Background/Purpose: The female predisposition for development of multiple autoimmune diseases is well recognized. The female to male ratio reaches a maximum during the reproductive years among SLE patients, suggesting a link between sexual development and disease. Additional epidemiologic data indicate an effect of sex chromosomes. To gain insight into molecular mechanisms of SLE, we investigated gene expression in PBMC of SLE patients and corresponding healthy donors of both genders using RNA-seq.

Methods: SLE samples were selected at a time of relative disease quiescence from a longitudinal cohort of patients. To minimize variation between male and female patients only demographically matched adults receiving low doses of steroids, hydroxychloroquine and mycophenolate motifil were selected and matched to healthy donors (HD). The analysis focused on identification of functional pathways affected in male and female SLE patients and abnormal gene expression from sex chromosomes.

Results: Principal component analysis differentiated the 4 donor groups, with PC1 and PC3 reflecting disease and PC2 reflecting gender. Male SLE patients received the highest score on PC1 and were placed closer to both SLE and healthy females than healthy males on PC2. We identified 796 and 99 differentially expressed genes in male and female SLE patients respectively, compared to HD (p< 0.05, logFC=1.5). Fewer genes (20 vs. 27) differed between genders in SLE vs. HD (p< 0.05, logFC=1.5). Weighted Gene Co-expression Network Analysis (WGCNA) identified 24 clusters of co-expressed genes in male and female patients. The most intriguing were clusters that differed in male and female HD and were upregulated in SLE of both genders. Those clusters include genes related to EGF receptor ligands (AREG, EREG, HBEGF), transcription factors (ATF3, NR4A1, NR4A2, NR4A3), cytokines and chemokines (CCL3, CXCL2, CXCL8, CCL3L3, IL1A, IL1B).  We also identified a group of X-chromosomal genes strongly upregulated in male SLE patients, including CXorf21.

Conclusion: Despite being clinically similar, male SLE patients showed a higher level of affected genes and had a lower divergence from females based on gender-related genes. Male HD had the lowest basal level of pro-inflammatory genes and EGF receptor ligands. The signaling through the EGF receptor has been shown to modulate the type I interferon response and may predispose females to autoimmune disease. The effect of X-chromosomal genes, including those that can escape inactivation in females, should be further investigated. We propose that gender-specific differences in gene expression reveal immunopathogenic mechanisms in autoimmune disease.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/gene-expression-analysis-of-male-and-female-sle-patients-reveals-candidate-pathogenic-pathways/