Objective: To determine the extent to which the gut microbiome influences systemic autoimmunity in a mouse model of lupus.
Methods: We generated germ-free (GF) lupus-prone BXD2 mice, which under normal conditions develop spontaneous germinal centers (GCs) and high titers of serum autoantibodies. GF status was confirmed by gut bacterial culture. The autoimmune phenotypes of 6- and 12-month-old gnotobiotic GF BXD2 mice and specific pathogen-free (SPF) BXD2 mice were compared. Serum levels of autoantibodies were measured by enzyme-linked immunosorbent assay. Histologic sections of the mouse kidney and joints were evaluated. Flow cytometry was used to analyze GCs and age-associated B cells. CD4+ T cells were analyzed for PD-1+ICOS+ activated T cells, T follicular regulatory (Tfr) cells (Foxp3+CD25+ PD-1+CXCR5+), and PD-1+ICOS+ T cells expressing interleukin-17A (IL-17A) or interferon-γ (IFNγ) after stimulation with phorbol myristate acetate (PMA)/ionomycin.
Results: In 6-month-old mice, GF status did not affect splenomegaly, GC B cells, age-associated B cells, or serum autoantibody levels, except for IgG antihistone. GF BXD2 mice exhibited a significantly higher percentage of Tfr cells compared to their SPF counterparts (P < 0.05). At 12 months of age, however, GF BXD2 mice had significantly diminished IgG autoantibody levels and a lower percentage of GC B cells and age-associated B cells (P < 0.05). Following stimulation with PMA/ionomycin, PD-1+ICOS+ CD4+ T cells expressed significantly lower IL-17A, but not IFNγ, levels in GF BXD2 mice compared to SPF BXD2 mice (P < 0.01). SPF BXD2 mice and GF BXD2 mice developed equivalent renal and joint disease with no significant differences in severity.
Conclusion: Our results suggest a model in which genetics plays a dominant role in determining the initial development of autoimmunity. In contrast, gut microbiomes may regulate the persistence of certain aspects of systemic autoimmunity.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9071869 | PMC |
| http://dx.doi.org/10.1002/art.42008 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Silica-mediated exacerbation of inflammatory arthritis: A novel murine model.
bioRxiv
January 2025
Department of Immunology and Microbiology, Scripps Research, La Jolla, San Diego, USA.
Objective: The mucosal origin hypothesis in rheumatoid arthritis (RA) posits that inhalant exposures, such as cigarette smoke and crystalline silica (c-silica), trigger immune responses contributing to disease onset. Despite the established risk posed by these exposures, the mechanistic link between inhalants, lung inflammation, and inflammatory arthritis remains poorly understood, partly from the lack of a suitable experimental model. As c-silica accelerates autoimmune phenotypes in lupus models and is a recognized risk factor for several autoimmune diseases, we investigated whether c-silica exposure could induce RA-like inflammatory arthritis in mice.
View Article and Find Full Text PDFIncreased development of T-betCD11c B cells predisposes to lupus in females: Analysis in BXD2 mouse and genetic crosses.
Clin Immunol
December 2023
Department of Medicine, Division of Clinical Immunology and Rheumatology, the University of Alabama at Birmingham, Birmingham, AL, USA; Research, Birmingham Veterans Affairs Health Care System, Birmingham, AL, USA. Electronic address:
Cardinal features of lupus include elevated B cell activation and autoantibody production with a female sex preponderance. We quantified interactions of sex and genetic variation on the development of autoimmune B-cell phenotypes and autoantibodies in the BXD2 murine model of lupus using a cohort of backcrossed progeny (BXD2 x C57BL/6J) x BXD2. Sex was the key factor leading to increased total IgG, IgG2b, and autoantibodies.
View Article and Find Full Text PDFThe ameliorative effects of choline on ethanol-induced cell death in the neural tube of susceptible BXD strains of mice.
Front Neurosci
September 2023
Department Anatomy and Neurobiology, University Tennessee Health Science Center, Memphis, TN, United States.
Introduction: Fetal alcohol spectrum disorders (FASD) are the leading preventable cause of intellectual disability, providing the impetus for evaluating various potential treatments to ameliorate ethanol's teratogenic effects, particularly in the nervous system. One treatment is the dietary supplement choline which has been shown to mitigate at least some of ethanol's teratogenic effects. The present study was designed to investigate the effects of genetics on choline's efficacy in ameliorating cell death in the developing neural tube.
View Article and Find Full Text PDFObjective: To determine the extent to which the gut microbiome influences systemic autoimmunity in a mouse model of lupus.
Methods: We generated germ-free (GF) lupus-prone BXD2 mice, which under normal conditions develop spontaneous germinal centers (GCs) and high titers of serum autoantibodies. GF status was confirmed by gut bacterial culture.
IL-23 Promotes a Coordinated B Cell Germinal Center Program for Class-Switch Recombination to IgG2b in BXD2 Mice.
J Immunol
July 2020
Division of Clinical Immunology and Rheumatology, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL;
IL-23 promotes autoimmune disease, including Th17 CD4 T cell development and autoantibody production. In this study, we show that a deficiency of the p19 component of IL-23 in the autoimmune BXD2 (BXD2- ) mouse leads to a shift of the follicular T helper cell program from follicular T helper (Tfh)-IL-17 to Tfh-IFN-γ. Although the germinal center (GC) size and the number of GC B cells remained the same, BXD2- mice exhibited a lower class-switch recombination (CSR) in the GC B cells, leading to lower serum levels of IgG2b.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!