Induction of autoimmunity by pristane and other naturally occurring hydrocarbons

Abstract

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.

Figure 1. Pathological and immunological abnormalities induced by TMPD

A. Chemical structure of 2,6,10,14-tetramethylpentadecane (TMPD, C₁₉H₄₀) more commonly known as pristane. Numbers indicate carbon molecules. B. Gross pathology (left, arrows indicate individual lipogranulomas) and microscopic pathology (formalin fixation, hematoxylin & eosin staining, right) of ectopic lymphoid tissue in a mouse given an intraperitoneal injection of TMPD. Low power (200x) shows numerous oil droplets and clusters of infiltrating lymphocytes and plasma cells (indicated by arrows, inset, 400x). C. Microscopic pathology of the lung of a patient with exogenous lipoid pneumonia due to the aspiration of mineral oil. Left, formalin-fixed tissue with hematoxylin & eosin staining; Right, unfixed tissue with oil red staining. Note the presence of lymphocytic infiltrates closely resembling those in TMPD treated mice (arrows) and the numerous oil droplets (left), which in unfixed tissue stain intensely with oil red. D. Structure of the U1 snRNP, an autoantigen containing immunostimulatory RNA. The U1 snRNP consists of a single molecule of U1 small nuclear RNA. Anti-RNP and anti-Sm antibodies recognize different subsets of the proteins bound to this RNA. Anti-RNP antibodies bind to proteins U1-A, U1−70K, and U1-C, whereas anti-Sm antibodies bind to the Sm B’, B, D1, D2, D3, E, F, and G proteins. The purified U1 RNA is a ligand for TLR7, capable of associating with TLR7 inside of endosomes and stimulating the production of the Type I interferons IFNα and IFNß.

Figure 2. Pathogenesis of autoimmunity in TMPD-treated mice

A. TMPD stimulates IFNα and IFNß production by immature (Ly6C^hi) monocytes. The IFN-I inducible chemokine MCP-1 (CCL2) is produced following intraperitoneal injection of TMPD and promotes the egress of immature monocytes bearing the markers CD11b, Ly6C^hi, Mac-3, F4/80, and CCR2 (the receptor for MCP-1) from the bone marrow. These cells enter the circulation and are recruited to the inflamed peritoneal cavity. In mice treated with TMPD, the Ly6C^hi monocytes down-that forms in response to the hydrocarbon. These cells persist for ∼3 days before undergoing programmed cell death (apoptosis). In mineral oil treated mice, the Ly6C^hi monocytes rapidly mature in the peritoneum to CD11b⁺, Ly6C⁻, Mac-3⁺, F4/80⁺ cells with numerous endocytic vacuoles. In contrast to TMPD elicited monocytes, these cells do not produce IFNα or ß. B. IFN-I and pro-inflammatory cytokine production can be stimulated through four main cellular pathways employing different adaptor proteins or signaling intermediates: i.e. via TRIF (TLRs 3 and 4), MyD88 (TLRs 7, 8, and 9), IPS-1 (Rig-I like helicases, RLH)), and TBK1 (receptor not yet clearly defined). The endosomal recognition of unmethylated CpG motifs in DNA by TLR9 or of single stranded RNA by TLR7 or TLR8 leads to the activation of IFNα and ß gene expression via a pathway involving the adapter protein MyD88, several kinases (not shown), and the transcription factor interferon regulatory factor (IRF) 7. In contrast, the endosomal recognition of dsRNA by TLR3 or cell surface recognition of lipopolysaccharide (endotoxin) by TLR4 leads to IFNα and ß gene expression via a pathway involving the adapter protein TRIF, kinases, and the transcription factor IRF-3. In addition to the endosomal pathways, the recognition of cytoplasmic (viral) dsRNA by the RLH Rig-I or Mda5 leads to the activation of IFNα and ß gene expression via the adapter protein IPS-1 and the transcription factors IRF3 and IRF7. Cytoplasmic DNA is detected by receptors that remain to be fully elucidated and signal via the kinase TBK-1, resulting in IFNα and ß gene expression. All these pathways converge on nuclear factor kappa B (NFκB). The induction of IFNα and ß by TMPD relies exclusively on the TLR7-MyD88-IRF7 pathway, whereas the other three pathways are dispensable.