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

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.

Keywords: autoantibody (autoAb); genetic polymorphism; interferon; interferon-stimulated genes (ISGs); keratinocytes; polymorphonuclear neutrophils (PMN); systemic autoimmune diseases (SADs); systemic lupus erythematosus (SLE).

FIGURE 1

Schematic model of the cascade of events characterizing the IFN response in SADs. Blue: antigen drive; gradient blue: facilitator mechanisms for antigen uptake; yellow: receptors; green: intracellular signaling; red: IFN and ISG. The arrows indicate feed-forward regulatory mechanisms. Orange ovals: main cells implicated in IFN-I production. Abbreviations: IC: immune complexes; IFNAR: interferon-alpha/beta receptor; ISG: interferon-stimulated gene; ISRE: IRF: interferon regulatory factor; JAK: Janus kinase; LDG: low-density granulocyte; LL-37: cathelicidin-37; pDC: plasmacytoid dendritic cell; PMN: polymorphonuclear neutrophil; PRR: pattern recognition receptor; SADs: systemic autoimmune diseases; STAT: signal transducer and activator of transcription.

FIGURE 2

Schematic representation of pathways leading to interferon (IFN) production and IFN responses in many cell types. Highlighted the intracellular sensors of viral and endogenous DNA/RNA; the main interferon regulatory factors; the primary response characterized by IFN-beta production with autocrine and paracrine responses. Abbreviations: IFNAR: interferon-alpha/beta receptor; ISGF: interferon-stimulated gene factor; ISRE: interferon-stimulated response element; IRF: interferon regulatory factor; JAK: Janus kinase; MDA5: melanoma differentiation–associated protein 5; RIG-1: retinoic acid inducible gene-1; STAT: signal transducer and activator of transcription; STING: stimulator of interferon genes; Tyk: tyrosine kinase. Dashed line: negative feedback response.

FIGURE 3

Schematic representation of pathways leading to interferon (IFN) production and IFN responses in plasmacytoid dendritic cells (pDCs). Highlighted are the role of immune complexes and LL-37 in shuttling DNA/RNA into endosomes; the subsequent the role of TLR in inducing interferon regulatory factors and their role in gene transcription of IFN-alpha and other interferon-induced gene products, including feed-forward loops. RNA, particularly long double-stranded RNA, is preferentially sensed by MDA5 and RIG1. Abbreviations: Ab: antibody; FcgR: Fc gamma receptor; IRF: interferon regulatory factor; LL-37: cathelicidin-37; MDA5: melanoma differentiation–associated protein 5; MyD88: myeloid differentiation primary response 88; RIG-1: retinoic acid inducible gene-1; STING: stimulator of interferon genes; TLR: toll-like receptor.