Causal molecular pathway signatures in systemic lupus erythematosus

A PhD project for the 2022 doctoral clinical fellows programme with Carola Vinuesa (primary supervisor, Crick) and Anisur Rahman (UCL). 

Project description

Carola Vinuesa

Senior Group Leader, Francis Crick Institute

Anisur Rahman

Professor of Rheumatology, Inflammation, Faculty of Medical Sciences, UCL

Systemic lupus erythematosus (SLE) is the prototypic human systemic autoimmune disease with a prevalence of 97 per 100,000 in the UK. SLE can affect any organ or tissue in the body, 90% of cases are women and it typically presents in the childbearing years.

Severe, organ-threatening manifestations include renal, neuropsychiatric and haematological disease. SLE is heterogeneous not only with regards to the very different clinical presentations, diseases course, or end-organs affected, but also according to the very different peripheral blood mononuclear cell transcriptomic signatures: Indeed, SLE can be stratified into at least 5 different patient subgroups according to their transcriptional profile [1].

SLE patients are treated with high dose corticosteroids and immunosuppressive agents including cyclophosphamide and mycophenolate. These globally immunosuppressive techniques have improved clinical outcomes in SLE but can lead to multiple side-effects and organ damage over time. Furthermore, some aspects of the disease such as fatigue and increased risk of cardiovascular disease do not respond to these therapies and an important subgroup of patients are refractory to these drugs [2]. It is therefore important to develop new targeted therapies for SLE based on understanding disease pathogenesis. In a successful trial of the anti-interferon agent anifrolumab, better outcomes were seen in a group with a high interferon gene signature [3].

We have now undertaken whole genome or exome sequencing of hundreds of patients with systemic autoimmunity (https://database.cpi.org.au) and identified novel causes of monogenic SLE from patients with pediatric-onset lupus. We have developed bespoke SLE “mouse patients” by introducing the orthologous mutations found in the human patients into mice using CRIPSR/Cas9 editing, and are uncovering the pathogenic mechanisms in these models [4,5]. 

To resolve SLE heterogeneity we are identifying causal molecular pathway signatures (CAMPS) in our established cohort of monogenic patients and CRISPR engineered “mouse patients”. Multi-parameter assessments of patient/mouse immunity include antibody-coupled single-cell (sc) RNAseq (CITE-seq) together with BCR and TCR sequencing, metabolomic profiling, and functional in vitro assays.
The successful PhD candidate will apply these assays to non-Mendelian adult-onset SLE patients that are regularly followed up, for which we have collected clinical history, disease activity, treatment and serology, and have a biobank of serum samples. Activity is recorded using the organ-based British Isles Lupus Assessment Group (BILAG) index, allowing comparison of patients with disease in different organs. 

The aim will be to investigate whether defined CAMPS can identify distinct patient subgroups as defined by total blood transcriptomic signature, disease course, disease activity, or the nature of symptoms and end-organs affected. The candidate will also investigate how some of the rare cell subsets, cytokines, metabolites, as well as B cell and T cell clonotypes that define each CAMP, participate in disease pathogenesis. 

This work will be instrumental to understand the fundamental pathogenic mechanisms in human SLE and to refine clinical diagnosis. An important outcome will be the possibility to stratify patients for existing precision therapies. 

The partner institution for this project is UCL.

References

  1. Banchereau, R., et al., Personalized Immunomonitoring Uncovers Molecular Networks that Stratify Lupus Patients. Cell, 2016. 165(6): p. 1548-1550.
  2. Bakshi, J., et al., Unmet Needs in the Pathogenesis and Treatment of Systemic Lupus Erythematosus. Clin Rev Allergy Immunol, 2018. 55(3): p. 352-367.
  3. Morand, E.F., et al., Trial of Anifrolumab in Active Systemic Lupus Erythematosus. N Engl J Med, 2020. 382(3): p. 211-221.
  4. Jiang, S.H., et al., Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus. Nat Commun, 2019. 10(1): p. 2201.
  5. In Review: https://doi.org/10.21203/rs.3.rs-152145/v1)