Distinctive Patterns of Autoimmune Response Induced by Different Types of Mineral Oil

Kuroda, Yoshiki; Akaogi, Jun; Nacionales, Dina C.; Wasdo, Scott; Szabo, Nancy J.; Reeves, Westley H.; Satoh, Minoru

doi:10.1093/toxsci/kfh063

Cited by 54 publications

(42 citation statements)

References 34 publications

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“…Little IgG1 was seen in any of the mice. This latter finding parallels the frequent paucity of this isotype in the autoantibodies of many (but not all) SLE models (48). Normally, IgG1 is the most prominent T-dependent IgG subclass against soluble protein Ags, although viruses and bacteria can provoke T-dependent, IgG2a-skewed responses (40,41).…”

Section: Discussionmentioning

confidence: 67%

T Cell-Independent Spontaneous Loss of Tolerance by Anti-Double-Stranded DNA B Cells in C57BL/6 Mice

Tsao

Jiao

et al. 2008

The Journal of Immunology

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Systemic lupus erythematosus is characterized by loss of tolerance to DNA and other nuclear Ags. To understand the role of T cells in the breaking of tolerance, an anti-DNA site-specific transgenic model of spontaneous lupus, B6.56R, was studied. T cells were eliminated by crossing B6.56R with CD4−/− or TCRβ−/−δ−/− mice, and the effects on anti-dsDNA serum levels, numbers of anti-dsDNA Ab-secreting cells, and isotypes of anti-dsDNA were analyzed. In addition, the development and activation of B cells in these mice were examined. Surprisingly, the presence of T cells made little difference in the development and character of the serum anti-dsDNA Ab in B6.56R mice. At 1 mo of age, anti-dsDNA Abs were somewhat lower in mice deficient in αβ and γδ T cells. Levels of Abs later were not affected by T cells, nor was autoantibody class switching. B cell activation was somewhat diminished in T cell-deficient mice. Thus, in the B6 background, the presence of an anti-dsDNA transgene led the production of autoantibodies with a specificity and isotype characteristic of murine systemic lupus erythematosus with little influence from T cells. TLR9 also did not appear to play a role. Although we do not yet understand the mechanism of this failure of immunoregulation, these results suggest that similar processes may influence autoimmunity associated with clinical disease.

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Section: Discussionmentioning

confidence: 67%

T Cell-Independent Spontaneous Loss of Tolerance by Anti-Double-Stranded DNA B Cells in C57BL/6 Mice

Tsao

Jiao

et al. 2008

The Journal of Immunology

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“…Under the same experimental conditions, a number of mineral oils acted as adjuvants by promoting elevated concentrations of autoantibodies. While injection of 0.5 ml n-hexadecane, squalene or incomplete Freund's adjuvant induced autoantibody responses to nuclear antigens in female Balb/c mice, medicinal mineral oils (MO-HT, MO-S (C 20 -C 40 ), MO-F (C 15 -C 40 )) induced lipogranulomas, but only selected anti-nuclear autoantibodies and no clinical manifestations (Satoh, 2003;Kuroda et al, 2004, Nacionales et al, 2006.…”

Section: Animal Experimentsmentioning

confidence: 99%

Scientific Opinion on Mineral Oil Hydrocarbons in Food

2012

EFS2

107

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Consumers are exposed to a range of mineral oil hydrocarbons (MOH) via food. Mineral oil saturated hydrocarbons (MOSH) consist of linear and branched alkanes, and alkyl-substituted cyclo-alkanes, whilst mineral oil aromatic hydrocarbons (MOAH) include mainly alkyl-substituted polyaromatic hydrocarbons. Products, commonly specified according to their physico-chemical properties, may differ in chemical composition depending on the oil source. Technical grade MOH contain 15 -35 % MOAH, which is minimised in food grade MOSH (white oils). Major sources of MOH in food are food packaging and additives, processing aids, and lubricants. Estimated MOSH exposure ranged from 0.03 to 0.3 mg/kg b.w. per day, with higher exposure in children. Specific production practices of bread and grains may provide additional MOSH exposure. Except for white oils, exposure to MOAH is about 20 % of that of MOSH. Absorption of alkanes with carbon number above C 35 is negligible. Branched and cyclic alkanes are less efficiently oxidised than n-alkanes. MOSH from C 16 to C 35 may accumulate and cause microgranulomas in several tissues including lymph nodes, spleen and liver. Hepatic microgranulomas associated with inflammation in Fischer 344 rats were considered the critical effect. The no-observed-adverse-effect level for induction of liver microgranulomas by the most potent MOSH, 19 mg/kg b.w. per day, was used as a Reference Point for calculating margins of exposure (MOEs) for background MOSH exposure. MOEs ranged from 59 to 680. Hence, background exposure to MOSH via food in 1 On request from the European Commission, Question No EFSA-Q-2010-00170, adopted on 3 May 2012. 2 SUMMARYFollowing a request from the European Commission, the EFSA Panel on Contaminants in the Food Chain (CONTAM Panel) was asked to deliver a scientific opinion on mineral oil hydrocarbons (MOH) in Food. Mineral oil hydrocarbons occur in food both as a result of contamination and from various intentional uses in food production. In order to assess the need for possible regulatory measures as regards MOH in food, EFSA was requested to assess the risks related to their occurrence in food. More specifically, the opinion should evaluate whether new toxicity data are available and whether the current acceptable daily intakes (ADIs) are still applicable, explore whether certain classes (or subclasses) of MOH are more relevant due to their toxicity or to differences in the way they are metabolised by the human body, and identify the different background sources, other than from adulteration or misuse, of MOH occurrence in food. In addition a dietary exposure assessment was requested for the general population and for specific subgroups of the population (e.g. infants, children and people following specific diets), by taking into account the background occurrence of MOH in food. Included in the request was also to advise on MOH and food classes to be included if monitoring were to be set up for their presence in food.The scientific literature and other sources were s...

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“…In the TMPD model, 60 -70% of treated BALB/c mice exhibit anti-Sm/RNP Abs after 4 -6 mo vs 0% of IFNAR Ϫ/Ϫ mice (9). These autoantibodies either appear less frequently or are completely absent in mice treated with other adjuvant oils such as n-hexadecane, squalene, or mineral oil (23). Interestingly, treatment with n-hexadecane (which induces antiSm/RNP in ϳ25% of treated animals) elicited the accumulation of Ly6C high monocytes, albeit the response was milder than with TMPD, whereas squalene (which induces a weak anti-Sm/RNP response in Ͻ10% of treated animals) recruited mostly mature monocytes/macrophages and few Ly6C high monocytes, resembling the pattern seen with mineral oil (Fig.…”

Section: Accumulation Of Ly6c High Monocytes Is Associated With Autoamentioning

confidence: 99%

A Novel Type I IFN-Producing Cell Subset in Murine Lupus

Lee

Weinstein

Nacionales

et al. 2008

The Journal of Immunology

110

139

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Excess type I IFNs (IFN-I) have been linked to the pathogenesis of systemic lupus erythematosus (SLE). Therapeutic use of IFN-I can trigger the onset of SLE and most lupus patients display up-regulation of a group of IFN-stimulated genes (ISGs). Although this “IFN signature” has been linked with disease activity, kidney involvement, and autoantibody production, the source of IFN-I production in SLE remains unclear. 2,6,10,14-Tetramethylpentadecane-induced lupus is at present the only model of SLE associated with excess IFN-I production and ISG expression. In this study, we demonstrate that tetramethylpentadecane treatment induces an accumulation of immature Ly6Chigh monocytes, which are a major source of IFN-I in this lupus model. Importantly, they were distinct from IFN-producing dendritic cells (DCs). The expression of IFN-I and ISGs was rapidly abolished by monocyte depletion whereas systemic ablation of DCs had little effect. In addition, there was a striking correlation between the numbers of Ly6Chigh monocytes and the production of lupus autoantibodies. Therefore, immature monocytes rather than DCs appear to be the primary source of IFN-I in this model of IFN-I-dependent lupus.

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Distinctive Patterns of Autoimmune Response Induced by Different Types of Mineral Oil

Cited by 54 publications

References 34 publications

T Cell-Independent Spontaneous Loss of Tolerance by Anti-Double-Stranded DNA B Cells in C57BL/6 Mice

T Cell-Independent Spontaneous Loss of Tolerance by Anti-Double-Stranded DNA B Cells in C57BL/6 Mice

Scientific Opinion on Mineral Oil Hydrocarbons in Food

A Novel Type I IFN-Producing Cell Subset in Murine Lupus

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