Heterogeneity in Lupus: Lessons from the Autoimmune Centers of Excellence

“The more we investigate, the more we find leads that take us into uncharted territories of how the immune system is dysregulated differentially from one patient to another,” she summarized. “Hopefully in following these leads, we are going to be able to understand the pathogenic pathways that operate in each of our patients and be able to rationally design successful clinical trials.”

Quantifying in situ Inflammation in Human Lupus Nephritis

Marcus R. Clark, MD

Marcus R. Clark, MD, professor of medicine, chief, Section of Rheumatology, co-director, Knapp Center for Lupus and Immunology Research, Pritzker School of Medicine, University of Chicago, shared findings specific to lupus nephritis.^8–10  He was available for interview.

TR: What do you hope to accomplish with your research?

Dr. Clark: We aim to characterize the in situ immune cell heterogeneity of lupus nephritis, including defining major groups that differ in underlying mechanisms and prognosis.

TR: Can you summarize your most exciting findings? 

Dr. Clark: Lupus nephritis can be thought of as really two diseases. The first disease is a glomerulonephritis (GN) that arises from systemic autoimmunity, including deposition of autoantibodies (especially anti- double stranded deoxyribonucleic acid [anti-dsDNA]). The second disease arises from local autoimmunity and affects the tubulointerstitium. This local autoimmunity is much more complex and fundamentally different than GN. It includes networks of antigen presenting cells, T cell subsets and local antigen-driven B cell selection that feed forward to drive local inflammation and damage.

Last year, we published that among adaptive immune cells, there are different pathways or trajectories of inflammation marked by either B cells or CD4-negative T cells including gamma delta and CD8 T cells. Surprisingly, the CD4-negative T cell trajectory was associated with progressive disease, while a predominance of B cells predicted a good outcome. These provide an example of how in situ immunity is so different from systemic autoimmunity. Most recently, we have demonstrated very distinct in situ myeloid states that likely have prognostic and therapeutic implications. We are currently investigating the spatial relationships between adaptive and innate cell networks in the lupus nephritis kidney. 

TR: What might be the clinical implications of your findings in the future as they pertain to patient care? 

Dr. Clark: Ultimately, we hope to define simple biomarkers that can be assayed on renal biopsies to define different prognostic and therapeutic groups. By defining mechanistic heterogeneity, we hope to arrive at personalized treatments for the kidney that would complement treatment for systemic autoimmunity.