B cells and plasma cells in black SLE. Mechanisms of disease heterogeneity

LRA Global Team Science Award recipient Dr. Ignacio Sanz and his team hope to define the changes in immune cells called B cells in lupus patients that correspond to patients’ clinical symptoms and disease outcomes. Lupus is most common in African American females. In SLE, these B cells make antibodies that attack the patient’s own organs and it hasn’t been clear why patients can have a wide range of symptoms with many different treatment outcomes. One reason seems to be because the B cells in each lupus patient can be different. Dr. Ignacio Sanz’s research has already identified many distinct B cell populations found in African American females with severe lupus. But more research is needed to understand the differences in B cells and how these differences contribute to the progression of lupus in patients. Dr. Sanz and his team hope to do this by pinpointing the contribution of specific B cell populations to the disease manifestation and progression in African American patients with lupus. Researchers will create “B cell profiles” which will group together distinct B cell types that can be associated with specific types of lupus, and thus help guide individualized patient treatment. This work will help us better understand the origin of the disease in specific patients, development of certain symptoms, and variability in responses to treatment. Ultimately, this research will help to develop more personalized therapies for lupus patients.

What this study means for people with lupus:

“This research will enable clinical investigators to more precisely design and evaluate clinical studies and standard of care treatments with the ultimate goal of implementing safer and more effective personalized treatments,” said Dr. Sanz.

Systemic Lupus Erythematosus (SLE) is characterized by diverse clinical presentations and outcomes and myriad immunological abnormalities. This diversity is particularly prominent within the B cell and autoantibody compartments and is most accentuated in Black patients with severe disease. These observations indicate a large degree of disease heterogeneity with underlying mechanistic differences in the quality, intensity and regulation of the B cell compartment. While pathogenesis and heterogeneity in SLE are mediated by genetic, epigenetic, environmental and immunological factors, B cells and plasma cells (PC) are central contributors and a major therapeutic target. Our goal is to elucidate the B cell undergirding of SLE heterogeneity in unique cohorts of Black patients, a population with the highest concentration of severe disease. We shall 1) determine the mechanistic contribution of B cells and PC to the clinical heterogeneity of SLE; 2) establish the value of phenotypic, functional and molecular B cell and PC profiles as biomarkers/correlates of different types of disease; and 3) demonstrate their utility to design and monitor targeted therapeutic strategies. We will also determine the role of the microbiome in disease heterogeneity and its correlation with heterogeneous B cell variables. Our model postulates a central role for distinct B cell endotypes; incorporates the entity of B cell-independent Lupus (BCIL), an important concept that remains to be formally established; predicts the absence of SLE-associated molecular signatures in BCIL; and postulates the extinction of SLE B cell molecular signatures with sustained remissions and favorable response to B cell-targeted therapies. These questions will be addressed through the study of unique SLE cohorts from the American South.

Our work will be pursued in two phases. Phase 1 (Year 1) will conduct cellular and molecular studies as well as investigation of the plasma microbiome in a training set of selected patients spanning the clinical spectrum of disease. This phase will identify the phenotypic, functional and molecular sources and patterns of B cell and PC diversity to determine candidate features potentially associated with clinical heterogeneity. In addition, we will investigate the plasma microbiome to determine the heterogeneity of a compartment of importance in lupus pathogenesis and B cell regulation. Phase 2 (Years 2-3) will use a validation cohort to establish the association between the most informative variables identified in Phase 1.

The knowledge gained from our studies will greatly enhance our understanding of SLE pathogenesis and the contribution of different responses to separate clinical manifestations, outcomes and therapeutic responses. Moreover, it will enable clinical investigators to more precisely design and evaluate clinical studies and standard of care treatments with the ultimate goal of implementing mechanistic-based precision medicine.