From altered skin signature to Lupus
1 PhD project offered in the IPP summer call Molecular Biomedicine & Ageing
Scientific Background
Lupus erythematosus (LE) is a complex autoimmune disease. Once fully established, response to immunosuppressive therapy is unsatisfactory, disease is lifelong and cumulative damage and glucocorticoid toxicity occur. A key determinant of short and long-term outcomes is initial diagnosis and treatment. In other autoimmune diseases such as rheumatoid and psoriatic arthritis, early intervention has been shown to induce disease remission, prevent organ damage, and even prevent disease onset. Understanding early events in the LE disease process would facilitate early diagnosis and reveal targets for early intervention, changing the current paradigm from ‘long-term management of chronic inflammation’ to ‘prevention’.
SLE is diagnosed by the presence of antinuclear antibody (ANA) and a combination of other clinical symptoms (e.g. dermatitis and arthritis). ANA can be detected in serum up to 10 years before clinical features develop and is much more common than SLE, affecting 5-10% of healthy adults. Individuals with ANA therefore constitute an At-Risk population of whom a minority progress to SLE. There is also lack of knowledge regarding the regulatory mechanisms at play which prevent development of SLE in most ANApos individuals.
Thus, the most important current gaps in knowledge affecting patients’ outcome are
- ability to identify imminent SLE in the preclinical phase,
- identification of appropriate therapeutic targets or immune regulatory interventions for this stage, and
- insight into regulatory mechanism which prevent progression into a systemic disease (and/or limit extent of skin involvement) and their therapeutic exploitation.
PhD Project: From altered skin signature to Lupus: understanding early events in cutaneous Lupus inflammation with regard to disease or health outcome
This project will address these knowledge gaps. We have previous experience with a unique preclinical At-Risk cohort (people referred with positive ANA, musculoskeletal symptoms but not initially diagnosed with SLE) that has already revealed novel insights into mechanism of initiation. Based on these findings, we aim to focus in this project on the early molecular autoimmune and regulatory events in the skin.
Overall Aim: To understand the molecular events within the skin compartment that lead to breakdown OR maintenance of tolerogenic responses in initiation of LE.
This project will focus on establishment and regulation of the cutaneous type I interferon (IFN) response. In close collaboration with a specialised clinic for “early” Lupus we will investigate blood and skin immunological parameters which may support development into Lupus disease OR protection from developing Lupus.
Methods will include cell culture including with patient derived skin and blood cells, flow cytometry including with skin and blood derived cells, scRNAseq, spatial transcriptomics, proteomics (mass spectrometry, multiplex ELISA techniques). Working with patient derived samples and thus some flexibility regarding timing of the planned experiments will be necessary.
Publications relevant to this project
Psarras A, Wittmann M, Vital EM. (2022) Emerging concepts of type I interferons in SLE pathogenesis and therapy. Nat Rev Rheumatol.18(10):575-590 Link
Berekméri A, Tiganescu A, Alase AA, Vital E, Stacey M, Wittmann M. (2019) Non-invasive Approaches for the Diagnosis of Autoimmune/Autoinflammatory Skin Diseases-A Focus on Psoriasis and Lupus erythematosus. Front Immunol. 10:1931. Link