Sex Effects on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

Abstract

PurposeSjögren syndrome is an autoimmune disease that occurs primarily in women, and is associated with lacrimal gland inflammation and aqueous-deficient dry eye. We hypothesize that sex-associated differences in lacrimal gland gene expression are very important in promoting lymphocyte accumulation in this tissue and contribute to the onset, progression, and/or severity of the inflammatory disease process. To test our hypothesis, we explored the nature and extent of sex-related differences in gene expression in autoimmune lacrimal glands.MethodsLacrimal glands were collected from age-matched, adult, male and female MRL/MpJ-Tnfrsf6lpr (MRL/lpr) and nonobese diabetic/LtJ (NOD) mice. Glands were processed for the analysis of differentially expressed mRNAs by using CodeLink Bioarrays and Affymetrix GeneChips. Data were evaluated with bioinformatics and statistical software.ResultsOur results show that sex significantly influences the expression of thousands of genes in lacrimal glands of MRL/lpr and NOD mice. The immune nature of this glandular response is very dependent on the Sjögren syndrome model. Lacrimal glands of female, as compared with male, MRL/lpr mice contain a significant increase in the expression of genes related to inflammatory responses, antigen processing, and chemokine pathways. In contrast, it is the lacrimal tissue of NOD males, and not females, that presents with a significantly greater expression of immune-related genes.ConclusionsThese data support our hypothesis that sex-related differences in gene expression contribute to lacrimal gland disease in Sjögren syndrome. Our findings also suggest that factors in the lacrimal gland microenvironment are critically important in mediating these sex-associated immune effects.

Testosterone Influence on Gene Expression in Lacrimal Glands of Mouse Models of Sjögren Syndrome

“…As we reported recently,30 counts of unique mappings of probes to gene identifications in the CL and Affy arrays demonstrated that there were 15,711 and 13,265 unique genes, respectively, in these arrays. Examination of the intersection of these lists showed that there was an overlap of 11,299 genes.…”

“…As we30,33–35 and other investigators36–39 have discovered, the vast majority of lacrimal gland genes in MRL/lpr and NOD female mice, which were identified as differentially expressed by the CL and Affy microarrays, were unique to each platform. Indeed, as demonstrated in Table 4, only 8.5% to 11.1% (T>P), and 7.3% to 16.8% (P>T) of the regulated genes were found by both microarrays.…”

“…Lacrimal glands of female MRL/lpr and male NOD mice, compared to their opposite sexes, contain a significantly greater expression of genes, ontologies, and KEGG pathways related to inflammatory responses, antigen processing, and chemokine signaling 30. We hypothesized that many of these immune-related genes, ontologies, and pathways are analogous to those T suppresses in female MRL/lpr, and induces in female NOD mouse lacrimal tissues.…”

“…We also compared our results to data from our studies examining the influence of sex in adult MRL/lpr and NOD mice ( n = 15–18/sex/strain),30 and 2 weeks of P or T treatment of nonautoimmune, ovariectomized BALB/c mice ( n = 5–6 mice/condition/experiment),31 on lacrimal gland gene expression. The sex- and hormone-related data are available through the NCBI GEO via series accession numbers GSE5876 and GSE3995, respectively.…”

Parity Attenuates Intraepithelial Corneal Sensory Nerve Loss in Female Mice

“…Animal models have shown active participation of CD4+ T cells [ 52 , 53 ]. Although both sexes are affected, dry eye affects more women than men, and its prevalence increases sharply in women in the 5th decade [ 10 , 11 , 13 , 54 , 55 , 56 ] Because of its strong association in women and perimenopause, the influences of sex hormones have been postulated as playing roles in either promoting or ameliorating dry eye disease [ 57 , 58 , 59 ]. Our results evaluating aging MP and NP mice suggest that hormonal changes associated with pregnancy may influence the overall health of corneal nerves.…”