B Cell Complexity in Human SLE
Ignacio “Iñaki” Sanz, MD
Ignacio “Iñaki” Sanz, MD, Mason I. Lowance Professor of Medicine and Pediatrics, chief, Division of Rheumatology, director, The Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, shared findings on B cell complexity in SLE.2–4 He was available for interview.
TR: Ultimately, what do you hope to accomplish with your research?
Dr. Sanz: Through our research we aim to better understand the mechanisms underlying the autoimmune response in SLE—in particular, the different mechanisms and pathways through which SLE patients generate pathogenic B cells, plasma cells and autoantibodies. Notably, we have recently demonstrated that these mechanisms also contribute to an autoimmune response in non-lupus patients with severe COVID-19 infection.
TR: Can you summarize your most exciting findings?
Dr. Sanz: We have defined new B cell populations that become highly active during SLE flares. The activation of these populations depends on the recruitment of new B cells and the generation of autoantibodies rather than the expansion of pre-formed memory cells that are present for many years in SLE patients. Interestingly, the participation of these cells is promoted by epigenetic imprinting of the corresponding B cells.
TR: What might be the clinical implications of your findings in the future as they pertain to patient care?
Dr. Sanz: The new B cell mechanisms that we have described are not present in all patients. Instead, they are more prominent in patients with SLE who are Black with severe disease. These findings reflect a large degree of disease heterogeneity and should allow for better tailoring of treatments and clinical trials to the patient populations more likely to respond.
A Systems Biology Approach for Pediatric & Adult AI Diseases
Virginia Pascual, MD
Virginia Pascual, MD, Ronay Menschel Professor of Pediatrics, Weill Cornell Medical College, New York, New York also shared work on a systems biology approach for pediatric and adult autoimmune disease.5–7 “Systems biology approaches use high throughput technologies and generate large amounts of data,” she explained. Her group’s goal is to understand the heterogeneity of SLE to stratify patients and find the right therapies for them as soon as possible.
“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.
Conclusion
SLE is different for every patient who has it, and ACE’s researchers are getting closer to understanding why and how. We look forward to a future when tailored therapies for SLE patients are reality. We may not be that far off.
Samantha C. Shapiro, MD, is the executive editor of Harrison’s Principles of Internal Medicine. As a clinician educator, she practices telerheumatology and writes for both medical and lay audiences.
References
- National Institute of Allergy and Infectious Diseases (NIAID).
- Jenks SA, Cashman KS, Zumaquero E, et al. Distinct effector B cells induced by unregulated toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity. 2018;49(4).
- Scharer CD, Blalock EL, Mi T, et al. Epigenetic programming underpins B cell dysfunction in human SLE. Nat Immunol. 2019;20(8).
- Woodruff MC, Ramonell RP, Haddad NS, et al. Dysregulated naive B cells and de novo autoreactivity in severe COVID-19. Nature. 2022;611(7934).
- Nehar-Belaid D, Hong S, Marches R, et al. Mapping systemic lupus erythematosus heterogeneity at the single-cell level. Nat Immunol. 2020;21(9).
- Caielli S, Veiga DT, Balasubramanian P, et al. A CD4+ T cell population expanded in lupus blood provides B cell help through interleukin-10 and succinate. Nat Med. 2019;25(1).
- Caielli S, Cardenas J, de Jesus AA, et al. Erythroid mitochondrial retention triggers myeloid-dependent type I interferon in human SLE. Cell. 2021;184(17).
- Li H, Tsokos MG, Tsokos GC. Lymphocytes in the neighborhood: Good or bad for the kidney? J Clin Invest. 2022;132(13).
- Abraham R, Durkee MS, Ai J, et al. Specific in situ inflammatory states associate with progression to renal failure in lupus nephritis. J Clin Invest. 2022;132(13).
- Liarski VM, Sibley A, Panhuys N van, et al. TD-03 convolutional neural networks identify in situ adaptive immune cell architectures in human lupus.
