Defining the determinants of lupus progression and cancerous transformation

Federico Gaiti, Ph.D., Scientist, Princess Margaret Cancer Centre, University Health Network 

B cells produce antibodies that target foreign invaders like viruses and bacteria to protect us from infections. In systemic lupus erythematosus (SLE), B cells can become self-reactive, producing autoantibodies that mistakenly recognize a person’s own cell contents as foreign, leading to inflammation and organ damage. Most treatment options for SLE involve non-specific anti-inflammatory or immunosuppressive drugs that can cause harmful side effects and leave the person more likely to get infections. Targeted therapeutics and early intervention strategies are needed to eliminate disease-causing B cells. However, the factors that push self-reactive B cells to promote SLE are unclear. To define these factors, Dr. Gaiti will identify genetic and epigenetic (tags that impact how your body reads DNA), changes that determine the “tipping point” at which self-reactive B cells can promote SLE, revealing potential treatment targets and biomarkers of severe disease. 

SLE is not the only disease that features harmful B cells. A type of cancer called B cell lymphoma occurs when B cells become fast-growing cancer cells. SLE and B cell cancers share many similarities, including alterations in some of the same genes and molecular pathways. Also, people with SLE have a higher risk of developing B cell cancers, but what causes this is unknown. To determine the reprogramming B cells undergo to promote SLE and potentially become cancer cells, Dr. Gaiti will analyze thousands of cells from people with SLE to understand how mutations, particularly those linked to B cell cancer, affect the cells. The altered genes or pathways could be used as biomarkers of mutated B cells or targets for new treatments. Co-Principal Investigator Dr. Leandro Venturutti will then study a mouse model of lupus to explore how B cells in SLE, particularly those with B cell cancer-related mutations, respond to chronic inflammation and how this influences SLE severity. 

What this study means for people with lupus 

B cells are a key player in SLE, and a lack of understanding of how they progress to promote SLE has hindered the development of targeted therapies. Findings from this study could uncover biomarkers that could be used in the clinic to predict more severe disease and shift the paradigm in the field, setting the stage for early intervention to eliminate harmful B cells with fewer side effects. 

BACKGROUND AND SIGNIFICANCE: Systemic Lupus Erythematosus (SLE) is a complex disease with varied biological and clinical characteristics. Although SLE is a chronic condition, severe flare-ups can lead to life-threatening complications. Current treatments, which involve strong anti-inflammatory drugs and immune suppressants, lack specificity, and negatively impact patients’ quality of life. While genetic, epigenetic, and immune factors contribute to SLE heterogeneity, the relationship and hierarchy between these factors and the alternative paths taken by pathogenic B-cells are still unclear. Recent research identified “lymphoma mutations” (i.e., targeting genes typically affected in B-cell lymphomas) in subsets of B-cells driving autoimmune disorders. These mutations may support B-cell clonal bursts, but direct information from clinical specimens on how these influence SLE disease evolution or malignant transformation is missing.

OBJECTIVE: Our primary objective is to understand the (epi)genetic and immune niche factors that drive SLE pathogenesis and the transformation of B-cells into malignant forms.

HYPOTHESIS: We propose that a combination of intrinsic cellular characteristics and the surrounding microenvironment determine the “tipping point” at which self-reactive B-cells acquire the potential and constraints necessary for promoting SLE progression, including malignant transformation.

SPECIFIC AIMS AND APPROACH: We will utilize innovative technologies, such as single-cell multi-omics approaches, developed by our research groups. We will apply these techniques to both clinical specimens and animal models to address the following objectives: Aim 1, Investigate the transcriptional and epigenetic rewiring caused by lymphoma mutations in clonal B-cells from SLE patients; Aim 2, Dissect the contribution of the dysregulated immune microenvironment in SLE to the malignant transformation of B-cells.

IMPACT: Our project will bridge critical gaps in our understanding of SLE heterogeneity and disease progression. It will enable the discovery of much-needed identifiable biomarkers for early detection and risk stratification of B-cell clones associated with SLE pathogenesis and progression. Furthermore, it will uncover essential dependencies on these cells, leading to the development of therapeutic strategies aimed at eliminating these abnormal clones, potentially offering curative and preventive treatments.

INNOVATION: Our novel approach incorporates multiple layers of information, conveying great potential to identify new molecular targets and pathways for the early detection of clones associated with SLE pathogenesis and the establishment of targeted treatment options. We will use new animal models of disease, and multi-omic single-cell methods and analytics to combine epigenetic, genomic, and transcriptional information, and track B-cell trajectories and how these change over time.