Molecular and clinical sexual dimorphism in systemic autoimmunity

• Biological differences between the sexes of a species, also known as sexual dimorphism, can be found throughout developmental, physiological and pathological processes. In human disease, sexual dimorphism can explain marked differences in disease susceptibility. Rheumatic diseases, such as systemic lupus erythematosus (SLE) and primary Sjögren’s syndrome (pSS), are chronic systemic autoimmune disorders that predominantly affect more women than men. Although many mechanisms have been put forward in order to explain this sex bias, the molecular underpinnings and their translation into disease phenotype are still not fully understood. Therefore, the aim of this thesis was to explore potential sex differences in genetic aspects that contribute to disease development, as well as to characterize clinical features that might exhibit a sexually dimorphic pattern. In Paper I, we studied the expression of genes associated with pSS at basal state in splenic immune cells from wild type mice. The analysis revealed minor differences between female and male murine cells. Similar findings were obtained when human B cells and monocytes were investigated. Although these results suggested potential intrinsic differences, the extent of the sexual dimorphism observed in gene expression of risk loci could not entirely explain the marked sex skew in disease susceptibility. To instead address differences in gene regulation rather than expression, in Paper II we examined whether single nucleotide polymorphisms (SNPs) associated with SLE and pSS could affect the gene expression in a sex-specific manner. The analysis resulted in identification of sex-specific expression quantitative loci (eQTLs) in human B cells. The study of sex-influenced eQTLs in other cell subtypes and in whole blood highlighted the context-dependent effect of these eQTLs. Since variation in gene regulation of risk loci among the sexes can lead to a heterogeneous disease phenotype, in Paper III, Paper IV and Paper V we aimed to identify relevant sex differences in the clinical presentation of incident pSS, prevalent pSS and prevalent SLE, respectively. Our analyses showed that, despite being less prone to systemic autoimmune disorders, men have a more severe disease phenotype, characterized by more organ manifestations, an enhanced serological profile and more critical long-term complications when compared to their female counterparts. In summary, our present work demonstrates the importance of sexual dimorphism in disease susceptibility and phenotype; also, it sheds light on possible molecular mechanisms that orchestrate the immune regulation of these complex disorders. Our results should raise awareness of relevant clinical sex differences that can aid in providing a tailored treatment to these patients. n summary, our present work demonstrates the importance of sexual dimorphism in disease susceptibility and phenotype; also, it sheds light on possible molecular mechanisms that orchestrate the immune regulation of these complex disorders. Our results should raise awareness of relevant clinical sex differences that can aid in providing a tailored treatment to these patients.

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