Clin Rheumatol

DOI 10.1007/s10067-017-3811-6

REVIEW ARTICLE

Pristane-induced lupus: considerations on this

experimental model
Eduarda Correa Freitas 1 & Mayara Souza de Oliveira 1 & Odirlei André Monticielo 1

Received: 29 March 2017 / Revised: 20 August 2017 / Accepted: 28 August 2017

# International League of Associations for Rheumatology (ILAR) 2017

Abstract Systemic lupus erythematosus (SLE) is a multifac- Introduction

torial, autoimmune inflammatory disease with pleomorphic
clinical manifestations involving different organs and tissues. Systemic lupus erythematosus (SLE) is characterized by mul-
The etiology of this disease has been associated with a dys- tisystem inflammation and the loss of tolerance of T and B
functional response of B and T lymphocytes against environ- lymphocytes to host antigens. The etiology of SLE is still
mental stimuli in individuals genetically susceptible to SLE, poorly known and is considered multifactorial, involving ge-
which determines an immune response against different netic, hormonal, and environmental aspects. Patients with this
autoantigens and, consequently, tissue damage. The study of disease have various clinical symptoms including renal dis-
different murine models has provided a better understanding ease, non-erosive arthritis, serositis, hematological and respi-
of these autoimmune phenomena. This review primarily fo- ratory manifestations, as well as the production of antinuclear
cuses on that has been learned from the pristane-induced lupus antibodies (ANA). The genetic profile and clinical and labo-
(PIL) model and how this model can be used to supplement ratory changes of SLE can be studied in experimental models.
recent advances in understanding the pathogenesis of SLE. Animal models of SLE induced in healthy mouse strains by
We also consider both current and future therapies for this exposure to hydrocarbon oils, such as pristane, have facilitated
disease. The PubMed, SciELO, and Embase databases were research into this disease by providing insight into the role of
searched for relevant articles published from 1950 to 2016. environmental factors that may predispose to SLE [1–3].
PIL has been shown to be a useful tool for understanding the Furthermore, they allow study of the initial events that lead
multiple mechanisms involved in systemic autoimmunity. In to a break in tolerance in the absence of genetic defects, and
addition, it can be considered an efficient model to evaluate provide a better understanding of the cellular mechanisms
the environmental contributions and interferon signatures involved in SLE development and progression. In this review,
present in patients with SLE. we will discuss what has been learned from the pristane-
induced lupus (PIL) model and how this model can be used
to supplement recent advances in understanding the pathogen-
Keywords Animal model . Lupus . Pristane . esis of SLE.
Pristane-induced lupus . Systemic lupus erythematosus

Materials and methods

The PubMed, SciELO, and Embase databases were searched

* Odirlei André Monticielo for articles published from 1950 to 2016, using the following
omonticielo@yahoo.com.br
terms and combinations thereof: Bpristane-induced lupus,^
1
Btetramethylpentadecane-induced lupus,^ Bpristane-treated
Laboratory of Autoimmune Diseases, Division of Rheumatology,
Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio
mice,^ Bmurine lupus,^ and Bhydrocarbon oil pristane.^
Grande do Sul, Rua Ramiro Barcelos, 2350, room 645, Porto Articles in Portuguese, Spanish, and English were included
Alegre 90035-003, Brazil in this review.
 Clin Rheumatol

Pristane in this model. Animals deficient in the production of these

cytokines are not able to produce autoantibodies [18, 19]. In
Numerous chemicals and drugs have been identified as capa- the mouse PIL model, IFN-γ deficiency has been shown to
ble of triggering the production of autoantibodies or inducing have a protective effect on renal disease and production of
a syndrome similar to SLE [4, 5]. However, none of them autoantibodies [20]. The role of IFN will be described in more
reproduce completely the spectrum of autoantibodies ob- detail in the next sections, due to its importance in this model.
served in human SLE. Drugs such as procainamide, hydral- BALB/c IL-6−/− mice do not produce anti-ssDNA, anti-
azine, quinidine, chlorpromazine, methyldopa, and isoniazid, dsDNA, or anti-chromatin antibodies, but continue to produce
which act on gene expression, induce a highly restricted and anti-RNP/Sm and anti-Su (Fig. 1). In the same study, produc-
directed response against chromatin antigens (ssDNA, his- tion of anti-dsDNA antibodies in BALB/c IL-6+/+ occurred
tones) [5, 6]. Pristane, acting differently from the above, is 5 months after intraperitoneal injection of pristane, well after
capable of inducing in mice a wide range of autoantibodies the onset of nephritis, suggesting that this antibody is not re-
specific to or associated with SLE [7–10]. sponsible for the induction of renal disease. These results sug-
Pristane, also known as hydrocarbon oil (2,6,10,14- gest that induction of anti-DNA and anti-chromatin antibodies
tetramethylpentadecane, TMPD), is an isoprenoid alkane. In in mice treated with pristane is strictly dependent on IL-6,
nature, this oil can be found in small amounts in vegetables whereas the induction of anti-RNP/Sm and anti-Su autoanti-
[11], in the liver of some sharks [12], and as a byproduct of bodies is not [21]. Anti-RNP/Sm antibodies are associated with
petroleum distillation [11]. Mice administered pristane into IL-12 production. IL-12−/− mice exposed to PIL do not develop
the abdominal cavity develop an ascitic fluid enriched with anti-RNP antibodies or nephritis [22]. In conjunction with
monoclonal antibodies, local chronic inflammation interleukin-18 (IL-18), IL-12 promotes differentiation of naive
(lipogranulomas), and a rheumatoid-like erosive arthritis T cells into Th1 cells. IL-12 is produced primarily by antigen-
[13], as well as autoantibodies and clinical manifestations presenting cells (APCs), such as macrophages and dendritic
similar to those of SLE [7, 14]. cells. These mice have a relative defect, but are not entirely
The mechanisms by which pristane induces a breakdown in devoid of Th1 responses [23]. In the absence of IL-12, IFN
tolerance and intracellular targets become antigenic remain to production can be induced by IL-18 signaling [24], although
be defined. Pristane is a membrane-activating compound that this process is believed to require the presence of other cyto-
interacts with the phospholipid bilayer. It has a cytotoxic effect kines, such as interleukin-2 (IL-2) [25]. These studies demon-
dependent on concentration and cell lineage, although the strate that the production of autoantibodies can be induced by
mechanism of this cytotoxicity also remains unknown [15]. different cytokine pathways that contribute to pathogenesis.
Apoptosis may explain how autoantigens become available to
the immune system [16]. One study demonstrated that pristane The role of interferon in pristane-induced lupus
induces programmed cell death both in lymphoid cell lines
and in peritoneal exudate cells of mice in vitro and in vivo. IFN is an antiviral cytokine that plays an important role in
This suggests that pristane-induced apoptosis provides a suf- SLE. Interferon type I (IFN-I) is composed of IFN-α and β
ficient autoantigen substrate for immune tolerance to be bro- subunits, which bind to the same receptor (IFNAR). Through
ken, causing an immune disorder linked to overproduction of microarray and quantitative PCR techniques in peripheral
interferon alpha and beta (IFN-α and β), which consequently blood, it was observed that two-thirds of adults and nearly
leads to the development of an autoimmunity similar to SLE all children with SLE exhibit overexpression of IFN-I and
[17]. interferon-stimulated genes (ISGs) [26–28]. Also known as
BIFN signature,^ this phenomenon is closely associated with
Cytokine production disease activity, lupus nephritis, and autoantibody production
[28–31].
The production of inflammatory cytokines plays an important Pristane-treated mice exhibit a robust IFN signature [32].
role in PIL. IFN-α, β and γ, interleukin-6 (IL-6), and The ectopic lymphoid tissue formed in PIL increases the ex-
interleukin-12 (IL-12) stimulate the formation of autoantibodies pression of ISGs [33]. In IFNAR−/− mice, anti-DNA, anti-

Fig. 1 Cytokines that can modify the production of autoantibodies and clinical expression in pristane-induced lupus
Clin Rheumatol

chromatin, anti-RNP, anti-Sm, and anti-Su antibodies are not TLR7, TLR8, and TLR9 by these internalized endogenous
produced and glomerulonephritis is definitely reduced, dem- nucleic acids [49, 50]. Thus, the production of autoantibodies
onstrating that IFN-I plays an important role in the pathogen- against autoantigens containing RNA (U1 snRNP) is a pre-
esis of PIL [18, 34]. Although autoantibody production de- requisite for the production of IFN-I. However, in the PIL
velops around the third or fourth month after induction with model, IFN-I production precedes the appearance of anti-
pristane, IFN-I production is already detectable as early as dsDNA, anti-RNP, or anti-Sm autoantibodies. FcγR−/− ani-
2 weeks after induction [35]. mals are able to produce autoantibodies and IFN, thus exclud-
Dendritic cells are the main source of IFN-I production in ing the role of ICs in initial IFN generation [44, 51].
healthy individuals and in patients with SLE, although their TLR9−/− BALB/c mice injected intraperitoneally with pris-
role may be limited in the PIL model [36]. In PIL, Ly6Chi tane develop more severe autoimmunity than do their TLR-
monocytes are the cell type responsible for IFN-I production. sufficient cohorts. Early indications include an increased ac-
In response to intraperitoneal injection of pristane, these cells cumulation of TLR7-expressing Ly6Chi inflammatory mono-
accumulate in the inflamed peritoneum, where they are trig- cytes at the site of injection, upregulation of ISGs expression
gered to synthesize IFN. Normally absent in the peritoneum, in the peritoneal cavity, and an increased production of mye-
these cells are attracted through CCL2, and represent about loid lineage precursors (common myeloid progenitors and
30% of the peritoneal exudate 2 weeks after pristane injection, granulocyte myeloid precursors) in the bone marrow. These
suggesting that monocytes play an important role in the mice also develop higher autoantibody titers against RNA,
interferonopathy observed in the PIL model [37]. neutrophil cytoplasmic antigens, and myeloperoxidase than
The mechanism for IFN-I overproduction in SLE cells is do pristane-injected wild-type (WT) BALB/c mice, as well
known to utilize various innate receptors in response to as a marked increase in glomerular IgG deposition and infil-
pathogen-associated molecules [38]. The toll-like receptors 7 trating granulocytes, much more severe glomerulonephritis,
(TLR7), 8 (TLR8), and 9 (TLR9) have received considerable and a reduced lifespan. The BALB/c pristane model recapitu-
attention because of their ability to recognize endogenous lates other TLR7-driven spontaneous models of SLE and is
nucleic acids [39–41]. TLR7 and TLR9 are expressed intra- negatively regulated by TLR9 [52].
cellularly in dendritic cells, macrophages, and B cells [42, 43], However, recent research has also suggested that
within an endosomal compartment, and trigger IFN-I secre- opsonization of dead cells by C3 and IgM in PIL is involved
tion via the myeloid differentiating factor 88 (MyD88) protein in the pathogenesis of the IFN signature. The data imply that
signaling pathway. Indeed, experiments with TLR knockout complement receptor-mediated phagocytosis of dead cells op-
mice have revealed that production of IFN-I in PIL occurs via sonized by natural IgM and complement generates IFN-I and
the TLR7-MyD88 pathway [44]. There is no production of other proinflammatory cytokines in PIL. Like C3-deficient
anti-RNP, anti-Sm, and anti-Su antibodies or accumulation of mice, C4-deficient lupus patients do not exhibit an IFN signa-
Ly6Chi monocytes and development of glomerulonephritis in ture. This novel pathway, which likely involves the early clas-
TLR7−/− mice [45]. The Ly6Chi monocytes of the peritoneal sical complement cascade, is essential for the IFN signature in
cavity express high levels of TLR7 and are considered the PIL and also appears to be relevant in human SLE [53].
main source of IFN-I production. TLR8 is not associated with Pristane-primed macrophages from C3-deficient mice did
IFN-I production in humans or in mice, possibly because den- not exhibit impaired cytokine production. In contrast, C1q-
dritic cells and B cells do not express this receptor [46]. deficient pristane-primed resident peritoneal macrophages se-
The activation mechanism of TLR7 in the PIL model is still creted significantly less CCL3, CCL2, CXCL1, and IL-6
undefined. As the chemical structure of pristane is different when stimulated in vitro with a TLR7 ligand. Furthermore,
from that of TLR7 ligands, this compound cannot directly C1q−/− mice developed lower titers of circulating antibodies
activate the receptor [44]. It is possible that pristane increases and milder arthritis compared with controls. These findings
the effects of TLR7 ligands, such as the endogenous U1 RNA demonstrate that C1q deficiency impairs TLR7-dependent
Sm and RNP antigen. Furthermore, when incorporated into chemokine production by pristane-primed peritoneal macro-
the cell membrane, pristane can modify the endosomal site, phages and suggest that C1q, and not C3, is involved in the
providing access to TLR7 [47]. However, neither TLR7 local- handling of pristane by phagocytic cells, which is required to
ization nor phagocytosis is altered by pristane [44]. Pristane trigger disease in this model [54].
also lacks the ability to increase TLR7 expression. Patients with SLE present decreased expression of an
In SLE, an increase in apoptotic and necrotic cells is be- estrogen-regulated microRNA, miR-302d, in their monocytes.
lieved to result in the formation of immunocomplexes (ICs) Its target is the interferon regulatory factor 9 (IRF9), a critical
formed by autoantibodies and autoantigens containing DNA component of the transcriptional complex that regulates the
and RNA [48]. In vitro, the Fcγ receptors (FcγR) of dendritic expression of ISGs. Thus, with reduced miR-302d expression,
cells have been shown to mediate transport of DNA- or RNA- IRF9 levels increase, as does the expression of ISGs. In the
containing ICs into endosomes, allowing the activation of PIL model, transfection of miR-302d has a protective effect
 Clin Rheumatol

against pristane-induced inflammation, suggesting that mod- mutant mice exhibited enhanced autoimmune responses after
ulation of miR-302d levels may be protective in SLE. Thus, pristane treatment [64]. Severe glomerular renal damage, char-
these findings classify miR-302d as a key regulator of IFN-I- acterized by hypercellularity, mesangial expansion, crescent
directed gene expression, underscoring the importance of non- formation, and interstitial mononuclear cell infiltration, was
coding RNA in the regulation of the IFN pathway both in the also observed. In PIL, a lack of caspase-1 does not alter the
PIL model and in patients [55]. recruitment of inflammatory cells into the peritoneal cavity or
In summary, the literature demonstrates that pristane may change the formation of lipogranulomas, which are consid-
mimic human SLE by causing synergistic abnormalities in ered a nidus of chronic inflammatory mediators for disease
interferon production along with defective clearance of apo- development [65]. In caspase-1−/− mice, anti-dsDNA and
ptotic cells and overactive B cell signaling. IFN production is anti-RNP autoantibody production is attenuated, as is
essential for development of the disease. PIL may be a good hypergammaglobulinemia. These mice mount intact immune
model for studying dysregulation of this cytokine. responses, but do not develop an expanded marginal zone B
cell population in response to pristane [66]. This may be one
Lymphoid neogenesis and autoantibody production explanation for reduced autoantibody production in these
mice [66]. Furthermore, levels of circulating inflammatory
The production of autoantibodies is a central event in the cytokines, such as IL-6 and IL-17, were lower in control and
pathogenesis of SLE [56]. BALB/c, SJL/J, and C57BL/6 mice PIL caspase-1−/− mice, suggesting an overall reduced inflam-
injected intraperitoneally with pristane develop SLE-specific matory phenotype [65].
autoantibodies, including anti-dsDNA, anti-ssDNA, anti-Sm, Disease induction and production of autoantibodies in the
anti-RNP, and anti-ribosomal P [7, 14, 57, 58]. Antibody pro- PIL model are independent of exogenous organisms, such as
duction after pristane injection was first described by Satoh viral, bacterial, and parasitic agents. Experiments with
et al. in 1995 [59]. Pristane also causes polyclonal BALB/c mice free of exogenous organisms and treated with
hypergammaglobulinemia, which stimulates the production pristane showed chronic peritoneal inflammation with
of cytokines. Both the production of antinuclear antibodies lipogranuloma formation, cytokine production,
and hypergammaglobulinemia are characteristics of human hepatosplenomegaly, and hypergammaglobulinemia similar
SLE [11], as are the production of antibodies against type II to those observed in conventionally housed animals. This in-
collagen and the presence of rheumatoid factor [60]. dicates that stimulation by exogenous agents is not necessary
In BALB/c mice, a single intraperitoneal injection of 0.5 ml for this inflammatory process to occur [67]. Regarding the
pristane is able to stimulate the production of autoantibodies origin of the autoantibodies, the literature describes that
against the RNA component of U1 small nuclear ribonucleo- BALB/cnu/nu (nude) mice [68] or mice deficient in T cell re-
proteins via TLR7-driven IFN-I production [61]. The in- ceptors (C57BL6 TcRβ−/−, TcRô−/−) [69] do not develop IgG
creased TLR7 expression may contribute to B cell hyperactiv- or IgM anti-snRNP/Sm/Su autoantibodies after administration
ity and autoantibody production in SLE [62]. PIL features an of pristane, but produce rheumatoid factor (IgM), which is
expanded population of B cells with a switched memory-like independent of T lymphocytes [70]. This demonstrates that
phenotype and hyperresponsiveness to synthetic TLR7 li- production of these antibodies occurs through a T cell-
gands and apoptotic cells, probably resulting from increased dependent immune response, similar to that observed in pa-
TLR7 expression due to IFN-I production [63]. Also, a build- tients with SLE [68].
up of dead cells in lupus tissues may help maintain high serum Lipogranulomas are inflammatory lesions resembling ger-
levels of anti-RNP/Sm autoantibodies [63]. Production of Su minal centers that arise in response to the presence of pristane
autoantigens persists in 50–90% of animals 4–6 months after in the peritoneal cavity, and represent an example of lymphoid
injection, and production of anti-dsDNA for even longer, be- neogenesis [33]. This formation of ectopic lymphoid tissue at
tween 6 and 10 months [7, 14]. Titers of anti-Su and anti- sites of inflammation [71] is associated with the production of
snRNP/Sm are present in this model at levels as high as autoantibodies [72]. Ectopic lymphoid tissue resembles sec-
1:25,000–1:250,000 (ELISA). This level of autoantibody pro- ondary lymphoid tissue. It often exhibits B cell, T cell, and
duction resembles that found in spontaneous autoimmune dis- dendritic cell zones. The organization of this tissue occurs
eases [59]. through the presence of CCL19, CCL21, CXCL12, and
Recently, a role for caspase-1 in murine lupus was de- CXCL13 lymphoid chemokines. These lymphoid tissues form
scribed, indicating an involvement of inflammasomes in the when the body cannot clear a pathogen, and are also common
development of SLE. Nlrp3-R258W mice with PIL were ob- in autoimmune diseases [72]. Cytokines produced in ectopic
served to have higher mortality than WT mice following pris- lymphoid tissue may play an important role in the production
tane injection. Furthermore, anti-dsDNA and total IgG levels of autoantibodies [33, 73]. Indeed, lipogranulomas exhibit
were increased in the serum of Nlrp3-R258W mice compared proliferation and interaction of T and B cells [69], and may
with those of WT mice. These data indicate that Nlrp3-R258W be a site of antibody production by B cells.
Clin Rheumatol

Clinical manifestations of pristane-induced autoimmune PIL is one of the few inducible models that can progress to
disease glomerulonephritis. Glomerulonephritis is induced in about
one-third of BALB/c mice following intraperitoneal adminis-
Epidemiological studies suggest that occupational exposure to tration of pristane, a frequency similar to that of nephritis in
mineral oil or petroleum residue is associated with rheumatoid humans with SLE [78]. The inflammatory process in PIL ne-
arthritis (RA) and SLE [74, 75]. Since the first description of phritis is mediated by the interaction between ICs containing
PIL in mice, substantial progress has been made in character- IgG and myeloid effector cells, monocytes/macrophages, with
izing the relevant immunobiological events. In addition to proteinuria beginning 4–6 months after pristane injection [14,
pristane, other compounds such as incomplete Freund’s adju- 79, 80]. Mice deficient of IL-6 [21] and IL-12 [22] are highly
vant (IFA) and squalene (2,6,10,15,19,23-hexamethyl- resistant to induction of renal disease. Monocyte influx also
2,6,10,14,18,22-tetracosahexane) have been reported to in- appears to play an important role in the pathogenesis of lupus
duce lupus-related anti-nRNP/Sm and anti-Su autoantibodies nephritis in humans and mice [81]. Several chemokines in-
in non-autoimmune BALB/c mice. Induction of these autoan- volved in recruitment of monocytes are products of IFN, for
tibodies appeared to be associated with the hydrocarbon’s example, IFN-α and β induce CCL2. The decrease in glomer-
ability to induce IL-12, IL-6, and TNF-alpha, suggesting a ular cell production in response to immune complexes could
relationship with adjuvanticity. Thus, the potential of hydro- modulate the severity of renal disease in IFN-α and β knock-
carbon oils to induce autoimmunity has implications for the out mice.
use of oil adjuvants in basic research [76]. Despite the important role of IFN-I in the development of
Animals subjected to intraperitoneal injection of pristane several clinical manifestations of this model, the anemia pres-
develop clinical manifestations such as arthritis [60], glomer- ent in PIL animals is TNF-α dependent and IFN-I indepen-
ulonephritis with immunoglobulin and complement deposi- dent. The bone marrow of animals administered pristane in-
tion, pulmonary capillaritis, anemia, and autoantibody pro- traperitoneally exhibits high levels of TNF-α, an abnormality
duction (Fig. 2). Many of these manifestations are cytokine- also present in patients with SLE [82].
driven. As in human SLE, they develop primarily in females, Pristane administration to apolipoprotein E (apoE)
at an approximate female-to-male ratio of 9:1 [77]. knockout C57BL/6 mice led to the development of an
Regarding arthritis, BALB/c mice developed synovial hy- experimental model of lupus with atherosclerosis. The an-
perplasia, periostitis, and marginal erosions reminiscent of RA imals presented had poor spirit, less activity, obvious hair
[13, 60]. Arthritis in patients with lupus is generally not ero- loss, splenomegaly, and renomegaly. Also, levels of ANA,
sive, although erosions similar to those of RA may develop in anti-dsDNA, and anti-Sm antibodies were significantly
some cases. The overlapping characteristics of both autoim- higher. The same study also evaluated expression of
mune diseases are known as rhupus. The nature of joint dis- TLRs, and found that pristane induced abnormally high
ease in animals suggests an arthritis similar to that found in expression of TLR2 and TLR4 in the aorta and TLR2,
this syndrome [11]. TLR4, TLR7, and TLR9 in the kidney [83].

Fig. 2 Clinical manifestations in

BALB/c over the trial period
 Clin Rheumatol

Diffuse alveolar hemorrhage (DAH) is not present in mortality from DAH. TLR-activated genes are targeted
the PIL model in BALB/c mice, but occurs, in a manner by IL-10 [91], and pristane induces proinflammatory cy-
similar to that seen in human patients, when this model is tokine production via TLR7 [44]. Unexpectedly,
developed in C57BL/6 and C57BL/10 mice. Although MyD88−/− and TRIF−/− mice developed DAH at a fre-
only 3% of SLE patients develop DAH, this is a signifi- quency similar to that of WT mice [88]. In summary,
cant problem associated with > 50% mortality, and its induction of DAH is independent of TLR,
cause is unknown [84, 85]. In PIL, approximately half inflammasomes, and inducible nitric oxide; its mortality
of animals die during the experiment [79, 86]. These is increased in IL-10-deficient mice; and pristane treat-
animals develop pulmonary capillaritis with a ment decreases IL-10 receptor expression in monocytes
perivascular infiltrate of macrophages, neutrophils, lym- and STAT-3 phosphorylation in lung macrophages [88].
phocytes, and eosinophils and deposition of ICs, with Similar to IFN production in PIL, ischemia-reperfusion
moderate-to-severe alveolar inflammation [79, 86]. After injury in mice is mediated by the early classical comple-
intraperitoneal injection, pristane migrates to the lung, ment cascade and natural IgM. Thus, the pathogenesis of
causing cell death, small-vessel vasculitis, and alveolar DAH involves opsonization of dead cells by natural IgM
hemorrhage similar to that seen in DAH in humans. and complement followed by complement receptor-
Anti-neutrophil cytoplasmic antibodies (ANCAs) are ab- mediated lung inflammation. The disease is macro-
sent [79]. The recruitment of macrophages and neutro- phage-dependent, and IL-10 is protective. It follows that
phils precedes hemorrhage, starting 3 days after pristane complement inhibition and/or macrophage-targeted ther-
injection and peaking at 2 weeks [87]. Furthermore, DAH apies may reduce mortality in lupus-associated DAH.
is independent of MyD88, TLR7, Fcγ receptor, Fas, and
T cells, but immunoglobulin-deficient mice are resistant
[87]. B cell-deficient animals do not develop DAH [87], Relevance of animal models to human SLE
possibly because of the lack of production of immuno-
globulins or other B cell functions. DAH is also absent in Animal models are advantageous when they reproduce all or
C3−/− and CD18−/− mice [88]. Thus, DAH in PIL is me- some clinical features of the disease in humans. Such models
diated by IgM, C3, and CD18, a component of the C3b exist for SLE and have contributed significantly to our under-
receptors CR3 and CR4 [88]. With regard to the under- standing of its pathogenesis.
lying mechanism of DAH, pristane was also detected in SLE in animals may occur spontaneously or be induced.
the lungs of treated C3−/− mice, but not untreated C3−/− Induction of lupus in animals can be accomplished by a vari-
mice, indicating that C3 is not necessary for migration of ety of methods, such as genetic manipulation (expression or
pristane from the peritoneum to lung [88]. As noted ear- suppression), autoimmune serum or lymphocyte-lymphocyte
lier, peritoneal pristane injection also causes bone mar- injection, dendritic cell vaccination with apoptotic debris, im-
row inflammation [82], and pristane was detected in the munization with antigens such as protein complex DNA and
bone marrow of PIL mice, but not in bone marrow of RNA, or by hydrocarbons such as pristane [7, 20]. Unlike
untreated mice, which suggests that the oil was widely other autoimmune and inflammatory experimental models,
dispersed following IP injection. Examination of lung PIL most closely resembles human SLE.
tissue by the terminal deoxynucleotidyl transferase In BALB/c mice, PIL induces mild glomerulonephritis
dUTP nick-end labeling (TUNEL) assay revealed dead [14], arthritis [13, 60], and the production of several autoanti-
cells in pristane-treated mice but not in untreated con- bodies characteristic of SLE, including anti-dsDNA and anti-
trols. Dead cells also accumulate in the bone marrow of Sm [7]. However, in this model, animals are not genetically
PIL mice [82], which suggests that pristane might be prone to developing the disease as are human patients with
cytotoxic. Taken together, these data indicate that pris- SLE. Thus, this model does not provide insight into the ge-
tane migrates from the peritoneum to the lungs and other netic abnormalities involved in SLE. Nevertheless, overpro-
tissues, where it may cause death of certain cell types. duction of IFN-I, which is a core feature of SLE pathogenesis,
Opsonization of these dead cells by IgM and C3 may is present in this model. Moreover, PIL is useful for examining
promote pulmonary inflammation, as also seen in the the role of environmental triggers involved in the disease [7,
peritoneum [53]. Lung interstitial macrophages and epi- 14]. It is possible to assume that the model induction pathways
thelial cells are anti-inflammatory and secrete IL-10. may be relevant for SLE patients [92, 93]. In addition to
Although alveolar macrophages are normally anti-inflam- BALB/c, almost all other strains of mice are susceptible to
matory, when activated via TLRs, IL-10R signal trans- pristane induction to varying extents, with production of au-
duction is inhibited and they become proinflammatory toantibodies and other manifestations similar to those of hu-
[89, 90]. Thus, IL-10 is a crucial regulator of lung in- man SLE [58], corroborating the importance of environmental
flammation. IL-10 −/− mice had significantly increased factors in the pathophysiology of this disease.
Clin Rheumatol

Table 1 Major studies using the pristane-induced lupus model

Author Objective Treatment Summary Main treatment effects

(Reference)

Zhou L To investigate the effect of melatonin on Melatonin Female BALB/c mice (age 2 months) were Delayed production of
et al. environmental-related SLE divided into 6 groups (n = 10 animals anti-ssDNA and histone
2010 per group): normal control, PIL, IgM antibodies;
[98] prednisone 5 mg/kg, melatonin Decreased IL-6 and IL-13;
0.01 mg/kg, melatonin 0.1 mg/kg, and Increased IL-2;
melatonin 1.0 mg/kg; daily intragastric Greater kidney damage
treatment with onset after disease
induction.
Minhas U To investigate the therapeutic effect of Withania Female BALB/c mice (age 3–4 months) Reduction of
et al. Withania somnifera pure root powder somnifera were divided into 6 groups (n = 8 lipogranulomas;
2012 on pristane-induced lupus in BALB/c animals per group): normal control, PIL, Reduction of IL-6 and
[99] mice indomethacin 3 mg/kg treatment, TNF-α levels in serum
Withania somnifera 500 mg/kg, and ascitic fluid;
Withania somnifera 1000 mg/kg, or 2% Inhibitory effect on
gum acacia; daily oral treatment starting proteinuria;
1 month after disease induction. Decreased nephritis;
Decreased inflammatory
markers
Wang Z To evaluate the preventive effects of Resveratrol Female BALB/c mice (age 2–3 months) Inhibitory effect on
et al. resveratrol on pristane-induced lupus were divided into 4 groups (n = 10 proteinuria;
2014 animals per group): normal control, PIL, Significant reduction in
[101] resveratrol 50 mg/kg, and resveratrol glomerular lesions;
75 mg/kg; oral treatment in daily diet Decreased IgG and IgM
starting on day 2 after disease induction. deposition in the kidney
Li M et al. To investigate the potential therapeutic A20 Three months after pristane injection, Decreased
2015 effect of A20 on renal inflammation in female BALB/c mice (age 6–8 weeks) proinflammatory
[102] pristane-induced lupus were randomized into 3 groups and cytokine production;
injected with 1.0 × 109 plaque forming Reduction in anti-dsDNA
units (PFU) of adenovirus-A20, control and anti-nRNP levels in
adenovirus or PBS (100 μl, n = 6–8 per serum;
group) i.p. Inhibition of lupus-related
renal injury
Bender A To determine the therapeutic efficacy of M7583 (Btk Starting 2 months after pristane injection, Reduction in clinical signs
et al. Btk inhibition in two mouse lupus inhibitor) female DBA/1 mice (age 11–12 weeks) of arthritis;
2016 models driven by TLR7 activation and were fed chow formulated with Reduction of anti-dsDNA,
[104] type I interferon M7583 at a concentration of 25 mg anti-histone, and
compound/kg chow. anti-Ro/SSA, but not
anti-Sm/RNP antibody
levels
He Y et al. To investigate the potential therapeutic Methyl salicylate Female BALB/c mice (age 7–8 weeks), Reduction in DNA
2016 effect of MSL in SLE and explore the 2-O-β-d-lactos- 45 days after PIL induction, were autoantibody titers;
[106] underlying mechanisms ide (MSL) randomly divided into 5 groups: PIL, Total IgG concentrations in
low-dose MSL (200 mg/kg), lupus mice were
medium-dose MSL (400 mg/kg), significantly lower at
high-dose MSL (800 mg/kg), or months 4–6;
prednisone 5 mg/kg; doses were Reduction in IL-6 levels on
administered orally once daily. day 60 after induction;
On day 180, IL-17A levels
were not significantly
reduced.
Lin Y et al. To investigate the effects of SAA in Salvianolic acid A 60 female BALB/c mice were randomly Reduction in anti-Sm
2017 pristane-induced lupus in BALB/c mice (SAA) divided into five equal groups: control, autoantibody titers;
[107] model, SAA, prednisone, or aspirin Inhibition of IKK, IκB, and
(n = 12 per group). Mice in the control NFκB phosphorylation
and model groups were given saline in renal tissue
each day by gavage, while mice in the
SAA, prednisone and aspirin groups
were administered SAA (5 mg/kg/d),
prednisone (5 mg/kg/d) or aspirin
 Clin Rheumatol

Table 1 (continued)

Author Objective Treatment Summary Main treatment effects

(Reference)

(300 mg/kg/d) by gavage, respectively.

Treatment began 1 month after pristane
injection.
Mihaylova To examine the possibility of suppressing Anti-ANX A1 Female BALB/c mice (age 8 weeks) were Decreased expression of T
N et al. autoreactive B and T cells with a randomized into 3 groups (n = 10 each). cell activation markers;
2017 monoclonal antibody against ANX A1 Pristane-injected mice were immunized Decreased number of
[109] in murine pristane-induced lupus every 6 days with 200 ng/mouse of anti-dsDNA IgG
anti-ANX A1 antibody i.p., while the antibody-secreting
control group of pristane-injected plasma cells;
animals was treated with PBS. Attenuated lupus
symptoms in
pristane-injected mice

Treatments in pristane-induced lupus with resveratrol treatment included decreased proteinuria, im-
munoglobulin deposition in the kidney, glomerulonephritis,
Animal models have been used not only to improve knowl- and serum levels of IgG1 and IgG2a treatment. At the end
edge of the mechanisms involved in SLE, but also to test of the experiment period, IFN-α levels in mice in the resver-
potential therapies. In addition to assessing possible therapeu- atrol groups were lower than those of control mice, but the
tic targets, animal models are indispensable before clinical difference was not statistically significant. This suggests that
trials. The following section summarizes the main therapeutic resveratrol has protective effects in murine PIL and may rep-
studies performed with the PIL model (Table 1). Most of these resent a novel approach for the treatment of SLE [97].
treatments are preventive. Considering the development of new therapies for the con-
Researchers tested the regulatory effect of melatonin at trol of systemic inflammation in patients with SLE, treatment
concentrations of 0.01, 0.1, and 1.0 mg/kg/daily for 6 months with A20 has been proposed [98]. A20, also known as tumor
via intragastric administration. Melatonin slowed the increase necrosis factor alpha-induced protein 3 (TNFAIP3), is an anti-
in anti-ssDNA and histone IgM antibody levels, decreased IL- inflammatory factor induced by TNF [99]. A20 overexpres-
6 and IL-13, and increased IL-2 production in the splenocyte sion significantly mitigated pristane-induced systemic inflam-
supernatant of pristane-treated mice. In addition, melatonin mation and renal injury in mice. The therapeutic effect of A20
decreased the renal damage caused by pristane. These results may be associated with inhibition of the NLRP3
suggest that melatonin has a beneficial effect on PIL through inflammasome and NFκB activation in macrophages.
cytokine regulation [94]. Because of this dual inhibitory effect, A20 may be a promising
In 2012, the therapeutic effect of the herb Withania new candidate for the treatment of SLE [98].
somnifera in PIL was tested. Treatment with root powder at Likewise, Bender et al. found that Bruton’s tyrosine kinase
concentrations of 500 and 1000 mg/kg was administered oral- (Btk) inhibition treats TLR7/IFN-driven murine lupus [100].
ly once daily, starting 1 month after disease induction. Btk is expressed in a variety of immune cells, and previous
Animals treated with the 1000 mg/kg concentration exhibited work has demonstrated that blocking this protein is a promis-
reduced lipogranuloma formation compared to the untreated ing strategy for treating autoimmune diseases. In PIL, Btk
disease group. Furthermore, treatment was associated with a inhibition suppressed arthritis, but neither autoantibodies nor
reduction in IL-6 and TNF-α levels in both serum and ascitic the IFN gene signature was significantly affected, suggesting
fluid, and was shown to have a potent inhibitory effect on efficacy was mediated through inhibition of Fc receptors
proteinuria, nephritis, and inflammatory markers. However, [100].
the production of autoantibodies in serum appeared to be un- Methyl salicylate 2-O-β-d-lactoside (MSL) is a novel
changed in both groups treated with W. somnifera, demon- salicylic acid analogue, extracted from the traditional
strating the same pattern of nuclear fluorescence [95]. Chinese herbal medicine Gaultheria yunnanensis that has
Resveratrol (3,5,4-trihydroxystilbene) is a natural antimi- been widely used for treatment of swelling and various in-
crobial compound found in various plants and fruits [96]. It flammatory responses in the southern regions of the People’s
has anti-inflammatory and immunoregulatory properties and Republic of China [101]. In PIL, MSL was found to antago-
was recently tested in the PIL model. In this study, resveratrol nize the increasing levels of antibodies and cytokines, sup-
was added to the animals’ diet at concentrations of 50 and pressing joint swelling, and having an inhibitory effect on
75 mg/kg and administered for 7 months. The results obtained arthritis-like symptoms. It also significantly decreased the
Clin Rheumatol

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Financial support Funding for this study was provided by the
tosus. Curr Opin Rheumatol 15:557–562
Research and Event Incentive Fund (FIPE-HCPA).
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Compliance with ethical standards induced lupus. J Immunol 175:4777–4782
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Disclosure None. Deficiency of the type I interferon receptor protects mice from
experimental lupus. Arthritis Rheum 56:3770–3783. https://doi.
org/10.1002/art.23023
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