Sex Dependent and Sjögren Disease Like Immune Responses Against Phosphoantigens in Balb/C Mice

The initial aim of this study on Balb/C mice was to investigate the putative effects on feeding and appetite of isopentenyl pyrophosphate (IPP) and E-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), also known as phosphoantigens (pAgs). HMBPP was recently shown to increase blood meal appetite in malaria mosquitoes. Both IPP and HMBPP are metabolites produced by the normal gut microbiota and apicomplexan parasites such as Plasmodium. To explore potential effects on appetite, male and female mice were treated by gavage with these metabolites, and body mass and gene expression were monitored in brain, stomach and small intestine at 3 h and 7 weeks. Body mass gain did not clearly differ between pAg-treated and water control mice. However, beginning between 4 and 7 weeks, the salivary glands of IPP-treated males began to swell. With the autoimmune Sjögren disease (SjD) in mind, we subsequently investigated the salivary glands after 1, 4 and 7 weeks of IPP treatment. Fast gene set enrichment analysis (FGSEA) of marginal zone B-cell (MZB) transcripts from salivary glands, together with B-cell infiltration in both sexes at 4 weeks, suggested similarities to SjD pathology. Using ELISA, we measured serum autoantibodies against Ro52, Ro60 and La. Multivariate analysis at 7 weeks showed treatment-associated trends: levels of anti-Ro52 and anti-La tended to increase in IPP-treated males, but not in females. Notably, IL-6 serum levels displayed a sex-dependent pattern, and PCA analyses of transcriptomic data from brain, stomach and small intestine-though with some exceptions-also indicated differential responses to pAgs between males and females.