Sex differences and the interplay of androgens and oestrogens in the modulation of human immune responses

Project overview

The immunological response to foreign antigens is distinct in men and women, as was so clearly demonstrated during the recent Covid-19 pandemic. Sex hormones are well known to regulate physiology however our understanding of their influence on innate and adaptive immune responses is growing. Testosterone and progesterone are associated with anti-inflammatory signatures and thus ‘immune-dampening’ in males and females respectively, whereas oestrogens at a physiological level typically stimulate pro-inflammatory responses and antibody production. High circulating oestrogen concentrations during the later stages of pregnancy however directly correlate with a systemic anti-inflammatory state. This is associated with remission of many autoimmune diseases, including rheumatoid arthritis (RA). In contrast, the decline in oestrogen postpartum and post-menopause is thought to contribute to chronic inflammation and autoimmune disease onset and flares, including in RA. The exact mechanism behind this observation remains poorly understood. In a related phenomenon, there is a strong sex bias in autoimmune disease with the incidence being much higher in women, and sex hormones are again likely to play a role in pathogenesis.

Tissue microenvironments are multifaceted cellular networks and tissue homeostasis relies on complex crosstalk between stromal cells such as fibroblasts and surveying immune cells. Fibroblasts are considered to be metabolically and transcriptionally inactive in healthy tissue, but when activated in response to injury or inflammation, they drive tissue remodelling and influence immune cell behaviour. It is suspected that sex hormones exert dynamic and variable effects in different microenvironments and on alternate cell types. Tissue macrophages extracted from various microenvironments have been reported to be very sensitive to changes in sex hormone concentration, but data on their resultant functional effects are often contradictory and only a small proportion are derived from human studies. Recent evidence has also revealed a sex-based transcriptional difference in activated fibroblasts and altered activity in response to androgens. Despite these initial observations, the exact mechanisms and effect of sex hormones on tissue cellular networks remains unclear. Moreover, the effect of dynamic hormonal changes in women during the menstrual cycle is rarely investigated and there is no standardised approach to addressing its influence to promote inclusive research.

This project consequently seeks to understand how variation in exposure of different sex hormones affects metabolic, transcriptional, and functional immune responses in human tissue.

To achieve this, you will undertake a comprehensive literature review before jointly designing a rigorous and tailored method for determining key timepoints in hormonal changes in the menstrual cycle of healthy women and their impact on innate (neutrophil, monocyte, macrophage) and adaptive (lymphocyte) immune function. The aim is that will become a reference standard for future human research. Participants’ cycle period will be determined by using questionnaires and calendar tracking, followed by at-home ovulation testing and serology for hormone level analysis. Male participants will be matched by age, and sample collection time will complement the individual female participants. Supported by other group members and your supervisory team you will identify methods to assess the dose-dependent effect of oestradiol, progesterone and testosterone on fibroblast and monocyte/macrophage function (central to innate-adaptive linkage), metabolic and transcriptional activity and cell-cell interactions in vitro and/or ex vivo. You will further validate the differences in immune response in tissue between men and women in vivo by undertaking human immune challenge paradigms (e.g. intradermal endotoxin challenge) incorporating modulation of those responses by sex steroid blockers or supplements. Inflammation and immune response in the tissue will be assessed using a combination of non-invasive imaging techniques and invasive tissue biopsies for histological and cellular analysis. You will learn cutting edge cellular immunology techniques and analyses whilst working as part of a cohesive team of clinicians, translational and discovery scientists who focus on human immunology and addressing the effect of sex on immunology and disease.

Training

The Nuffield Department of Orthopaedics, Rheumatology, and Musculoskeletal Sciences encompasses many different research areas, which enables and encourages research and education into the causes of multiple diseases of the musculoskeletal system and their treatment. Training will be provided in techniques including human immune challenges, flow cytometry, histochemistry, CellDive, ELISA, and in vitro cell cultures of human fibroblasts and immune cells.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. Students will also be required to attend regular seminars within the Department and those relevant in the wider University. Students will be expected to participate and present data regularly at the lab meetings, in Departmental seminars, and to attend external conferences to present their research globally, with limited financial support from the Department. Students will also have the opportunity to work closely with the Coles and Buckley groups at the Kennedy Institute of Rheumatology.

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme).

Key Publications

Croft et al. Distinct fibroblast subsets drive inflammation and damage in arthritis. Nature 2019; 570, 246–251. https://doi.org/10.1038/s41586-019-1263-7

Alivernini et al. Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis. Nat Med 2020; 26, 1295–1306. https://doi.org/10.1038/s41591-020-0939-8

Baker Frost et al. Elucidating the cellular mechanism for E2-induced dermal fibrosis. Arthritis Res Ther 23, 68 (2021). https://doi.org/10.1186/s13075-021-02441-x

Buters et al. Intradermal lipopolysaccharide challenge as an acute in vivo inflammatory model in healthy volunteers. Br J Clin Pharmacol 2022; 88 (2): 680- 690. https://doi.org/10.1111/bcp.14999

SUPERVISORS

James Fullerton is Associate Professor of Clinical Therapeutics in the Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences (NDORMS), and Honorary Consultant in Clinical Pharmacology and Acute General Medicine at the John Radcliffe (JR) Hospital.  His research focuses on promoting scientific translation for patient benefit, in particular, the utility and development of human immune challenge models, seeking to design novel paradigms that will enable and catalyse the work of academic and industrial partners.

Christopher Buckley is Professor of Translation Rheumatology and Director of Clinical Research at the Kennedy Institute of Rheumatology. His group aims to uncover the stromal basis of chronic inflammation and related tissue pathology to target fibroblasts across a range of immune-mediated inflammatory diseases as a leading contributor to the Arthritis Therapy Acceleration Programme (A-TAP).

Laura Coates is Senior Clinical Research Fellow in the NDORMS, and Clinician Scientist at the National Institute for Health and Care Research. Her research focuses on improving the preventative strategies, early diagnosis and optimal treatment pathways in psoriatic arthritis (PsA). She is also one of the leading scientists in the global effort of SAGE-PsA study that aims to uncover biological and socio-cultural mechanisms that underlie treatment disparities in PsA.

How to Apply

It is recommended that, in the first instance, you contact the relevant supervisor(s) and the Graduate Studies Office (graduate.studies@ndorms.ox.ac.uk), who will be able to advise you of the essential requirements.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable). The application guide and form is found online and the D.Phil will commence in October 2024.

Applications should be made using the specified course code:

D.Phil in Molecular and Cellular Medicine (course code: RD_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.