Background/Purpose:  Males and females differ in mounting immune response to pathogens. Females appear immune privileged, mounting stronger immune response to pathogens and vaccination. While this limits females’ susceptibility to infection compared to males, it increases their likelihood, in some cases, by 10-15-fold to develop autoimmune disease. Mechanisms underlying the sex dimorphism in immune/autoimmune responses are not well understood. Since many immune response genes are encoded on sex chromosomes, we posit that a differential expression and/or function of these X/Y-linked genes underlie the differences in immune/autoimmune responses. Here, we investigate the responses of immune cells to two X-linked genes, toll-like receptor 7 and 8 (Tlr7 and Tlr8).

Methods:  To dissect the role of sex chromosomes in the absence of confounding hormonal influences, we used the four-core genotype (FCG) mouse model where findings in the XX females (XXF) can be compared with XY females [XYF, XY^–Sry]; and XX males [XXM, XX.Sry^Tg] can be compared with XY males [XYM, XY^–Sry.Sry^Tg]. Spleen cells from XYF and XXF mice were stimulated with TLR agonists IMI, R848, Poly I:C, and CpG and then analyzed for cellular proliferation by flow cytometry. Poly I:C and CpG, which stimulate TLR3 and TLR9, respectively, showed similar proliferation patterns to control in both XXF and XYF. IMI and R848, which target TLRs located on the X chromosome (TLR7 and TLR7/8, respectively), were also used to stimulate cells. XYF spleen cells showed increased cellular proliferation in response to stimulation by high concentrations of IMI and R848.

Results:  First, we found that as compared to XXF mice, XYF mice had splenomegaly, with increased total cells per spleen (p < 0.05, n = 6). The proportion of individual immune cells also varied between XXF and XYF mice, with higher proportions of granulocytes and lower proportions of T and B cells in XYF mice as compared to XXF mice, although the absolute numbers of all cell types were higher in XYF vs. XXF spleens. Second, XYF and XYM spleen cells proliferated more vigorously to TLR7 ligand imiquimod and TLR7/8 ligand R848 than XXF and XXM, respectively, whereas the proliferative responsiveness to TLR3 and TLR9 ligands, Poly I:C and CpG, respectively, were not different between XX and XY mice, regardless of the gender. XYF and XXF spleen cells responded similarly to anti-CD3/CD28 stimulation.

Conclusion:  These results suggest that the sex chromosome genotype might have consequences for the composition of immune cells and the responsiveness to innate receptors, which in turn could significantly alter immune/autoimmune responses. Ongoing studies will investigate mechanisms underlying these sex-related differences. Acknowledgement: B.P. is an undergraduate Barry Goldwater Scholar, I.V. is a recipient of an NIH/NHLBI K01 grant, and R.R.S. is supported by NIH R01 AR56465, AI80778, and R21 HD82812.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/responsiveness-to-x-linked-toll-like-receptors-differs-between-mice-with-xy-and-xx-sex-chromosome-complement-regardless-of-the-gonadal-sex/