Abundance and nuclear antigen reactivity of intestinal and fecal Immunoglobulin A in lupus-prone mice at younger ages correlate with the onset of eventual systemic autoimmunity

Wei Sun,Radhika R Gudi,Benjamin M Johnson,Chenthamarakshan Vasu

doi:10.1038/s41598-020-71272-8

Wei Sun, Radhika R Gudi + Show 2 more

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https://doi.org/10.1038/s41598-020-71272-8

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Journal: Scientific Reports	Publication Date: Aug 31, 2020
Citations: 10	License type: open-access

Affiliation: Medical University of South Carolina

Abstract

Our recent studies, using (SWRxNZB)F1 (SNF1) mice, showed a potential contribution of the gut microbiota and pro-inflammatory immune responses of the gut mucosa to systemic autoimmunity in lupus. Here, using this mouse model, we determined the abundance and the nAg reactivity of IgA antibody produced in the intestine under lupus susceptibility. Intestinal lymphoid tissues from SNF1 mice, females particularly, showed significantly higher frequencies of nAg (dsDNA and nucleohistone) reactive IgA producing B cells compared to B6 females. Most importantly, younger age fecal IgA -abundance and -nAg reactivity of lupus-prone mice showed a positive correlation with eventual systemic autoimmunity and proteinuria onset. Depletion of gut microbiota in SNF1 mice resulted in the diminished production of IgA in the intestine and the nAg reactivity of these antibodies. Overall, these observations show that fecal IgA features, nuclear antigen reactivity particularly, at preclinical stages/in at-risk subjects could be predictive of autoimmune progression.

Highlights

Abbreviations SLE Systemic lupus erythematosus SNF1 mice (SWRxNZB)-F1 mice nAg Nuclear antigen Peyer’s patches (PP) Peyers’ patch LP Lamina Propria SI Small intestine GF Germ-free specific pathogen free (SPF) Specific pathogen free TLR Toll-like receptors Abx Antibiotic cocktail MUSC Medical University of South Carolina ELISA Enzyme-linked immunosorbent assay dsDNA Double stranded DNA
We have shown that significant amounts of circulating autoantibodies against nucleohistone and dsDNA are detectable in these mice by 16 weeks of age and severe nephritis indicated by high proteinuria is observed after 20 weeks of a ge[13,17]
We have reported that gut mucosa of female SNF1 mice, as compared to their male counterparts, harbor higher frequencies of activated B cells including plasma cells, as well as express high levels of pro-inflammatory cytokines as early as at juvenile age (4 weeks) and have amplified levels of these factors at adult a ges[17]

Summary

Introduction

Abbreviations SLE Systemic lupus erythematosus SNF1 mice (SWRxNZB)-F1 mice nAg Nuclear antigen PP Peyers’ patch LP Lamina Propria SI Small intestine GF Germ-free SPF Specific pathogen free TLR Toll-like receptors Abx Antibiotic cocktail MUSC Medical University of South Carolina ELISA Enzyme-linked immunosorbent assay dsDNA Double stranded DNA. Our recent studies that used lupus-prone (SWRxNZB)F1 (SNF1) mice showed a potential contribution of pro-inflammatory immune response initiated in the gut mucosa, and gut microbiota in triggering the disease associated gender bias observed in S LE16,17. Anti-DNA antibodies of IgA class are found in the serum of patients with SLE24–29, suggesting that they may be of gut primed B cell origin These reports along with our s tudies[16,17] showing pro-inflammatory immune phenotype and higher plasma cell frequency by lupus-prone female mouse intestine suggests the degree of IgA secretion in the gut lumen could show gender bias and may be indicative of lupus susceptibility and autoimmune progression. The reactivity of fecal IgA in a lupus-prone background with nuclear antigens and the potential association with disease onset has never been studied

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