Skewed peripheral B- and T-cell compartments in patients with ANCA-associated vasculitis

Abstract

Objectives To characterize lymphocytes dysregulation in patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Methods Using flow cytometry, we analysed B- and T-cell subsets in peripheral blood from 37 untreated patients with active disease (29 GPA and 8 MPA) and 22 healthy controls (HCs). Results GPA patients had increased Th2 (1.8 vs 1.0%, P = 0.02), Th9 (1.1 vs 0.2%, P = 0.0007) and Th17 (1.4 vs 0.9%, P = 0.03) cells compared with HC. Patients with MPO-ANCAs had significantly more CD21– B cells than HC or PR3-ANCA patients (6.9 vs 3.3% and 4.4%, P = 0.01). CD69 expressing B cells were significantly higher in GPA and MPA (3.0 and 5.9 vs 1.4%, P = 0.02 and P = 0.03, respectively) compared with HC, whereas B-cell activating factor-receptor expression was decreased in GPA and MPA (median fluorescence intensity ratio 11.8 and 13.7 vs 45.1 in HC, P < 0.0001 and P = 0.003, respectively). Finally, IL-6-producing B cells were increased in GPA vs HC (25.8 vs 14.9%, P < 0.0001) and decreased in MPA vs HC (4.6 vs 14.9%, P = 0.005), whereas TNF-α-producing B cells were lower in both GPA and MPA patients compared with controls (15 and 8.4 vs 30%, P = 0.01 and P = 0.006, respectively). Conclusion Skewed T-cell polarization towards Th2, Th9 and Th17 responses characterizes GPA, whereas B-cell populations are dysregulated in both GPA and MPA with an activated phenotype and a decreased B-cell activating factor-receptor expression. Finally, inflammatory B cells producing IL-6 are dramatically increased in GPA, providing an additional mechanism by which rituximab could be effective.

Granulomatous Inflammation in ANCA-Associated Vasculitis

“…Although regulatory B cells have been investigated in AAV [ 141 , 142 , 143 ], little if anything is known with regard to their appearance and function in inflamed tissue of GPA or MPA. A study indicated that the number of circulating neutrophils positively correlates with the number of circulating memory B cells in GPA [ 144 ]. It may be of interest to find out if this association is maintained in situ as well, especially in light of the increased IL-6 production by circulating CD19 + B cells in GPA [ 144 ].…”

“…A study indicated that the number of circulating neutrophils positively correlates with the number of circulating memory B cells in GPA [ 144 ]. It may be of interest to find out if this association is maintained in situ as well, especially in light of the increased IL-6 production by circulating CD19 + B cells in GPA [ 144 ]. Sustained expression of IL-6 has been linked to local perivascular accumulation of B cells and mature plasma cells in a transgenic mouse model [ 145 ].…”

Serological Biomarkers and Indices for the Current Activity and Prognosis of ANCA-Associated Vasculitis: Experience in a Single Centre in Korea

“… 20 In terms of T-cell related biomarkers, T cell population was reported to be polarisation toward T H 2 and T H 17 cells. 21 In terms of complement related biomarkers, complement (C)3a, C5a, soluble C5b-9 and the alternative pathway components factor B may be associated with active AAV. 22 In terms of neutrophil related biomarkers, neutrophil extracellular traps are correlated with the current activity and may be suggested as a therapeutic target.…”

Targeting immune checkpoints in anti-neutrophil cytoplasmic antibodies associated vasculitis: the potential therapeutic targets in the future

“…Meanwhile, neutrophils could also be activated and express PR3 and MPO to combine with the ANCA secreted by plasma cells (9)(10)(11). The fragment a of fifth complement (C5a) produced by activating cAP could connect with the C5a receptor on neutrophils (12,13).…”