Investigation of type I interferon responses in ANCA-associated vasculitis

Isabella Batten,Zoe Wigston,Barbara Fazekas,Conor C Murphy,Arthur White,Mark W Robinson,Mark A Little,Edward M Vital,Cathal Walsh,Joan Ní Gabhann-Dromgoole,Nollaig M Bourke,Emily Greenan,Suzanne D’Arcy,Antonia Buettner,Jason Wyse

doi:10.1038/s41598-021-87760-4

Abstract

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) is an autoimmune disease characterised by necrotising inflammation of small blood vessels. The underlying biology of AAV is not well understood, however several studies have noted abnormalities in type I IFN responses. We hypothesised that type I IFN responses are systemically dysregulated in AAV, consistent with features of a type I interferonopathy. To investigate this, we measured the expression of seven interferon regulated genes (IRGs) (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) in peripheral blood samples, as well as three type I IFN regulated proteins (CXCL10, MCP-1 and CCL19) in serum samples from AAV patients, healthy controls and disease controls. We found no difference in type I IFN regulated gene or protein expression between AAV patients and healthy controls. Furthermore, IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Thus, we conclude that systemic type I IFN responses are not key drivers of AAV pathogenesis and AAV should not be considered a type I interferonopathy.

Highlights

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions
Expression of specific interferon regulated genes (IRGs) are elevated in blood from patients with type I interferonopathies and correlate with disease severity in these conditions[2,20,21]; we investigated the expression of a panel of these IRGs (ISG15, SIGLEC1, STAT1, RSAD2, IFI27, IFI44L and IFIT1) using mRNA extracted from whole blood samples
Our results indicate no link between systemic type I IFN regulated gene and protein expression and Associated Vasculitis (AAV), suggesting that AAV is not a type I interferonopathy and that patients are unlikely to benefit from interferon inhibiting therapies

Summary

Introduction

Type I interferon (IFN) dysregulation is a major contributory factor in the development of several autoimmune diseases, termed type I interferonopathies, and is thought to be the pathogenic link with chronic inflammation in these conditions. IRG and IFN regulated protein expression did not correlate with clinical measurements of disease activity in AAV patients. Type I IFNs are essential mediators of immune functions and are noted for their anti-viral, antiproliferative and immuno-regulatory properties[3] These cytokines regulate a wide range of biological processes and, under normal homeostatic conditions, their activation is tightly r egulated[4]. In 2009, while studying the process of NETosis in AAV, Kessenbrock et al found increased MxA expression, a typical interferon regulated gene (IRG), in the glomeruli and tubules of active AAV patients They noted increased IFN-α concentrations in the serum of active AAV patients in comparison to AAV remission patients and healthy controls, suggesting a role for these cytokines in AAV a ctivity[16]. To our knowledge, type I IFNs have never been conclusively investigated as causative factors of AAV initiation or progression and, with specific therapies designed to target various elements of type I IFN responses currently undergoing clinical trials for the treatment of type I interferonopathies, investigations into the role of these cytokines in AAV has become even more p ressing[18,19]

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