Type I Interferon Production by Tertiary Lymphoid Tissue Developing in Response to 2,6,10,14-Tetramethyl-Pentadecane (Pristane)

Abstract

Lymphoid neogenesis is associated with antibody-mediated autoimmune diseases such as Sjogren's syndrome and rheumatoid arthritis. Although systemic lupus erythematosus is the prototypical B-cell-mediated autoimmune disease, the role of lymphoid neogenesis in its pathogenesis is unknown. Intraperitoneal injection of 2,6,10,14-tetramethyl-pentadecane (TMPD, pristane) or mineral oil causes lipogranuloma formation in mice, but only TMPD-treated mice develop lupus. We report that lipogranulomas are a form of lymphoid neogenesis. Immunoperoxidase staining of lipogranulomas revealed B cells, CD4(+) T cells, and dendritic cells and in some cases organization into T- and B-cell zones. Lipogranulomas also expressed the lymphoid chemokines CCL21, CCL19, CXCL13, CXCL12, and CCL22. Expression of the type I interferon (IFN-I)-inducible genes Mx1, IRF7, IP-10, and ISG-15 was greatly increased in TMPD- versus mineral oil-induced lipogranulomas. Dendritic cells from TMPD lipogranulomas underwent activation/maturation with high CD86 and interleukin-12 expression. Magnetic bead depletion of dendritic cells markedly diminished IFN-inducible gene (Mx1) expression. We conclude that TMPD-induced lupus is associated with the formation of ectopic lymphoid tissue containing activated dendritic cells producing IFN-I and interleukin-12. In view of the increased IFN-I production in systemic lupus erythematosus, these studies suggest that IFN-I from ectopic lymphoid tissue could play a role in the pathogenesis of experimental lupus in mice.

Vaccination-Induced Systemic Autoimmunity in Farmed Atlantic Salmon

“…6Aa), as reported previously (7,9) and similar to changes described in mice treated ip with adjuvant oil (26). Isolated granulomas were also seen in liver (Fig.…”

“…The i.p. vaccination in salmon induces chronic granulomatous inflammation similar to the peritoneal granuloma of rodents with adjuvant-oil induced lupus (26). Lymphoid neogenesis in affected tissues of various human autoimmune diseases, such as synovium in rheumatoid arthritis, thyroid gland in chronic thyroiditis, and salivary gland in Sjögren's syndrome, has been well described (47).…”

“…A mouse model of lupus induced by an i.p. injection of the adjuvant oil pristane is I-IFN dependent (26). Microbial constituents in vaccines may also play a role in I-IFN induction via TLR stimulation (32).…”

Dysfunctional CD4+,CD25+ regulatory T cells in untreated active systemic lupus erythematosus secondary to interferon‐α–producing antigen‐presenting cells

“…Blanco et al (32) showed that up to 60% of IFN␣ production in the peripheral blood of lupus patients may come from cells other than plasmacytoid DCs. Myeloid DCs and monocyte-derived DCs could serve as alternative IFN␣-producing cells, as hinted at by studies in a mouse model 810 YAN ET AL of pristane-induced lupus (33). In the present study, the term of "IFN␣-producing APCs" was used to represent such cell populations.…”

Scientific Opinion on Mineral Oil Hydrocarbons in Food

“…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.…”