This article was originally published here
Arthritis Rheumatol. 2021 Nov 1. doi: 10.1002/art.42008. Online ahead of print.
OBJECTIVE: To determine the extent of gut microbiome in influencing systemic autoimmunity, we generated germ-free (GF) BXD2 lupus mice, which otherwise develop spontaneous germinal centers (GCs) and high titers of serum autoantibodies.
METHODS: The GF status was confirmed by gut bacterial culture. The autoimmune phenotypes in 6- and 12-mo-old gnotobiotic GF BXD2 mice and specific pathogen-free (SPF) BXD2 mice were compared. Serum levels of autoantibody were measured using ELISA. Histologic sections of kidney and joints were evaluated. Flow cytometry was used to analyze GC and age-associated B cells (ABCs). CD4+ T cells were analyzed for PD-1+ ICOS+ activated T cells, follicular T-regulatory cells (Tfr, Foxp3+ CD25+ PD-1+ CXCR5+ ), and PMA/ionomycin stimulated IL-17A+ or interferon-gamma (IFN-&ip.gamma;)+ PD-1+ ICOS+ T cells.
RESULTS: At 6-mo of age, the GF status did not affect splenomegaly, GC B cells, ABCs or serum autoantibodies except for IgG anti-histone. GF BXD2 mice exhibited a significantly higher percent of Tfr cells, compared to the SPF counterpart. At 12-mo-old, however, there were significantly diminished IgG autoantibodies and a lower percent of GC B cells and ABCs in GF BXD2 mice. Following stimulation, PD-1+ ICOS+ CD4 T cells expressed significantly lower IL-17A but not IFN-&ip.gamma; in GF BXD2 mice, compared to SPF mice. Both SPF 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 play a dominant role in determining the initial development of autoimmunity. In contrast, gut microbiomes may regulate the persistence of certain aspects of systemic autoimmunity.