The Role of Type I Interferon in Interstitial Lung Disease

A shared feature of all systemic autoimmune diseases (SADs) is interstitial
lung disease (ILD), which is a leading cause of death. Type I Interferon
(IFN-I) plays a key role in the pathogenesis of SADs. However, much is still
unknown and one of the unanswered questions is whether IFN-I also plays a role
in the development of ILD in SADs. New treatments blocking the IFN-I pathway
activation are emerging and IFN-I might be a potential treatment target for
ILDs as well. Moreover, there are patients who do not meet criteria for a
certain SAD, but have a combination of ILD and autoimmune features. These are
patients with IPAF (Interstitial Pneumonia with Autoimmune Features). It would
be valuable to study whether these patients also have increased IFN-I activity,
so that they too can be considered for anti-IFN therapies.

The overall aim of this project is to unravel the role of IFN-I in ILD in the
known/classified SADs and in ILD with autoimmune features but without a
specific SAD diagnosis (IPAF), with as ultimate goal better treatment. Since
13-40% of ILD patients will develop a progressive fibrosing form of ILD, we
will also look into the relation between IFN-I and fibrosis. We will do this by
assessing IFN-I activity in patients with a typically fibrotic ILD but without
autoimmune features i.e. Idiopathic Pulmonary Fibrosis (IPF) and by performing
mechanistic studies in in vitro models for fibrosis. Furthermore, we want to
explore whether IFN-I activity can be predictive for response of ILD to
standard care immunosuppression and be used as a stratification tool for
selection of ILD patients for immunosuppression or for anti-fibrotic agents.
The 5 objectives are:
1: To assess IFN-I activity in different SADs with and without ILD to determine
possible differences in IFN-I activity
2: To assess IFN-I activity in patients with IPAF
3: To assess IFN-I activity in patients with IPF
4: To study whether baseline IFN-I activity predicts the response to standard
care immunosuppressive therapy after 3 months of treatment defined as increase
in pulmonary function test
5: To elucidate the relation between IFN-I and lung fibrosis in in vitro models
for fibrosis

Blood samples will be collected from 30 SAD patients without ILD, 30 SAD
patients with ILD, 30 IPAF and 30 IPF patients. To assess IFN-I activity, five
IFN-I induced genes (i.e. IFN-I signature) will be assessed by PCR in whole
blood and IFN-I protein will be measured by Simoa (single-molecule array) in
serum. Blood tests for assessing IFN-I activity and pulmonary function tests
will be performed in ILD SAD and IPAF patients before start of standard care
immunosuppressants and 3 months after to evaluate whether IFN-I activity can
predict the level of response to standard care immunosuppression. The relation
between IFN-I and fibrosis will be studied in two in vitro models for fibrosis.

The burden on the patients in this study is negligible. Clinical data will be
collected anonymized and extra study blood samples will only be taken in
addition to blood samples drawn for clinical use. Pulmonary function tests will
be performed as part of standard clinical care. In this way there are no extra
risks for the participating patients.