The Molecular Basis Of The Sex-linked Functional Differences In B Cells
Lead Research Organisation:
University of Edinburgh
Department Name: Sch of Biological Sciences
Abstract
The risk of mortality from Covid-19 is up to two-fold higher in men versus women, especially in the
middle-age category, across different cultures and social structures. However, the biological
reasons behind this difference is unknown. Recent research has highlighted significant divergences
in the immune system response between the two sexes. This observation has been paralleled by
the discovery of tissue-specific euchromatinisation of the inactive X chromosome in both B and T
cells, accompanied by the identification of immune-related genes that specifically escape X
inactivation in B cells. One of these escapees, TLR7, is a receptor for ssRNA viruses such as SARSCoV-
2. Its increased dosage caused by bi-allelic expression in women, has been shown to be
advantageous for B cells response upon stimulation of TLR7. Moreover, recent studies have shown
hypomorphic alleles of TLR7 lead to severe Covid-19 in young men. We hypothesised that,
following escape from X inactivation, double-dosage of one or more X-encoded genes involved in B
cell activation could be at the basis of the sex-linked differential mortality from Covid-19. To
identify the X-encoded B-cell specific proteins that are present in higher dosage in women, we
propose an unbiased approach, employing quantitative mass spectrometry from B cells from
healthy, middle-aged men and women. We thus aim at identifying relevant proteins which could
represent potential pharmaceutical targets to improve the prognosis of SARS-CoV-2.
middle-age category, across different cultures and social structures. However, the biological
reasons behind this difference is unknown. Recent research has highlighted significant divergences
in the immune system response between the two sexes. This observation has been paralleled by
the discovery of tissue-specific euchromatinisation of the inactive X chromosome in both B and T
cells, accompanied by the identification of immune-related genes that specifically escape X
inactivation in B cells. One of these escapees, TLR7, is a receptor for ssRNA viruses such as SARSCoV-
2. Its increased dosage caused by bi-allelic expression in women, has been shown to be
advantageous for B cells response upon stimulation of TLR7. Moreover, recent studies have shown
hypomorphic alleles of TLR7 lead to severe Covid-19 in young men. We hypothesised that,
following escape from X inactivation, double-dosage of one or more X-encoded genes involved in B
cell activation could be at the basis of the sex-linked differential mortality from Covid-19. To
identify the X-encoded B-cell specific proteins that are present in higher dosage in women, we
propose an unbiased approach, employing quantitative mass spectrometry from B cells from
healthy, middle-aged men and women. We thus aim at identifying relevant proteins which could
represent potential pharmaceutical targets to improve the prognosis of SARS-CoV-2.
| Description | The work is ongoing, but so fare we have been able to isolate the B cells from human donors and validate the mono-versus-biallelic expression of the X-linked gene that we use as proof-of-principle, TLR7. |
| Exploitation Route | The results of this research will be of interest for both scientists working in the human X inactivation field and for scientists and medics interested in the differences in the immune response in middle-age man and women. Once we will have identified the X-linked genes that are not silenced in the women, it will possible to identify the immune pathways that work differently between man and woman in an age-range where the differences are maximal. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |