Pristane-induced autoimmunity in germ-free mice

Mizutani, Akiei; Shaheen, Victoria M.; Yoshida, Hideo; Akaogi, Jun; Kuroda, Yoshiki; Nacionales, Dina C.; Yamasaki, Yoshioki; Hirakata, Michito; Ono, Nobutaka; Reeves, Westley H.; Satoh, Minoru

doi:10.1016/j.clim.2004.09.010

Cited by 39 publications

(27 citation statements)

References 35 publications

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“…This suggests that complete removal of microbiota does not affect disease progression in these mice. The same phenomenon was observed in the pristane-induced lupus model [9]. However, completely depleting the microbiota might have neutralized the respective effects of “good” and “bad” microbes.…”

Section: Introductionsupporting

confidence: 64%

Control of lupus nephritis by changes of gut microbiota

et al. 2017

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BackgroundSystemic lupus erythematosus, characterized by persistent inflammation, is a complex autoimmune disorder with no known cure. Immunosuppressants used in treatment put patients at a higher risk of infections. New knowledge of disease modulators, such as symbiotic bacteria, can enable fine-tuning of parts of the immune system, rather than suppressing it altogether.ResultsDysbiosis of gut microbiota promotes autoimmune disorders that damage extraintestinal organs. Here we report a role of gut microbiota in the pathogenesis of renal dysfunction in lupus. Using a classical model of lupus nephritis, MRL/lpr, we found a marked depletion of Lactobacillales in the gut microbiota. Increasing Lactobacillales in the gut improved renal function of these mice and prolonged their survival. We used a mixture of 5 Lactobacillus strains (Lactobacillus oris, Lactobacillus rhamnosus, Lactobacillus reuteri, Lactobacillus johnsonii, and Lactobacillus gasseri), but L. reuteri and an uncultured Lactobacillus sp. accounted for most of the observed effects. Further studies revealed that MRL/lpr mice possessed a “leaky” gut, which was reversed by increased Lactobacillus colonization. Lactobacillus treatment contributed to an anti-inflammatory environment by decreasing IL-6 and increasing IL-10 production in the gut. In the circulation, Lactobacillus treatment increased IL-10 and decreased IgG2a that is considered to be a major immune deposit in the kidney of MRL/lpr mice. Inside the kidney, Lactobacillus treatment also skewed the Treg-Th17 balance towards a Treg phenotype. These beneficial effects were present in female and castrated male mice, but not in intact males, suggesting that the gut microbiota controls lupus nephritis in a sex hormone-dependent manner.ConclusionsThis work demonstrates essential mechanisms on how changes of the gut microbiota regulate lupus-associated immune responses in mice. Future studies are warranted to determine if these results can be replicated in human subjects.Electronic supplementary materialThe online version of this article (doi:10.1186/s40168-017-0300-8) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 64%

Control of lupus nephritis by changes of gut microbiota

et al. 2017

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“…A recent report on the production of Lupus antibodies induced by pristane in germ-free mice is in line with our results, showing an increase in the total IgG2a/IgG1 ratio, 30 which is similar to the shift observed for anti-HSP65 in the susceptible LIII animals. Besides, peritoneal cells from pristane-injected animals produced more IL-6 and IL-12 (p40/p70) than PBS-treated mice 6 months after injection.…”

Section: Discussionsupporting

confidence: 81%

Involvement of antibody production quantitative trait loci in the susceptibility to pristane-induced arthritis in the mouse

et al. 2005

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Mice obtained by bidirectional selective breeding for high (HIII) or low (LIII) antibody (Ab) production are resistant or extremely susceptible to pristane-induced arthritis (PIA), respectively. Several quantitative trait loci regulating Ab production (Ab QTL) have been mapped in these lines, which were used to investigate the influence of these Ab QTL in PIA. Parental HIII and LIII mice and their F 1 and F 2 intercrosses were injected twice with pristane, and arthritis was observed for 200 days. In LIII mice PIA was more severe and incidence was 100% at day 105, while F 1 and F 2 mice showed intermediate values. HIII mice were totally resistant. Microsatellite polymorphisms of Ab QTL were analysed and D3Mit100 alleles cosegregated significantly with PIA incidence, severity and onset in F 2 intercross mice, while the other four markers showed suggestive values. Results indicate colocalization of QTL for Ab production and PIA susceptibility. Moreover, the different cytokine and IgG isotype profiles observed in HIII and LIII lines after PIA induction are useful to candidate genes endowed with the regulation of the Ab production and arthritis phenotypes.

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“…The presence of more microbes appeared to be associated with enhanced hypergammaglobulinemia and autoantibody production in murine model [14]. However, germ-free mice lacking normal flora also developed hypergammaglobulinemia and autoantibodies, indicating that microbial products are not essential [20]. Furthermore, adjuvant hydrocarbon oil itself without microbial Table 1 for detail).…”

Section: Discussionmentioning

confidence: 96%