Investigation of type I interferon responses in ANCA-associated vasculitis

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.

Monocyte-derived macrophages aggravate pulmonary vasculitis via cGAS/STING/IFN-mediated nucleic acid sensing

“…ISG or IFN-I have been shown to be increased in patients with active vasculitis (Kessenbrock et al 2009). However, a recent study did not find increased IFN-I or ISG expression in ANCA vasculitis patients (Batten et al 2021). The reasons for this apparent disagreement are unresolved, although differences in disease severity across the different patient cohorts cannot be excluded.…”

Type I Interferon and the Spectrum of Susceptibility to Viral Infection and Autoimmune Disease: A Shared Genomic Signature

“…IFNa protein is also increased in pSS and has an increased IFN-I signature. Taken together, these observations suggest a common IFN-I mediated mechanism in autoimmune disease (35). Similar to viral infection, susceptibility to autoimmunity is variable, and the disease course of individuals with autoimmune disease is often heterogeneous (36).…”

Gene Signature of Regulatory T Cells Isolated from Children with Selective IgA Deficiency and Common Variable Immunodeficiency

“…Their characteristics are presented in Table 4. systemic lupus erythematosus [38], primary Sjögren's syndrome [39], autoimmune demyelinating CNS disorders [40], ankylosing spondylitis [41], Anti-neutrophil cytoplasmic antibody (ANCA)-Associated Vasculitis (AAV) [42], juvenile dermatomyositis (JDM) [43], systemic sclerosis [44], experimental autoimmune encephalomyelitis [45], type 1 diabetes [46] MX1 −5.23 (0.0176) MX dynamin-like GTPase 1…”

“…rheumatoid arthritis [57] IFI44L −4.42 (0.0294) interferon-induced protein 44-like primary Sjogren's syndrome [39], systemic lupus erythematosus [58], rheumatoid arthritis [59], (ANCA)-Associated Vasculitis (AAV) [42], mixed connective tissue disease [52], systemic sclerosis [60]…”