New research published in Immunity identifies a pathogenic function for the extra-follicular B cell differentiation pathway in patients with systemic lupus erythematosus (SLE).
B cells that undergo class switching but lack expression of immunoglobulin D and the memory marker CD27 are commonly referred to as double-negative (DN) B cells. These cells seem to serve different functions in the context of different diseases. In patients with HIV or malaria they have been characterized as having either an exhausted or anergic phenotype, respectively; however, a function in autoimmune disease is less clear.
To understand how these cells might contribute to autoimmunity, the researchers of the new study isolated and characterized DN B cells from two cohorts of patients with SLE. Patients in the SLE-2 cohort (n = 50) had higher disease activity, serum autoantibody titres and frequency of lupus nephritis than patients in the SLE-1 cohort (n = 40). Although the DN B cell population was expanded relative to healthy individuals in both cohorts, the DN B cell population from the SLE-2 cohort was highly enriched for a subset of DN B cells that lack the follicular homing marker CXCR5. Unlike CXCR5+ cells (called DN1 cells), these extra-follicular cells (called DN2 cells) were also more numerous in African–American individuals relative to people of other ethnic backgrounds, which might explain the high prevalence or severity of SLE in this population.
Using flow cytometry, epigenomics and transcriptomics, the researchers characterized the DN2 cells, showing that these cells are probably a unique lineage and that in patients with SLE they are frequently specific for known autoantigens.
“The DN2 cells show some differentiation characteristics of cells on the way to becoming a plasmablast, and are thus distinct from naive B cells,” says Steve Nutt, a B cell differentiation expert not associated with the new study.
So why do these autoreactive cells proliferate so much in patients with SLE?
“Cause and effect are extremely difficult to separate in a complex systemic autoimmune disease such as SLE,” cautions Nutt. “However, the DN2 cells show a striking hyper-plasmablast differentiation response to TLR7 agonists and a role for TLR7 hyper-responsiveness in the promotion of pathology is supported by studies in animal models.”
Whether these findings will translate into the development of therapeutics that target DN2 B cells is unclear, and Nutt points out that presently we have no way of depleting the DN2 B cell subset specifically. However, he is optimistic that these new data will be clinically important. “Detecting the frequency of DN2 B cells in patients may be useful for patient stratification and monitoring as well as provide a biomarker for clinical intervention studies,” he says.
Jenks, S. A. et al. Distinct effector B cells induced by unregulated Toll-like receptor 7 contribute to pathogenic responses in systemic lupus erythematosus. Immunity 49, 725–739.e6 (2018)
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Bernard, N.J. Double-negative B cells. Nat Rev Rheumatol 14, 684 (2018). https://doi.org/10.1038/s41584-018-0113-6