RESUMO
OBJECTIVE: This study examined the interactions between exogenous and endogenous factors shaping the phenotype of lupus in autoimmune (NZB x NZW)F(1) mice exposed to pristane, a model environmental trigger. METHODS: Frequencies of various autoantibodies in untreated NZB/NZW mice were determined by various means (immunoprecipitation, enzyme-linked immunosorbent assay [ELISA], Crithidia luciliae kinetoplast staining). Pristane or saline was administered intraperitoneally to 9-12-week-old NZB/NZW mice, followed by serial studies of autoantibodies, total Ig levels (ELISA), and proteinuria (dipstick). RESULTS: Besides antichromatin/DNA responses, NZB/NZW mice spontaneously produced novel autoantibodies against the double-stranded RNA binding protein RNA helicase A (RHA). In contrast, NZB/NZW mice (n = 70) did not produce autoantibodies against the nuclear RNP (nRNP), Sm, Ro, or La antigens. Pristane exposure synergistically activated the production of antichromatin/DNA antibodies and dramatically accelerated renal disease. Production of anti-nRNP/Sm and Su autoantibodies also was induced, indicating that the unresponsiveness of NZB/NZW mice to these antigens can be overcome. Curiously, pristane treatment did not enhance the production of anti-RHA, suggesting that these autoantibodies are regulated differently than anti-DNA/chromatin and Sm. In contrast to previous reports that suggest a critical role of deficient interleukin-12 (IL-12) production in the pathogenesis of lupus, there was overproduction of IL-12 in the peritoneal cavity of pristane-treated NZB/NZW mice, and their spleen cells also produced large amounts of IL-12. CONCLUSION: These data lead us to propose that environmental influences exacerbate autoimmune manifestations in genetically lupus-susceptible mice through their stimulatory effects on proinflammatory cytokines, such as IL-12.
Assuntos
Predisposição Genética para Doença , Imunossupressores/toxicidade , Nefrite Lúpica/etiologia , Terpenos/toxicidade , Animais , Anticorpos Antinucleares/análise , Líquido Ascítico/citologia , Líquido Ascítico/metabolismo , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Imunoglobulina G/análise , Imunossupressores/administração & dosagem , Injeções Intraperitoneais , Longevidade/efeitos dos fármacos , Nefrite Lúpica/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Proteinúria/urina , RNA Helicases/imunologia , Baço/citologia , Baço/efeitos dos fármacos , Baço/metabolismo , Terpenos/administração & dosagemRESUMO
Murine lupus can occur spontaneously or be induced by hydrocarbons, such as pristane. Spontaneous disease in MRL and NZB/W F1 mice is suppressed by the xid (X-linked immunodeficiency) mutation, which greatly diminishes T cell-independent type 2 responses as well as the number of peritoneal B1 cells. The present study asked whether lupus induced by i.p. injection of pristane likewise is inhibited by the xid defect. Male CBA/N (xid) mice were refractory to the induction of autoantibodies by pristane, whereas 23% of pristane-treated male CBA/CaJ controls produced anti-nRNP/Sm, -Su and/or -OJ (isoleucyl tRNA synthetase) antibodies. Unexpectedly, 43% (12 of 28) of the xid mice spontaneously produced anti-nuclear antibodies that proved highly specific for the lupus antigen RNA helicase A (RHA). Strikingly, this specificity was absent in CBA/CaJ mice (none of 51). Moreover, pristane treatment suppressed the production of anti-RHA antibodies when administered prior to the onset of autoantibody production, but enhanced anti-RHA levels when given after the onset of autoantibody production, suggesting that pristane interferes with anti-RHA production at an early stage. Large amounts of IgG1 anti-RHA autoantibodies were detected in the sera of xid mice, whereas pristane-induced anti-nRNP/Sm and -Su autoantibodies were almost exclusively IgG2a. Cytokine production within the peritoneal cavity reflected the predominant isotypes: IL-12 and IFN-gamma predominated in pristane-treated mice, whereas IL-4 and IL-6 were more predominant in untreated xid mice. The spontaneous production of anti-RHA by xid mice and its suppression by pristane treatment at the level of autoantibody induction supports the idea that lupus autoantibodies may be generated through a variety of mechanisms.
Assuntos
Agamaglobulinemia/imunologia , Autoanticorpos/biossíntese , Autoantígenos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , RNA Helicases/imunologia , Terpenos/farmacologia , Agamaglobulinemia/genética , Animais , Anticorpos Antinucleares/biossíntese , Citocinas/biossíntese , RNA Helicases DEAD-box , DNA de Cadeia Simples/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Imunoglobulina G/biossíntese , Imunossupressores/administração & dosagem , Imunossupressores/farmacologia , Injeções Intraperitoneais , Lúpus Eritematoso Sistêmico/induzido quimicamente , Lúpus Eritematoso Sistêmico/patologia , Masculino , Camundongos , Camundongos Endogâmicos CBA , Proteínas de Neoplasias , Terpenos/administração & dosagemRESUMO
Exposure to the hydrocarbon oil pristane induces lupus specific autoantibodies in non-autoimmune mice. We investigated whether the capacity to induce lupus-like autoimmunity is a unique property of pristane or is shared by other adjuvant oils. Seven groups of 3-month-old female BALB/cJ mice received a single intraperitoneal injection of pristane, squalene (used in the adjuvant MF59), incomplete Freund's adjuvant (IFA), three different medicinal mineral oils, or saline, respectively. Serum autoantibodies and peritoneal cytokine production were measured. In addition to pristane, the mineral oil Bayol F (IFA) and the endogenous hydrocarbon squalene both induced anti-nRNP/Sm and -Su autoantibodies (20% and 25% of mice, respectively). All of these hydrocarbons had prolonged effects on cytokine production by peritoneal APCs. However, high levels of IL-6, IL-12, and TNFalpha production 2-3 months after intraperitoneal injection appeared to be associated with the ability to induce lupus autoantibodies. The ability to induce lupus autoantibodies is shared by several hydrocarbons and is not unique to pristane. It correlates with stimulation of the production of IL-12 and other cytokines, suggesting a relationship with a hydrocarbon's adjuvanticity. The potential to induce autoimmunity may complicate the use of oil adjuvants in human and veterinary vaccines.