Type I interferon-mediated monogenic autoinflammation: The type I interferonopathies, a conceptual overview

Abstract

Type I interferon is a potent substance. As such, the induction, transmission, and resolution of the type I interferon-mediated immune response are tightly regulated. As defined, the type I interferonopathies represent discrete examples of a disturbance of the homeostatic control of this system caused by Mendelian mutations. Considering the complexity of the interferon response, the identification of further monogenic diseases belonging to this disease grouping seems likely, with the recognition of type I interferonopathies becoming of increasing clinical importance as treatment options are developed based on an understanding of disease pathology and innate immune signaling. Definition of the type I interferonopathies indicates that autoinflammation can be both interferon and noninterferon related, and that a primary disturbance of the innate immune system can "spill over" into autoimmunity in some cases. Indeed, that several non-Mendelian disorders, most particularly systemic lupus erythematosus and dermatomyositis, are also characterized by an up-regulation of type I interferon signaling suggests the possibility that insights derived from this work will have relevance to a broader field of clinical medicine.

Figure 1.

Type I interferon signaling and type I interferonopathies as currently assigned. Diseases considered as monogenic interferonopathies are represented by blue boxes. This schema alludes to at least seven possible cellular mechanisms resulting in sustained activation of interferon signaling caused by the following: (1) loss-of-function mutations leading to increased cytosolic DNA (TREX1 [Stetson et al., 2008] and SAMHD1 [Behrendt et al., 2013; Rehwinkel et al., 2013]) or RNA/DNA hybrid (RNASEH2A, RNASEH2B and RNASEH2C, POLA1) sensing (Hiller et al., 2012; Mackenzie et al., 2016; Starokadomskyy et al., 2016); (2) loss-of-function mutations leading to a defect in RNA editing and abnormal sensing of self–nucleic acid RNA species in the cytosol (ADAR1 [Liddicoat et al., 2015; Pestal et al., 2015]); (3) gain-of-function mutations leading to constitutive activation of cytosolic interferon signaling pathways/increased sensitivity to cytosolic nucleic acid ligands (MDA5 [Rice et al., 2014], RIG-I [Jang et al., 2015], and STING [Liu et al., 2014]); (4) loss-of-function mutations leading to aberrant RNA signaling via MAVS caused by a disturbance of the unfolded protein response (SKIV2L [Eckard et al., 2014]); (5) loss-of-function mutations in molecules responsible for limiting interferon receptor (IFNAR1/2) signaling leading to uncontrolled ISG production (USP18 [Meuwissen et al., 2016] and ISG15 [Zhang et al., 2015]); (6) proteasomal dysfunction leading to increased interferon signaling through an unknown mechanism (PSMA3, PSMB4, and PSMB8 [Brehm et al., 2015]; we do not include the so-far single-published mutations in PSMB9 and POMP); and (7) loss-of-function mutations in TRAP/ACP5 (Briggs et al., 2011; Lausch et al., 2011) and C1q (Lood et al., 2009; Santer et al., 2010) where we consider the mechanisms leading to type I interferon signaling are yet to be fully clarified (we do not include mutations in other molecules of the complement pathway as a clear demonstration of enhanced interferon signaling has not been established).

Figure 2.

Specific and overlapping features of monogenic type I interferonopathies. In the broadest sense, CNS and skin disease are the most common features of the type I interferonopathies. Discrete neurological phenotypes associated with mutations in AGS-associated genes include “nonsyndromic” spastic paraparesis (RNASEH2B, ADAR1, and IFIH1 [Crow et al., 2014]) and bilateral striatal necrosis (ADAR1 [Livingston et al., 2014]). Glaucoma is a common feature of AGS (Crow et al., 2015) and is also seen in the Singleton-Merton syndrome phenotype associated with gain-of-function mutations in IFIH1 (Bursztejn et al., 2015; Rutsch et al., 2015) and DDX58 (RIG-I [Jang et al., 2015]). SLE (lupus) is most frequently associated with mutations in ACP5 (An et al., 2016; Briggs et al., 2016) and C1q (Lood et al., 2009; Santer et al., 2010). Malignancy has only been reported in the context of SAMHD1 (Clifford et al., 2014; Merati et al., 2015). Lung inflammation is so far restricted to patients with mutations in TMEM173 (STING; Liu et al., 2014; Clarke et al., 2016; Picard et al., 2016). The phenotypes associated with mutations in POLA1 and SKIV2L appear distinct.

Figure 3.

Outline of treatment strategies in the type I interferonopathies. Dependent on the underlying pathological mechanism, therapeutic approaches in the type I interferonopathies might include blocking the generation (e.g., using reverse transcription inhibitors: https://clinicaltrials.gov/ct2/show/NCT02363452), sensing (e.g., cGAS inhibition by hydroxychloroquine [An et al., 2015]), or signaling (e.g., TBK1 inhibition [Hasan et al., 2015]) of putative self–nucleic acids engaging the type I interferon innate immune machinery and blocking of interferon itself (e.g., with anti–type I interferon antibodies), the IFNAR receptor, or the signaling cascades distal to interferon ligand binding (e.g., by JAK1 inhibition [Frémond et al., 2016]).