Th17-Immune Response in Patients With Membranous Nephropathy Is Associated With Thrombosis and Relapses

Abstract

Membranous nephropathy (MN) is a rare autoimmune kidney disease. Most autoimmune diseases are associated with a pro-inflammatory Th17-immune response, but little is known about immune dysregulation in MN. In China, MN was associated with exposure to fine air particulate matter (PM2.5) that could act as a danger signal and redirect immune response toward the Th2 or Th17 pathway. We aimed to analyze the cytokine profile of MN patients and to study the possible environmental factors involved in this immune reorientation, as well as the consequences on the prognosis of the disease. In this prospective study, 59 MN patients filled a comprehensive lifestyle questionnaire. Peripheral blood cells from MN patients were stimulated in vitro to measure the cytokines produced in supernatant. Cytokine profiles of MN patients were compared to 28 healthy donors and analyzed regarding individual PM2.5 exposure. Compared to healthy donors, MN patients had higher serum levels of Th17 and Th2 cytokines IL-17A (62 pg/ml [IQR, 16–160] versus 31 [IQR, 13–51], P=0.035), IL-6 (66767 pg/ml [IQR, 36860–120978] versus 27979 [IQR, 18672–51499], P=0.001), and IL-4 (12 pg/ml [IQR, 0–33] versus 0 pg/ml [IQR, 0–0], P=0.0003), respectively, as well as a deficiency of Th1 and regulatory T cell cytokines IFN-γ (5320 pg/ml [IQR, 501–14325] versus 18037 [IQR, 4889–31329], P=0.0005) and IL-10 (778 pg/ml [IQR, 340–1247] versus 1102 [IQR, 737–1652], P=0.04), respectively. MN patients with high IL-17A levels lived in areas highly exposed to PM2.5: 51 μg/m3 versus 31 μg/m3 for patients with low IL-17A levels (P=0.002) while the World Health Organization recommends an exposition below 10 μg/m3. MN patients with Th17-mediated inflammation had more venous thromboembolic events (P=0.03) and relapsed more often (P=0.0006). Rituximab treatment induced Th1 and regulatory T cell cytokines but did not impact Th17 cytokines. MN patients with Th17-mediated inflammation which appears to be related to an urban environment have worse prognosis. Alternative strategies targeting dysregulated cytokine balance could be considered for these patients at high risk of relapse.

Perspectives in membranous nephropathy

“…Treg frequencies increased after treatment with rituximab, indicating restoration of immune balance. In line with these results, MN patients were recently identified to have higher Th17 and Th2 cytokines (IL-17A, IL-6, and IL-4) and lower Th1 and Treg cytokines (interferon-γ and IL-10), showing a cytokine dysbalance in MN patients (Cremoni et al 2020). Interestingly, patients with the highest Th17 signature lived in areas with a higher burden of fine particulate matter, suggesting a connection between air pollution, immune dysregulation and incidence of MN.…”

Proteinuria as a Biomarker for COVID-19 Severity

“…All these cells would actively respond to IL6 ( Su et al, 2017 ). Moreover, plasma and urinary IL6 concentrations correlated with proteinuria in acute Hantavirus-induced nephritis ( Mäkelä et al, 2004 ) and increased IL6 plasma levels and a TH17 profile have already been described in glomerular diseases such as membranous nephropathy ( Cremoni et al, 2020 ).…”

“…Even if a case of collapsing glomerulopathy has been reported in COVID-19 ( Gaillard et al, 2020 ), acute tubular necrosis (ATN) with interstitial component probably remains the main cause of kidney injury. Other factors may contribute to kidney involvement: systemic inflammation and cytokine storm ( Burton and Harris, 1996 ; Coletta et al, 2000 ; Gohda et al, 2001 ; D’Amico and Bazzi, 2003 ; Imai, 2003 ; Thorevska et al, 2003 ; Mäkelä et al, 2004 ; Wassmann et al, 2004 ; Kielar et al, 2005 ; Abbate et al, 2006 ; Liu et al, 2007 ; Delvaeye and Conway, 2009 ; Murugan et al, 2010 ; Ranganathan et al, 2013 ; Darmon et al, 2014 , 2017 ; Su et al, 2017 ; Sarhan et al, 2018 ; Meissner et al, 2019 ; Cremoni et al, 2020 ; Mehta et al, 2020 ; Pan et al, 2020 ; Rossi et al, 2020 ; Siddiqi and Mehra, 2020 ; Tang et al, 2020 ; Vaninov, 2020 ; Zhang et al, 2020 ; Ruetsch et al, 2021 ), release of pathogen-associated molecular patterns (PAMPs), high levels of damage-associated molecular proteins (DAMPS) from lung injury and severe hypoxemic respiratory failure ( Burton and Harris, 1996 ; Coletta et al, 2000 ; Gohda et al, 2001 ; D’Amico and Bazzi, 2003 ; Thorevska et al, 2003 ; Mäkelä et al, 2004 ; Wassmann et al, 2004 ; Kielar et al, 2005 ; Abbate et al, 2006 ; Delvaeye and Conway, 2009 ; Ranganathan et al, 2013 ; Darmon et al, 2014 , 2017 ; Su et al, 2017 ; Sarhan et al, 2018 ; Meissner et al, 2019 ; Cremoni et al, 2020 ; Pan et al, 2020 ; Rossi et al, 2020 ; Siddiqi and Mehra, 2020 ; Tang et al, 2020 ; Vaninov, 2020 ; Zhang et al, 2020 ; Ruetsch et a...…”

“…Pro-inflammatory cytokines can also induce capillary leak syndrome and the production of thrombosis. Interestingly, IL6 could be produced by renal resident cells, including podocytes ( Burton and Harris, 1996 ; Coletta et al, 2000 ; Gohda et al, 2001 ; Mäkelä et al, 2004 ; Wassmann et al, 2004 ; Kielar et al, 2005 ; Abbate et al, 2006 ; Ranganathan et al, 2013 ; Su et al, 2017 ; Cremoni et al, 2020 ; Pan et al, 2020 ; Ruetsch et al, 2021 ), mesangial cells ( Coletta et al, 2000 ; Gohda et al, 2001 ), endothelial cells ( Wassmann et al, 2004 ) and tubular epithelial cells ( Kielar et al, 2005 ; Ranganathan et al, 2013 ). All these cells would actively respond to IL6 ( Su et al, 2017 ).…”

Anti-PLA2R Antibodies Measured by ELISA Predict the Risk of Vein Thrombosis in Patients With Primary Membranous Nephropathy

“…The correlation of anti-PLA2R antibody induced renal injury and activation of coagulation deserves further investigation. On the other hand, a recent study demonstrated that MN patients with Th17-mediated in ammation had more VTEs [27]. Th17-immune response is a proin ammatory immune pathway associated with autoimmune diseases [28,29].…”