Study on NRf2 Keap1 axis in b cells of systemic lupus erythematosus

Abstract

Systemic Lupus Erythematosus (SLE) is a multifaceted autoimmune disorder with inconsistent, multisystem clinical manifestations. The disease has relapsing and remitting courses with variable intensities. Moreover, a shortage of suitable biomarkers to predict disease activity of this heterogeneous disorder makes the diagnosis and management process more cumbersome. Oxidative stress has been considered as a potential target to the pathogenesis of inflammatory disorder SLE and Nrf2/Keap1 system has been described for its ability to equilibrate the concentration of free radicals. Therefore, the present study was designed to address Nrf2/Keap1 redox regulation in immune cells derived from SLE patients with inactive and active disease. For this, level of free radicals was determined in Peripheral Blood Mononuclear Cells (PBMCs), B cell subsets and Dendritic Cell (DCs) subsets and correlated with the expression of Nrf2 and Keap1 proteins. Since Nrf2 acts as a transcription factor and upregulates the expression of various antioxidants, the activity of Nrf2 governed antioxidants was assessed in isolated PBMCs and B cells. Additionally, the frequency of DC and B cell subsets in the peripheral blood was determined and compared with the levels of Type 1 IFNs, BAFF, APRIL and IL-6. The present study demonstrates that the impaired activity of antioxidants with increment in disease severity. Further, redox regulating Nrf2 and Keap1axis was differentially functional in PBMCs, B-subsets and DCs of patients in comparison to healthy controls. Differentiation of B-cell repertoire was found to be under the influence of Type- I Interferons. Furthermore, Nrf2 has emerged as a crucial redox regulating component in PBMCs and more specifically B cell subsets. The epigenetic aspect of B cells was also explored by scrutinizing histone acetylation and global hypoacetylation in H3 and H4 histone proteins observed in B-cells of lupus patients is a novel finding. Expression of DNA methyltransferase 1 was found to be reduced in lupus patients.