmunity directly, by
encoding autoantigens, or indirectly, by aecting
the expression of genes regulating immune
responses and tolerance.
20
Direct autoantigenicity
of the human endogenous retrovirus (ERV) HRES-
1 and of ERV-3 has been documented in SLE.
ERSs, if expressed, are likely targets of cross-reac-
tivity for virally induced immune responses. Such
cross-reactivity, i.e. molecular mimicry between
self-antigens and viral proteins, has been proposed
as a trigger of autoimmunity.
30
In addition to serv-
ing as cross-reactive targets of antiviral immunity,
ERSs may also have a direct role in regulating
immune responses.
20
ERSs and other retrotranspo-
sable elements possess a relatively high mobility
and may cause immune dysregulation by inser-
tional mutagenesis or cis- or trans-regulation of cel-
lular genes.
31
The human ERV HERV-K10 has an
integration site within the complement C2 gene.
32
Variable repeats of this element may have a role in
C2 expression.
Expression of HERV-E4-1 appears to be
increased in patients with SLE due to DNA hypo-
methylation.
33
Interestingly, higher expression
levels in SLE lymphocytes correlate with the pro-
duction of U1 snRNP,
34
which includes a 70 kDa
protein with a region of homology to gag antigens
of infectious ERV.
35
The 1q42 chromosomal region that has been
associated with lupus susceptibility
36
and harbors
the HRES-1 ERV
37
is genetically unstable.
38
1q42
has been identied as one of the three most
common fragile sites in the human genome.
39,40
In general, genomic loci harboring ERV have
been associated with increased chromosomal fragi-
lity. Fragility at 1q42 can be triggered with 5-aza-
cytidine (5AZA), a demethylating agent and
relative inducer of endogenous retroviral genes in
chicken cells.
41
This mechanism is particularly
interesting with regards to induction of T-cell auto-
reactivity by 5AZA and impaired DNA methyla-
tion in T-cells of patients with SLE.
42
Further evidence for the role of infectious agents
in the etiopathogenesis of SLE comes from the
coincidence of elevated frequencies of VH replace-
ment products in patients with either viral infec-
tions or autoimmune diseases.
43
Molecular mimicry
Immunological cross-reactivity between antigens of
infectious viruses and self-proteins has long been
documented. However, the demonstration of a
causal role of the implicated viruses has proven
challenging. EBV shows cross-reactivity to several
lupus autoantigens
44,45
and appears to infect lupus
patients earlier than control donors.
46
In addition,
epitope mapping of SmD revealed the existence of a
dominant epitope in the C-terminal region (SmD
95119) of the molecule that bears a striking
homology to a sequence of the viral protein
EBNA I (sequence 3558). Conversely, immuniza-
tion with the EBNA I peptide induces antibodies
reactive with SmD.
47
Another sequence of EBNA I, PPPGRRP-
aa398-404, is strongly homologous to the dominant
Infectiongenetics relationship in systemic lupus erythematosus
GD Sebastiani and M Galeazzi
1170
Lupus
at HINARI on September 20, 2012 lup.sagepub.com Downloaded from
epitope of SmB. Immunization with either the viral
or the autoantigen sequence induces lupus-like
autoimmunity in animals.
48
Taken together, these
observations suggest that EBV infection has the
potential to induce anti-Sm antibodies by molecu-
lar mimicry.
A role of molecular mimicry in the induction of
anti-RNP antibodies has also been suggested. In
fact, a subset of anti-U1-70 kd antibodies reacts
with a sequence of ve amino acids that is also
contained in the inuenza B matrix protein,
49
and
the retroviral p30gag antigen is homologous to an
antigenic portion of U1-70 kd.
50
Other viruses with strong cross-reactivity to self-
antigens, particularly, the human retroviruses, such
as HTLV-I and HIV 1, with homology to ERV-
encoded antigens, are dicult to implicate in dis-
ease pathogenesis, since these viruses rarely infect
patients with SLE.
25,51
Comprehensive epitope
mapping with 44 15-amino acid long peptides over-
lapping the entire protein HRES-1/p28 by 10
amino acids with antibodies of 16 HRES-1/p28
Western blot-seropositive SLE patients identied
three immunodominant epitopes, two of which
showed signicant homology to antigens of viruses
commonly infecting humans.
52
In this study it was
also demonstrated that co-infection with EBV and
TTvirus and molecular mimicry with immunodo-
minant HRES-1/p28 epitopes may mediate epitope
spreading to self-antigens such as the 70 kDa
U1snRNP, and thus contribute to formation of
ANAs in SLE.
Apoptosis
In recent years, there has been growing interest in
the role that apoptosis plays in the development of
autoimmunity. Casciola-Rosen et al.
53
demon-
strated that the intracellular components that
often make up the spectrum of target autoantigens
in lupus cluster in blebs on the surface of apoptotic
cells. This position enables them to be presented as
an antigen. Apoptosis is, however, a physiological
process. The part it plays in the development of
autoimmunity must, therefore, be dependent upon
dysfunction elsewhere. In a recent editorial,
54
Charles describes research ndings that could
account for this. Essentially, apoptotic fragments
are usually rapidly cleared, minimizing the produc-
tion of an immune response. If, however, the rate of
apoptosis overwhelms this function, or clearance is
suboptimal, immunogenicity is increased. Thus,
apoptosis may provide a central pivot for disease
production. Precipitating factors such as UV light,
infections or drugs may cause increased apoptosis.
Alternatively, they may induce dysfunctional clear-
ance of apoptotic particles. This in turn results
in increased exposure of the target antigens, and
subsequent production of the corresponding
autoantibodies.
Conversely, reduced apoptosis has been impli-
cated via a totally dierent mechanism.
55
Evidence suggests that some T-cells from patients
with lupus overexpress the oncogene bcl-2, promot-
ing cell survival by decreasing apoptosis. This could
potentially allow autoreactive T-cells to persist,
propagating the autoimmune response. Indeed,
some evidence exists for a role of Fas and bcl2
genes dysfunction in the immunopathogenesis of
SLE. When the immune system functions normally,
autoreactive lymphocytes undergo apoptosis or
inactivation in the thymus. This thymic deletion is
mediated by two genes, lpr and gld, both implicated
in the synthesis of Fas and Fas ligand. In mice, the
aberrant expression of these genes is associated
with the development of an autoimmune dis-
ease resembling SLE, and the overexpression
of bcl2, also involved in apoptosis regulation, is
associated with immune-complex mediate
glomerulonephritis.
56
Mannose binding lectin
Mannose binding lectin (MBL) is a serum protein
produced in the liver, and is a key molecule in
innate immunity.
57
MBL binds to various organ-
isms by its carbohydrate recognition domain
(CRD), and excises an opsonin eect. The binding
of MBL leads to agglutination of these microorgan-
isms and will help their clearance by phagocytes.
In addition, MBL activates the complement path-
way (the lectin pathway) through MBL-associated
serine proteases (MASPs). MBL is an acute phase
protein and its production is enhanced by inam-
matory stimuli, nevertheless, polymorphisms of the
MBL gene is known to greatly inuence serum
MBL concentration. The MBL gene, located on
the long arm of chromosome 10 at 10q11.2q21,
contains four exons.
58
There are ve known single
nucleotide polymorphisms (SNPs) that aect serum
MBL concentration.
59
The minority alleles are
designated allele D, B, C, respectively, while the
majority allele is designated allele A. The presence
of any of the minority alleles (collectively desig-
nated allele O) results in an amino acid substitution
and signicant reduction of serum MBL
Infectiongenetics relationship in systemic lupus erythematosus
GD Sebastiani and M Galeazzi
1171
Lupus
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concentration. Furthermore, homozygosity or a
combination of the minority alleles (genotype
OO) results in almost complete deciency of
serum MBL.
60
A number of studies have suggested
that MBL deciency, or low serum MBL levels
caused by the SNPs described above, may be asso-
ciated with the occurrence of SLE.
61
By a meta-
analysis of eight previous studies, it has been
shown that presence of the minority alleles (B, C
or D alleles) confer a 1.6 times overall increased
risk of acquiring SLE.
61
Two possible explanations
for the association between MBL deciency and the
occurrence of SLE are suggested. First, MBL can
bind to and initiate uptake of apoptotic cells by
macrophages,
62
and abnormal accumulation of
cell debris would occur in MBL decient indivi-
duals, and would serve as a source of autoantigens.
In accord with this hypothesis, Seelen et al.
63
recently reported that anticardiolipin and anti-
C1q antibodies were observed signicantly more
frequently in SLE patients with MBL minority
alleles than those without those alleles, and that
the presence of those antibodies was associated
with decreased serum MBL concentration and
function. It is also reported that MBL can bind
DNA, and MBL may have a role in clearance of
DNA.
64
Second, since MBL has a major role in
innate immunity, individuals with MBL deciency
might have higher possibilities of being infected
with pathogens that have some roles in the patho-
genesis of SLE. However, these hypotheses are yet
to be proved.
Micro RNA, virus and autoimmunity
RNA interference (RNAi) is an evolutionarily con-
served mechanism involved in the post-transcrip-
tional regulation of gene expression in many
eukaryotes. It was initially recognized as an anti-
viral mechanism that protected organisms from
RNA viruses
65
or the random integration of trans-
posable elements. Mediators of this mechanism are
the so-called microRNAs (miRNAs)
66
and it is now
clear that miRNAs comprise a novel class of endo-
genous, small, non-coding RNAs that also control
gene expression by directing their target messenger
RNAs (mRNAs) for degradation and/or trans-
lational repression. A growing body of exciting
evidence suggests that miRNAs are important reg-
ulators for cell dierentiation, proliferation/
growth, mobility, and apoptosis. Consequently,
dysregulation of miRNA function may lead to
human diseases such as cancer, cardiovascular
disease, liver disease, immune dysfunction, and
metabolic disorders.
67
Concerning autoimmune rheumatic disorders,
abnormal expression of miRNAs 146 and 155 was
recently reported in patients with rheumatoid
arthritis (RA).
68,69
More recently we have demon-
strated an impressive upregulation of miRNA-223
in peripheral and synovial CD3 positive lympho-
cytes of RA patients.
70
In addition, 16 miRNAs
expressed dierentially were identied in peripheral
blood mononuclear cells of SLE patients suggesting
that miRNAs could represent potential diagnosis
biomarkers and probable factors involved in the
pathogenesis of SLE.
71
Viral infections such as EBV, chronic hepatitis
C virus (HCV), HIV and Kaposis-sarcoma-asso-
ciated herpes virus are frequently associated with
the pathogenesis of rheumatic disorders.
72,73
Dierent reports also indicate that viruses encode
their own miRNAs and that viral-encoded
miRNAs control the expression of viral transcripts,
in addition to suppressing the host immune
response during infection
74,75
and to favoring dis-
ease development.
76
Finally it has been found that
overexpression of miRNA-122 favors HCV replica-
tion and virus accumulation in infected hepato-
cytes. As we have found a strong association of
type 2c virus genotype with cryoglobulinemia that
is in turn associated with HLA-DR3 allele, we can
hypothesize that the production of cryoglobulins,
by infected B-lymphocytes, may be drawn by over-
expression of particular miRNA in these cells. This
phenomenon may be also inuenced by HLA
genetic background in the host.
77
With regards to
this, it has been found that Su autoantigen can be
co-immunoprecipitated with GW182 (an
Argonaute-2-interacting protein) and Dicer antibo-
dies, indicating that this autoantigen is part of the
miRNA-processing machinery.
78
Remarkably,
anti-Su antibodies have been reported to be asso-
ciated with dierent autoimmune diseases, includ-
ing Sjo grens syndrome and SLE.
79
According to
these ndings, it is intriguing to speculate that
viruses may promote the development of auto-
immunity via their association with components
of the RNAi pathway. Therefore, future studies,
with a focus on the interplay among miRNA,
viruses, and autoimmunity, should help clarify
whether miRNA itself, or its association with an
invading virus, is directly linked to the pathogenesis
of systemic autoimmune diseases. In addition,
identications of viral-encoded miRNAs, possibly
associated with the pathogenesis of rheumatic dis-
orders, might also represent a novel potential target
for the treatment of these disorders.
Infectiongenetics relationship in systemic lupus erythematosus
GD Sebastiani and M Galeazzi
1172
Lupus
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Conclusion
SLE is an autoimmune disorder with unknown
etiology. Although the exact molecular mechanisms
underlying the pathophysiological processes in SLE
remain unknown, a complex interaction between
genetic and environmental co-factors for disease
onset must be assumed. Mostly, there is a strong
genetic predisposition, as disease concordance rate
is approximately 25% in monozygotic twins, but
only 2% in dizygotic twins. However, there is also
a strong environmental inuence, since vice versa,
three quarters of monozygotic twins do not become
sick, when one of the two has the disease. Among
the environmental risk factors, infectious agents
play a major role, by various mechanisms. For
example, molecular mimicry after common infec-
tions has been discussed as a trigger for SLE, due
to the clinical observation that SLE onset or exac-
erbation frequently followed an infection. Cross-
reactivity between SLE auto-antibodies and viral
antigens has been found in several cases.
Endogenous retroviruses may be activated in a
subset of patients. Among all infectious agents,
however, seroreactivity to EBV is most closely
associated with SLE in a signicant way. Other
mechanisms by which infectious agents may trigger
SLE include apoptosis and defective clearance of
microorganisms due to genetic linked immunode-
cit. Finally, it is intriguing to speculate that viruses
may promote the development of autoimmunity via
their association with components of the RNA
interfering pathway. In fact, miRNA role as a nat-
ural anti-viral response in mammals has been pos-
tulated and is also supported by the evidence that
mammalian viruses encode suppressors of miRNA.
References
1 Alarcon-Segovia D. The pathogenesis of immune dysregulation in
systemic lupus erythematosus. A troika. J Rheumatol 1984; 11:
588590.
2 Alarcon-Segovia D, Alarcon-Riquelme ME, Cardiel MH, et al.
Grupo Latinoamericano de Estudio del Lupus Eritematoso
(GLADEL). Familial aggregation of systemic lupus erythematosus,
rheumatoid arthritis, and other autoimmune diseases in 1,177 lupus
patients from the GLADEL cohort. Arthritis Rheum 2005; 52:
11381147.
3 Hochberg MC. The application of genetic epidemiology to systemic
lupus erythematosus. J Rheumatol 1987; 14: 867.
4 Reveille JD, Moulds JM, Ahn C, et al. Systemic lupus erythemato-
sus in three ethnic groups. I. The effects of HLA class II, C4 and
CR1 alleles, socioeconomic factors, and ethnicity at disease onset.
Arthritis Rheum 1998; 41: 11611172.
5 Galeazzi M, Sebastiani GD, Morozzi G, et al. European Concerted
Action on the Immunogenetics of SLE. HLA class II DNA typing in
a large series of European patients with systemic lupus erythemato-
sus. Correlations with clinical and autoantibody subsets. Medicine
2002; 81: 169178.
6 Galeazzi M, Sebastiani GD, Tincani A, et al. European Concerted
Action on the Immunogenetics of SLE. HLA class II associations
of anticardiolipin and anti-b2GPI antibodies in a large series of
European patients with systemic lupus erythematosus. Lupus 2000;
9: 4755.
7 Sebastiani GD, Galeazzi M, Tincani A, et al. European
Concerted Action on the Immunogenetics of SLE. HLA-
DPB1 alleles association of anticardiolipin and anti-beta2GPI
antibodies in a large series of European patients with SLE.
Lupus 2003; 12: 560563.
8 Rhodes B, Vyse TJ. The genetics of SLE: an update in the light of
genome-wide association studies. Rheumatology 2008; 47:
16031611.
9 Wandstrat A, Wakeland E. The genetics of complex autoimmune
diseases: non-MHC susceptibility genes. Nat Immunol 2001; 2:
802809.
10 Van Ghelue M, Moens U, Bendiksen S, Rekvig OP. Autoimmunity
to nucleosomes related to viral infection: a focus on hapten-carrier
complex formation. J Autoimmun 2003; 20: 171182.
11 James JA, Harley JB, Scofield RH. EpsteinBarr virus and sys-
temic lupus erythematosus. Curr Opin Rheumatol 2006; 18:
462467.
12 Rich SA. Human lupus inclusions and interferon. Science 1981;
213: 772775.
13 James JJ, Kaufman KM, Farris AD, Taylor-Albert E, Lehman
TJA, Harley JB. An increased prevalence of EpsteinBarr virus
infection in young patients suggests a possible etiology for systemic
lupus erythematosus. J Clin Invest 1997; 100: 30193026.
14 Parfanovich MI, Sokolov NN, Mekler LB, Fadeyeva LL, Zhdanov
VM. Use of iodinized antibody for revealing viral antigens in ultra-
thin sections of cells. Nature 1965; 206: 784786.
15 Nevraeva EG, Bogomolova NN, Chaplygina NM, Zavalishin IA,
Filimonova RG. Persistence of the measles virus genome in periph-
eral blood lymphocytes in patients with glomerulonephritis and
systemic lupus erythematosus. Ter Arkh 1991; 63: 108110.
16 Schneider-Schaulies S, Kreth HW, Hofmann G, Billeter M, ter
Meulen V. Expression of measles virus RNA in peripheral blood
mononuclear cells of patients with measles, SSPE, and autoim-
mune diseases. Virology 1991; 182: 703711.
17 Molokhia M, Hoggart C, Patrick AL, et al. Relation of risk of
systemic lupus erythematosus to west African admixture in a
Caribbean population. Hum Genet 2003; 112: 310318.
18 Edwards CJ, Syddall H, Goswami R, Goswami P, Dennison EM,
Cooper C. Infections in infancy and the presence of antinuclear
antibodies in adult life. Lupus 2006; 15: 213217.
19 Mellors RC, Mellors JW. Type C RNAvirus-specific antibody in
human SLE demonstrated by enzymoimmunoassay. Proc Natl
Acad Sci USA 1978; 75: 24632467.
20 Perl A. Role of endogenous retroviruses in autoimmune diseases.
Rheum Dis Clin North Am 2003; 29: 123143.
21 Hicks JT, Aulakh GS, McGrath PP, Washington GC, Kim E,
Alepa FP. Search for EpsteinBarr and type C oncornaviruses in
systemic lupus erythematosus. Arthritis Rheum 1979; 22: 845857.
22 Yoshiki T, Mellors RC, Strand M, August JT. The viral envelope
glycoprotein of murine leukemia virus and the pathogenesis of
immune complex glomerulonephritis of New Zealand mice. J
Exp Med 1974; 140: 10111025.
23 Krieg AM, Steinberg AD. Analysis of thymic endogenous retro-
viral expression in murine lupus. J Clin Invest 1990; 86: 809816.
24 Krieg AM, Gourley MF, Perl A. Endogenous retroviruses: poten-
tial etiologic agents in autoimmunity. FASEB J 1992; 6:
25372544.
25 Banki K, Maceda J, Hurley E, et al. Human T-cell lymphotropic
virus (HTLV)-related endogenous sequence, HRES-1, encodes a
28-kDa protein: A possible autoantigen for HTLV-I gag-reactive
autoantibodies. Proc Natl Acad Sci USA 1992; 89: 19391943.
26 Perl A, Colombo E, Dai H, et al. Antibody reactivity to the HRES-
1 endogenous retroviral element identifies a subset of patients with
systemic lupus erythematosus and overlap syndromes: correlation
with antinuclear antibodies and HLA class II alleles. Arthritis
Rheum 1995; 38: 16601671.
27 Brookes SM, Pandolfino YA, Mitchell TJ, et al. The immune
response to and expression of cross-reactive retroviral gag
Infectiongenetics relationship in systemic lupus erythematosus
GD Sebastiani and M Galeazzi
1173
Lupus
at HINARI on September 20, 2012 lup.sagepub.com Downloaded from
sequences in autoimmune disease. Br J Rheumatol 1992; 31:
735742.
28 Bengtsson A, Blomberg J, Nived O, Pipkorn R, Toth L, Sturfelt G.
Selective antibody reactivity with peptides from human endogen-
ous retroviruses and nonviral poly(amino acids) in patients with
systemic lupus erythematosus. Arthritis Rheum 1996; 39:
16541663.
29 Magistrelli C, Samoilova E, Agarwal RK, et al. Polymorphic gen-
otypes of the HRES-1 human endogenous retrovirus locus corre-
late with systemic lupus erythematosus and autoreactivity.
Immunogenetics 1999; 49: 829834.
30 Perl A. Mechanisms of viral pathogenesis in rheumatic diseases.
Ann Rheum Dis 1999; 58: 454461.
31 Perl A, Banki K. Human endogenous retroviral elements and auto-
immunity: data and concepts. Trends Microbiol 1993; 1: 153156.
32 Zhu ZB, Hsieh S-L, Bentley DR, Campbell D, Volanakis JE.
A variable number of tandem repeat locus within the human com-
plement C2 gene is associated with a retroposon derived from a
human endogenous retrovirus. J Exp Med 1992; 175: 17831787.
33 Ogasawara H, Naito K, Kaneko H, et al. Quantitative analysis of
messenger RNA of human endogenous retrovirus in systemic lupus
erythematosus. J Rheumatol 2001; 29: 16781682.
34 Piotrowski P, Duriagin S, Jagodzinski P. Expression of human
endogenous retrovirus clone 4-1 may correlate with blood plasma
concentration of anti-U1 RNP and anti-Sm nuclear antibodies.
Clin Rheumatol 2005; 24: 620624.
35 Query CC, Keene JD. A human autoimmune protein associated
with U1 RNA contains a region of homology that is cross-reactive
with retroviral p30gag antigen. Cell 1987; 51: 211220.
36 Tsao BP. Lupus susceptibility genes on human chromosome 1.
Int Rev Immunol 2000; 19: 319334.
37 Perl A, Isaacs CM, Eddy RL, Byers MG, Sait SN, Shows TB.
The human T-cell leukemia virus-related endogenous sequence
(HRES1) is located on chromosome 1 at q42. Genomics 1991; 11:
11721173.
38 Murty VVVS, Li R-G, Mathew S, et al. Replication error-type
genetic instability at 1q42-43 in human male germ cell tumors.
Cancer Res 1994; 54: 39833985.
39 Rocchi A, Pelliccia F. Synergistic effect of DAPI and thymidylate
stress conditions on the induction of common fragile sites.
Cytogenet Cell Genet 1988; 48: 5154.
40 Pelliccia F, Rocchi A. DAPI-inducible common fragile sites.
Cytogenet Cell Genet 1986; 42: 174176.
41 Groudine M, Eisenman R, Weintraub H. Chromatin structure of
endogenous retroviral genes and activation by an inhibitor of
DNA methylation. Nature 1985; 292: 311317.
42 Richardson B, Scheinbart L, Strahler J, Gross L, Hanash S,
Johnson M. Evidence for impaired T cell DNA methylation in
systemic lupus erythematosus and rheumatoid arthritis. Arthritis
Rheum 1990; 33: 16651673.
43 Liu Y, Fan R, Zhou S, Yu Z, Zhang Z. Potential contribution of
VH gene replacement in immunity and disease. Ann NY Acad Sci
2005; 1062: 175181.
44 Poole BD, Scofield RH, Harley JB, James JA. EpsteinBarr virus
and molecular mimicry in systemic lupus erythematosus.
Autoimmunity 2006; 39: 6370.
45 Harley JB, Harley IT, Guthridge JM, James JA. The curiously
suspicious: a role for EpsteinBarr virus in lupus. Lupus 2006;
15: 768777.
46 James JJ, Kaufman KM, Farris AD, Taylor-Albert E, Lehman
TJA, Harley JB. An increased prevalence of EpsteinBarr virus
infection in young patients suggests a possible etiology for systemic
lupus erythematosus. J Clin Invest 1997; 100: 30193026.
47 Migliorini P, Baldini C, Rocchi V, Bombardieri S. Anti-Sm and
anti-RNP antibodies. Autoimmunity 2005; 38: 4754.
48 James JA, Gross T, Scofield RH, Harley JB. Immunoglobulin epi-
tope spreading and autoimmune disease after peptide immuniza-
tion: Sm B/B0-derived PPPGMRPP and PPPGIRGP induce
spliceosome autoimmunity. J Exp Med 1995; 181: 453461.
49 Guldner HH, Netter HJ, Szostecki C, Jaeger E, Will H. Human
anti-p68 autoantibodies recognize a common epitope of U1 RNA
containing small nuclear ribonucleoprotein and influenza B virus.
J Exp Med 1990; 171: 819829.
50 Query CC, Keene JD. A human autoimmune protein associated
with U1 RNA contains a region of homology that is cross-reactive
with retroviral p30gag antigen. Cell 1987; 51: 211220.
51 Perl A, Rosenblatt JD, Chen IS, et al. Detection and cloning of
new HTLV-related endogenous sequences in man. Nucleic Acids
Res 1989; 17: 68416854.
52 Gergely P Jr, Pullmann R Jr, Stancato C, et al. Increased preva-
lence of transfusion transmitted virus and cross-reactivity with
immunodominant epitopes of the HRES-1/p28 endogenous retro-
viral autoantigen in patients with systemic lupus erythematosus.
Clin Immunol 2005; 116: 124134.
53 Casciola-Rosen LA, Anhalt G, Rosen A. Autoantigens targeted in
SLE are clustered in two populations of surface structures on
apoptotic keratinocytes. J Exp Med 1994; 179: 13171330.
54 Charles PJ. Defective waste disposal: does it induce autoantibodies
in SLE? Ann Rheum Dis 2003; 62: 13.
55 Rose LM, Latchman DS, Isenberg DA. Apoptosis in peripheral
lymphocytes in SLE: A review. Br J Rheumatol 1997; 36: 158163.
56 Rose LM, Latchman DS, Isenberg DA. Bcl-2 and Fas, molecules
which influence apoptosis A possible role in systemic lupus erythe-
matosus? Autoimmunity 1994; 17: 271278.
57 Holmskov U, Malhotra R, Sim RB, Jensenius JC. Collectins: col-
lagenous C-type lectins of the innate immune defense system.
Immunol Today 1994; 15: 6774.
58 Sastry K, Herman GA, Day L, et al. The human mannose-binding
protein gene. Exon structure reveals its evolutionary relationship to
a human pulmonary surfactant gene and localization to chromo-
some 10. J Exp Med 1989; 170: 11751189.
59 Madsen HO, Garred P, Kurtzhals JA, et al. A new frequent allele is
the missing link in the structural polymorphism of the human
mannan-binding protein. Immunogenetics 1994; 40: 3744.
60 Sumiya M, Super M, Tabona P, et al. Molecular basis of opsonic
defect in immunodeficient children. Lancet 1991; 337: 15691570.
61 Garred P, Voss A, Madsen HO, Junker P. Association of mannose-
binding lectin gene variation with disease severity and infections in
a population-based cohort of systemic lupus erythematosus
patients. Genes Immun 2001; 2: 442450.
62 Ogden CA, de Cathelineau A, Hoffmann PR, et al. C1q and man-
nose binding lectin engagement of cell surface calreticulin and
CD91 initiates macropinocytosis and uptake of apoptotic cells.
J Exp Med 2001; 194: 781795.
63 Seelen MA, van der Bijl EA, Trouw LA, et al. A role for mannose-
binding lectin dysfunction in generation of autoantibodies in sys-
temic lupus erythematosus. Rheumatology 2005; 44: 111119.
64 Palaniyar N, Nadesalingam J, Clark H, Shih MJ, Dodds AW, Reid
KB. Nucleic acid is a novel ligand for innate, immune pattern
recognition collectins surfactant proteins A and D and mannose-
binding lectin. J Biol Chem 2004; 279: 3272832736.
65 Waterhouse PM, Wang MB, Lough T. Gene silencing as an adap-
tive defence against viruses. Nature 2001; 411: 834842.
66 Pillai RS. MicroRNA function: multiple mechanisms for a tiny
RNA? RNA 2005; 11: 17531761.
67 Zhang C. MicroRNomics: a newly emerging approach for disease
biology. Physiol Genomics 2008; 33: 139147.
68 Nakasa T, Miyaki S, Okubo A, et al. Expression of microRNA-
146 in rheumatoid arthritis synovial tissue. Arthritis Rheum 2008;
58: 12841292.
69 Stanczyk J, Pedrioli DM, Brentano F, et al. Altered expression of
MicroRNA in synovial fibroblasts and synovial tissue in rheuma-
toid arthritis. Arthritis Rheum 2008; 58: 10011009.
70 Galeazzi M, Fulci V, Sebastiani GD, et al. Mir-223, C/EBP alfa
and PU.1 mRNA expression in peripheral T-lymphocytes from
rheumatoid arthritis patients. Arthritis Rheum Suppl, Poster
number 156 presented at the 2008 ACR Meeting, San Francisco,
CA, 2429 October 2008.
71 Dai Y, Huang Y-S, Tang M, et al. Microarray analysis of
microRNA expression in peripheral blood cells of systemic lupus
erythematosus patients. Lupus 2007; 16: 939946.
72 Leirisalo-Repo M. Early arthritis and infection. Curr Opin
Rheumatol 2005; 17: 433439.
73 Callan MF. EpsteinBarr virus, arthritis, and the development of
lymphoma in arthritis patients. Curr Opin Rheumatol 2004; 6:
399405.
Infectiongenetics relationship in systemic lupus erythematosus
GD Sebastiani and M Galeazzi
1174
Lupus
at HINARI on September 20, 2012 lup.sagepub.com Downloaded from
74 Stern-Ginossar N, Elefant N, Zimmermann A, et al. Host immune
system gene targeting by a viral miRNA. Science 2007; 317:
376381.
75 Scaria V, Hariharan M, Maiti S, Pillai B, Brahmachari SK.
Host-virus interaction: a new role for microRNAs. Retrovirology
2006; 3: 68.
76 Gottwein E, Mukherjee N, Sachse C, et al. A viral microRNA
functions as an orthologue of cellular miR-155. Nature 2007;
450: 10961099.
77 Giannitti C, Morozzi G, DAlfonso S, Bellisai F, Galeazzi M. Viral
genotype and HLA class II alleles influence on extra-hepatic manifes-
tations of chronic HCV infection. Reumatismo 2008; 60: 192198.
78 Jakymiw A, Ikeda K, Fritzler MJ, Reeves WH, Satoh M, Chan
EK. Autoimmune targeting of key components of RNA inter-
ference. Arthritis Res Ther 2006; 8: R87.
79 Lim LP, Lau NC, Garrett-Engele P, et al. Microarray analysis
shows that some microRNAs downregulate large numbers of
target mRNAs. Nature 2005; 433: 769773.
Infectiongenetics relationship in systemic lupus erythematosus
GD Sebastiani and M Galeazzi
1175
Lupus
at HINARI on September 20, 2012 lup.sagepub.com Downloaded from