CD11c+ T-bet+ CD21hi B Cells Are Negatively Associated With Renal Impairment in Systemic Lupus Erythematosus and Act as a Marker for Nephritis Remission

Abstract

Lupus nephritis (LN) is one of the most common manifestations of systemic lupus erythematosus (SLE), characterized by abnormal B cell activation and differentiation to memory or plasma effector cells. However, the role of these cells in the pathogenesis of LN is not fully understood, as well as the effect of induction therapy on B cell subsets, possibly associated with this manifestation, like aged-associated B cells (ABCs). Consequently, we analyzed the molecules defining the ABCs subpopulation (CD11c, T-bet, and CD21) through flow cytometry of blood samples from patients with lupus presenting or not LN, following up a small sub-cohort after six months of induction therapy. The frequency of ABCs resulted higher in LN patients compared to healthy subjects. Unexpectedly, we identified a robust reduction of a CD21hi subset that was almost specific to LN patients. Moreover, several clinical and laboratory lupus features showed strong and significant correlations with this undefined B cell subpopulation. Finally, it was observed that the induction therapy affected not only the frequencies of ABCs and CD21hi subsets but also the phenotype of the CD21hi subset that expressed a higher density of CXCR5. Collectively, our results suggest that ABCs, and more importantly the CD21hi subset, may work to assess therapeutic response since the reduced frequency of CD21hi cells could be associated with the onset of LN.

Update on novel blood-based biomarkers for lupus nephritis beyond diagnostic approaches

“…Interestingly, our group recently confirmed the potential utility of the CD11c + T-bet + CD21 lo/-B lymphocytes (known as age-associated B cells or ABCs) to assess lupus nephritis; however, we also reported the finding of a related cell subset CD11c + T-bet + CD21 hi B cells that are almost absent when renal manifestations arise 22 . Importantly, this CD 21hi subset could be used as a prognostic factor as their numbers strongly correlate with a lower SLE activity.…”

“…Interestingly, in the context of LN, serum levels of Galectin-9 also reflect kidney damage and not only SLE activity 7,14 . [6][7][8]18,22 . LN: lupus nephritis; Activity Scores -SLEDAI: systemic lupus erythematosus activity index; rSLEDAI: renal SLEDAI; ACR: American College of Rheumatology; AI: activity index; CI: chronicity index; SLICC: systemic lupus international collaborating clinics; BILAG: British Isles lupus assessment group; Biomarkers -Anti-ENO1: anti-α-enolase antibody; Anti-MDA: IgG anti-malondialdehyde protein; GAS6: growth arrest specific protein 6; HE4: human epididymis protein; HMGB-1: high-mobility group box-1; MCP-1: monocyte chemoattractant protein-1; NETs: neutrophil extracellular traps assay; Nox2: NADPH oxidase.…”

Editorial: New biomarkers for the diagnosis and treatment of systemic lupus erythematosus

“…In a 3-stage study including a total of 321 LN patients, a combination of four biomarkers, adiponectin, MCP-1, sVCAM-1 and PF4, were found to have the greatest predictive value for the detection of proliferative, active LN ( 18 ). Patients with LN exhibit a profound depletion of atypical age-associated B-cell (ABC) like CD11c + T-bet + CD21 hi B cells in comparison with healthy individuals and SLE patients without LN ( 19 ). Selected from 284 DEGs identified in two independent SLE cohorts in the Gene Expression Omnibus (GEO) database, machine learning validated ABCB1, IFI27, and PLSCR1 as top predictors of SLE in a Chinese validation cohort of patients over ethnically matched controls ( 13 ).…”

“…Therefore, integrating biomarkers into the signaling networks that connect the adaptive and innate arms of a dysfunctional immune system is critical for appreciating their significance for controlling pathogenesis, predicting flares or serving as target for treatment in SLE. Notably, only few of these studies involved cellular biomarkers ( 13 , 19 ) that can be connected to central pathways of lupus pathogenesis. Nevertheless, certain easily detectable biomarkers may also serve other purposes, such as sensing organ damage and obviating the need for invasive procedures, i.e., renal biopsy in LN ( 15 , 17 – 19 ).…”

“…Notably, only few of these studies involved cellular biomarkers ( 13 , 19 ) that can be connected to central pathways of lupus pathogenesis. Nevertheless, certain easily detectable biomarkers may also serve other purposes, such as sensing organ damage and obviating the need for invasive procedures, i.e., renal biopsy in LN ( 15 , 17 – 19 ). Fisetin was found to control depression by preventing the senescence of neuronal cells in the hippocampus of MRl/lpr mice ( 10 ).…”