Webb, Kate; (2019) Sex and puberty influence the innate immune system type 1 interferon response. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Type 1 IFNs are an antiviral cytokine family, important in jSLE which is more common in females, around puberty. It is reported here that plasmacytoid dendritic cells (pDC) from healthy females were more activated than males, and expressed more of the anti-viral surface protein, tetherin than males, suggesting that they are more primed to react to viral ligand. In healthy volunteers, females produced more type 1 IFN after TLR7 stimulation than males, regardless of puberty. There was however an increased production of type 1 IFN after TLR7 stimulation in post pubertal volunteers, regardless of sex. A unique human model including transgender volunteers and young women with TUS revealed that TLR7 induced type 1 IFN production related to X chromosome number, and serum testosterone concentration, in a manner which differed depending on the number of X chromosomes present. Female peripheral blood mononuclear cells (PBMC) expressed more of the genes coding for RNAsensors RIG-1 and MDA5 regardless of puberty, and TLR7 gene expression was increased in post pubertal females. Therefore, females were inherently more primed to respond to viral or endogenous RNA ligand than males, and produced more type 1 IFN after TLR7 stimulation, which associated with puberty in a manner that may partly explain why a type 1 IFN mediated autoimmune disease like jSLE is more common in females after puberty. Indeed, in this study, young people with jSLE had a diminished production of IFNα after TLR9 stimulation and a decreased gene expression of TLR9. Conversely, TLR7 induced IFNα production was unchanged and TLR7 gene expression was increased in jSLE patients with evidence of a high background IFN. Stratifying low disease activity patients with jSLE revealed that approximately half of these patients had an upregulated IFN score, which is less than previously reported in higher disease activity and may better represent the baseline. Stratifying by IFN score revealed that the gene expression of the endogenous retroelement LINE1 was relatively upregulated in jSLE as compared to healthy volunteers. These findings highlight the importance of TLR7 in the female predisposition toward jSLE, especially after puberty, and reveal TLR7 and LINE1 as potential targets for future investigation.

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