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.
Organisations
| Description | We have obtained the mass spec results that describe the differences in the male-versus-female proteome in resting and activated B cells. We have compiled a list of high confidence proteins that are of clinical insterest. |
| Exploitation Route | The dataset generated is extremly interesting, both clinically and for research purposes. We intend to use it now as the base to write a larger grant, to expand in the characterisation of the very clear and incredible differences in men and women B cells proteome. |
| Sectors | Healthcare,Pharmaceuticals and Medical Biotechnology |
| Title | Quantitative mass spec analysis of resting and activated B cells proteome from middle aged health men and women donors |
| Description | We have optimised the isolation, extraction and analysis methods for the mass spec analysis of donor proteins. |
| Type Of Material | Biological samples |
| Year Produced | 2023 |
| Provided To Others? | No |
| Impact | This data set is going to be very useful for basic researchers and clinical researcher. We are in the process to optimise the criteria of selection and deciding on the best method to make this data available. |