“It’s also been proposed that DN2 cells are associated with age. We don’t find that age association in SLE. In lupus, it’s very striking that even in very young patients with acute disease onset, essentially all the B cells in the blood are already DN2s,” he said. They also correlate with high levels of anti-Smith autoantibody and high SLEDAI (a measure of SLE disease activity). Molecular programming of DN2 B cells in lupus patients points to one marker, SLAMF7, which may have therapeutic implications. Elotuzumab, a SLAMF7 inhibitor, is already approved by the U.S. Food and Drug Administration (FDA) for treatment of refractory multiple myeloma.
DN2 cells are also highly responsive to interferon-λ, which is another therapeutic target of growing interest in lupus research. It is also possible that an anti-SLAMF7 antibody therapy might be able to wipe out both the extrafollicular B cell pathway and pre-established, long-standing plasma cells, which Dr. Sanz’ group are studying in a current clinical trial.
Epigenetics
Epigenetic dysregulation of B cells in SLE provides more clues. Conventional studies of B cells are too heterogeneous, so results can be misleading, said Dr. Sanz. At his laboratory, RNA sequencing, bisulfite sequencing and ATAC sequencing is used to understand DNA methylation, chromatin accessibility and their impact on transcriptional activity of subsets of B cells, generating a large data set. They hope to discover whether epigenetic programs can identify distinct fates, activation and differentiation of particular B cell pathways, and if SLE-specific B cell programs can help segment disease populations to identify more precise therapies, serving as surrogates for disease developments, remission, therapeutic response and B cell tolerance, he said.
“If we could at least show that disease-related, epigenetic modifications are reversed, it would be a very good surrogate of the disease response and, perhaps, B cell tolerance,” he said. His current research in this area includes methylation studies, which reveal significant clues. “There are a few thousand loci in lupus B cells that are more methylated than in healthy controls, and with RNA sequencing, we find that 1,000 more are highly expressed in lupus B cells and 500 are down-regulated.”
Epigenetic research in SLE shows that resting naive B cells display a poised pathogenic signature even before activation and have a unique chromatin accessibility signature, he said.4 Mounting evidence suggests that dysregulation of lupus B cells starts very early in the disease process in the patient’s bone marrow.
Therapeutic Horizons
B cell research may lead to new, more effective therapies for specific subsets of SLE patients. These include histone deacetylase inhibitors, which may modify renal disease by regulating B cells epigenetically to modulate their response in lupus nephritis patients, he said.
