Type I Interferons in Systemic Autoimmune Diseases: Distinguishing Between Afferent and Efferent Functions for Precision Medicine and Individualized Treatment.

François Chasset,Jean-Michel Dayer,Carlo Chizzolini

doi:10.3389/fphar.2021.633821

Abstract

A sustained increase in type I interferon (IFN-I) may accompany clinical manifestations and disease activity in systemic autoimmune diseases (SADs). Despite the very frequent presence of IFN-I in SADs, clinical manifestations are extremely varied between and within SADs. The present short review will address the following key questions associated with high IFN-I in SADs in the perspective of precision medicine. 1) What are the mechanisms leading to high IFN-I? 2) What are the predisposing conditions favoring high IFN-I production? 3) What is the role of IFN-I in the development of distinct clinical manifestations within SADs? 4) Would therapeutic strategies targeting IFN-I be helpful in controlling or even preventing SADs? In answering these questions, we will underlie areas of incertitude and the intertwined role of autoantibodies, immune complexes, and neutrophils.

Highlights

The interferon (IFN) response indicates a chain of molecular events in cells and tissues which comprises identification of genetic material by pattern recognition receptors (PRRs), signal transduction and initiation of IFN production, the response to IFN, and expression of IFNstimulated genes which exert their function and establish regulatory feed-forward loops (Figure 1)
We found that in multivariate analysis, only mucocutaneous and articular Systemic lupus erythematosus (SLE) clinical manifestations were associated with high IFN-I gene signature detected in peripheral blood (Chasset et al, 2020)
IFN-I self-stimulatory and amplificatory activity leading to high levels of interferon-stimulated genes (ISG) in systemic autoimmune diseases (SADs) may profoundly affect immunopathology participating both to the immune response and to tissue damage

Summary

INTRODUCTION

The interferon (IFN) response indicates a chain of molecular events in cells and tissues which comprises identification of genetic material by pattern recognition receptors (PRRs), signal transduction and initiation of IFN production, the response to IFN, and expression of IFNstimulated genes which exert their function and establish regulatory feed-forward loops (Figure 1). While almost all nucleated cells produce IFN-I including circulating leukocytes, pDCs expressing at their surface the inhibitory type II lectin receptor BDCA2 (blood dendritic cell antigen 2) are potent and well-recognized producers of IFN-alpha (Rönnblom and Alm, 2001) (Figure 3). PMN and LDG may participate to the IFN signature determined in peripheral blood and in tissue target of pathology (Kegerreis et al, 2019) This respect is relevant to stress that several cell types may contribute differentially to the production and IFN gene signature detected in blood. With these findings, when explored at single cell level by RNAsec, peripheral blood pDCs in SLE were found unable to produce IFN-α (Nehar-Belaid et al, 2020) These controversial findings highlight current difficulties in identifying the cells producing IFN-I in SADs

Methods

Findings

CONCLUSION