Thinking about more than B cells in lupus inflammation & pathogenesis
BARCELONA—With the excitement surrounding chimeric antigen receptor (CAR) T cell therapy as a potential treatment for systemic lupus erythematosus (SLE), one can be forgiven for forgetting about the other immune system cells involved in this disease.
At the EULAR 2025 session Not All About B Cells: Myeloid-Related Inflammation in Lupus Pathogenesis three speakers provided key insights into this important topic.
J. Michelle Kahlenberg, MD, PhD
Skin Considerations
The session’s first speaker was J. Michelle Kahlenberg, MD, PhD, the Giles Boles and Dorothy Mulkey Research Professor of Rheumatology, vice chair of basic and translational research, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor.
Dr. Kahlenberg began by noting that many of the conventional medications used in the treatment of SLE, such as methotrexate, mycophenolate mofetil and azathioprine, may help certain clinical domains, but often lack efficacy for cutaneous involvement. Anti-malarial medications, such as hydroxychloroquine, are often more helpful for cutaneous disease. Research from Zeidi et al. demonstrated that patients refractory to hydroxychloroquine show increased myeloid dendritic cell populations with higher tumor necrosis factor (TNF) α expression.1
Dr. Kahlenberg explained that active cutaneous disease in SLE is important because of its impact on quality of life and healthcare costs, as well as its direct link to systemic issues for patients. Skopelja-Gardner et al. showed that acute skin exposure to ultraviolet light can trigger a neutrophil-dependent injury response in the kidneys of patients with lupus. This response, which is characterized by upregulation of endothelial adhesion molecules and other markers associated with transient proteinuria, demonstrates a clear link between skin inflammation and kidney injury, with neutrophils serving as pathogenic mediators.2
Mitochondria
Virginia Pascual, MD
The session’s second speaker was Virginia Pascual, MD, director of the Drukier Institute for Children’s Health Research at Weill Cornell Medicine, New York. Dr. Pascual noted that SLE is an interferonopathy in which type I interferons—especially interferon-a—play a central and pathogenic role in the development and progression of the disease. Dr. Pascual connected this concept to an organelle rheumatologists may not routinely think about: mitochondria.
In healthy individuals, erythropoiesis involves the programmed removal of mitochondria from proerythroblasts via a hypoxia-inducible factor (HIF) mediated metabolic switch that activates the ubiquitin proteasome system and leads to the production of red blood cells free of mitochondria. Dr. Pascual and her colleagues found that, in a proportion of patients with SLE, this HIF-regulated process does not occur. Instead, an accumulation of mitochondria in red blood cells occurs. When these cells—termed Mito+ RBCs—are engulfed by macrophages, the result is activation of the cGAS/STING pathway, ultimately leading to the increased production of type I interferon.3
