Trends in Immunology
Volume 30, Issue 9, September 2009, Pages 455-464
Journal home page for Trends in Immunology

Review
Autoimmunity and the environment
Induction of autoimmunity by pristane and other naturally occurring hydrocarbons

https://doi.org/10.1016/j.it.2009.06.003Get rights and content

Tetramethylpentadecane (TMPD, or commonly known as pristane)-induced lupus is a murine model of systemic lupus erythematosus (SLE). Renal disease and autoantibody production strictly depend on signaling through the interferon (IFN)-I receptor. The major source of IFN-I is immature monocytes bearing high levels of the surface marker Ly6C. Interferon production is mediated exclusively by signaling through TLR7 and the adapter protein MyD88. It is likely that endogenous TLR7 ligands such as components of small nuclear ribonucleoprotein complexes are involved in triggering disease. Lupus autoantibodies are produced in ectopic lymphoid tissue developing in response to TMPD. This model is well suited for examining links between dysregulated IFN-I production and the pathogenesis of human SLE, which like TMPD-lupus, is associated with high levels of IFN-I.

Section snippets

The immunological effects of TMPD (pristane]

The naturally occurring hydrocarbon oil TMPD (2,6,10,14-tetramethylpentadecane), more commonly known as pristane, induces chronic inflammation when introduced into the peritoneal cavity. Over the past 15 years, it has been found that the inflammatory response to TMPD causes a lupus-like disease in mice. The mechanisms involved in TMPD-lupus are coming into clearer focus and may be highly relevant to human systemic lupus erythematosus (SLE), an immune disorder increasingly linked to the

Autoantibodies in TMPD-treated mice

Consistent with the evidence that exposure to adjuvant hydrocarbons may provoke inflammatory or autoimmune responses in humans, BALB/c mice injected intraperitoneally (i.p.) with TMPD develop a local inflammatory response (lipogranulomas) and an erosive arthritis resembling rheumatoid arthritis (RA) [18] and TMPD was subsequently found to induce autoantibodies and the clinical manifestations of SLE [19].

Susceptibility to TMPD-lupus among non-autoimmune prone mice is widespread [20]. The

Autoimmune disease in TMPD-treated mice

TMPD treated mice develop clinical manifestations of lupus, including arthritis, immune complex-mediated glomerulonephritis, and pulmonary capillaritis as well as autoantibodies. Inflammation of the pericardium and pleura also occurs, but it is unclear whether this is autoimmune in origin. SLE is a human syndrome classified using a set of 11 criteria and TMPD-treated mice meet these criteria (Table 2). As in TMPD lupus [36], human SLE is primarily a disease of females (female: male ratio ∼9:1).

The role of Type I interferon (IFN-I) in SLE

IFN-I is increasingly recognized as a key mediator of SLE. The IFN-I family includes multiple IFNα subtypes and IFNβ, all binding the same IFNAR (receptor) complex [49]. Initially described for its anti-viral effects, IFN-I links innate and adaptive immunity. Details of IFN-I biology and functions have been reviewed [49] and will not be discussed further. Elevated serum IFN-I was noted in SLE patients 30 years ago [50] and interest in the antiviral cytokine family has revived with recognition

Association of lymphoid neogenesis with autoimmunity

Although originally termed “lipogranulomas”, the inflammatory lesions arising in response to the presence of TMPD within the peritoneal cavity actually represent a striking example of lymphoid neogenesis [60]. Lymphoid neogenesis, the formation of ectopic lymphoid tissue at sites of inflammation [81], is strongly associated with autoantibody production [82]. Ectopic lymphoid tissue closely resembles secondary lymphoid tissue and arises by a similar developmental pathway. It frequently exhibits

Summary and conclusions

TMPD-lupus is a model of SLE associated with IFN-I dysregulation. The pathogenesis of lupus autoantibodies and glomerulonephritis in this model strictly requires IFNAR signaling. Most of the IFN-I is produced by immature monocytes instead of PDCs, and its production is mediated exclusively by the TLR7-MyD88 pathway. It is likely that endogenous TLR7 ligands such as U1RNA are involved, as germ-free mice are susceptible to disease induction. However, immune complex uptake via Fc receptors is

Acknowledgements

This work was supported by research grants AR44731 and AR51766 from the US Public Health Service and by the Lupus Foundation of America. P.Y.L and J.S.W are NIH T32 trainees (DK07518 and AR007603).

Glossary

ANA
antinuclear antibodies
AFC
antibody forming cell
dsDNA
double-stranded DNA
FcγR
Fcγ receptor
IFN
interferon
IFN-I
type-I interferons
IFNAR
Interferon alpha/beta receptor
i.p.
intraperitoneal
IPS-1
interferon-β promoter stimulator-1
ISG
Interferon stimulated gene
MCP
monocyte chemoattractant protein
MyD88
myeloid differentiation factor 88
NZB/W
(New Zealand Black X New Zealand White) F1 hybrid mice
NP-KLH
4-hydroxy-3-nitrophenyl acetyl-conjugated keyhole limpet hemocyanin
OVA
ovalbumin
PECs
peritoneal exudate cells
PDCs

References (93)

  • H. Zhuang

    Association of anti-nucleoprotein autoantibodies with upregulation of Type I interferon-inducible gene transcripts and dendritic cell maturation in systemic lupus erythematosus

    Clin. Immunol.

    (2005)
  • J. Banchereau et al.

    Type I interferon in systemic lupus erythematosus and other autoimmune diseases

    Immunity

    (2006)
  • D.C. Nacionales

    Type I interferon production by tertiary lymphoid tissue developing in response to 2,6,10,14 tetramethylpentadecane (pristane)

    Am. J. Pathol

    (2006)
  • E. Savarese

    U1 small nuclear ribonucleoprotein immune complexes induce type I interferon in plasmacytoid dendritic cells through TLR7

    Blood

    (2006)
  • A.C. Horsfall

    Autoantibody synthesis in salivary glands of Sjogren's syndrome patients

    J. Autoimmun.

    (1989)
  • G. Jego

    Plasmacytoid dendritic cells induce plasma cell differentiation through type I interferon and interleukin 6

    Immunity

    (2003)
  • K. Grob

    Mineral oil material in canned foods

    Food Additives & Contaminants

    (1997)
  • L. Castle

    Migration of mineral hydrocarbons into foods. 4. Waxed paper for packaging dry goods including bread, confectionary and for domestic use including microwave cooking

    Food Additives and Contaminants

    (1994)
  • I.R. Wanless et al.

    Mineral oil lipogranulomata in liver and spleen: a study of 465 autopsies

    Arch. Pathol. Lab. Med.

    (1985)
  • M. Potter et al.

    Induction of plasma-cell neoplasms in strain BALB/c mice with mineral oil and mineral oil adjuvants

    Nature (Lond.)

    (1962)
  • P.N. Anderson et al.

    Induction of plasma cell tumours in BALB/c mice with 2,6,10,14-tetramethylpentadecane (pristane)

    Nature (Lond.)

    (1969)
  • M. Potter et al.

    Plasmacytomagenesis in mice: model of neoplastic development dependent upon chromosomal translocations

    Carcinogenesis

    (1992)
  • M.W. Whitehouse

    Freund's adjuvants: relationship of arthritogenicity and adjuvanticity in rats to vehicle composition

    Immunology

    (1974)
  • M. Valentino

    Hand injuries due to high-pressure injection devices for painting in shipyards: circumstances, management, and outcome in twelve patients

    Am. J. Ind. Med.

    (2003)
  • A. Spickard

    Exogenous lipoid pneumonia

    Arch. Intern. Med.

    (1994)
  • H.P. Dincsoy

    Lipogranulomas in non-fatty human livers: a mineral oil induced environmental disease

    Am. J. Clin. Pathol.

    (1982)
  • B. Sverdrup

    Association between occupational exposure to mineral oil and rheumatoid arthritis: results from the Swedish EIRA case-control study

    Arthritis Res. Ther.

    (2005)
  • J. Dahlgren

    Cluster of systemic lupus erythematosus (SLE) associated with an oil field waste site: a cross sectional study

    Environ. Health

    (2007)
  • E.O. Koppang

    Vaccination-induced systemic autoimmunity in farmed Atlantic salmon

    J. Immunol.

    (2008)
  • M. Potter et al.

    Genetics of susceptibility to pristane-induced plasmacytomas in BALB/cAn: Reduced susceptibility in BALB/cJ with a brief description of pristane-induced arthritis

    J. Immunol.

    (1981)
  • M. Satoh et al.

    Induction of lupus-associated autoantibodies in BALB/c mice by intraperitoneal injection of pristane

    J. Exp. Med.

    (1994)
  • M. Satoh

    Widespread susceptibility among inbred mouse strains to the induction of lupus autoantibodies by pristane

    Clin. Exp. Immunol.

    (2000)
  • P.H. Wooley

    Pristane-induced arthritis. The immunologic and genetic features of an experimental murine model of autoimmune disease

    Arthritis Rheum.

    (1989)
  • M. Satoh

    Antinuclear antibody production and immune complex glomerulonephritis in BALB/c mice treated with pristane

    Proc. Natl. Acad. Sci. USA

    (1995)
  • Y. Kuroda

    Distinctive patterns of autoimmune response induced by different types of mineral oil

    Toxicol. Sci.

    (2004)
  • J. Craft

    Tolerance to self antigens in normal and lupus mice: the role of autoantigen specific B and T cell responses in autoantibody production

    Rheumatology in Europe Supplement

    (1995)
  • A. Jakymiw

    Autoimmune targeting of key components of RNA interference

    Arthritis Res. Ther.

    (2006)
  • H.B. Richards

    Disparate T cell requirements of two subsets of lupus-specific autoantibodies in pristane-treated mice

    Clin. Exp. Immunol.

    (1999)
  • Nacionales, D.C. et al. (2009) B cell proliferation, somatic hypermutation, and class switching in ectopic lymphoid...
  • N.G. Levitt

    Pristane induced arthritis in mice. IV. Immunotherapy with monoclonal antibodies directed against lymphocyte subsets

    J. Rheumatol

    (1992)
  • H.B. Richards

    IL–6 dependence of anti-DNA antibody production: evidence for two pathways of autoantibody formation in pristane-induced lupus

    J. Exp. Med

    (1998)
  • D.C. Nacionales

    Deficiency of the Type I interferon receptor protects mice from experimental lupus

    Arthritis Rheum.

    (2007)
  • Y. Mitani

    Cross talk of the interferon-alpha/beta signalling complex with gp130 for effective interleukin-6 signalling

    Genes Cells

    (2001)
  • D.E. Levy

    Synergistic interaction between interferon-alpha and interferon-gamma through induced synthesis of one subunit of the transcription factor ISGF3

    EMBO J

    (1990)
  • J.T. Beech et al.

    Anti-tumour necrosis factor therapy ameliorates joint disease in a chronic model of inflammatory arthritis

    Br. J. Rheumatol.

    (1997)
  • M. Satoh

    Autoantibodies to ribosomal P antigens with immune complex glomerulonephritis in SJL mice treated with pristane

    J. Immunol.

    (1996)
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