Type 1 interferonopathies

Crow Y, 2011

The type 1 interferonopathies represent a group of rare, genetically and phenotypically heterogeneous diseases caused by a malfunction of the innate immune system (Crow YJ 2011). With the exception of multifactorial SLE, these are very rare disorders.

Note: By elucidating the genetic causes of rare monogenic disease patterns associated with chronic type 1 interferon activation, new disease mechanisms have been identified that can be linked to autoinflammation and autoimmunity.

Thus, the central role of type I interferons in the pathogenesis of autoimmune diseases first became apparent in systemic lupus erythematosus (SLE) (Vallin H et al. 1999). SLE patients exhibit a strong Toll-like receptor-mediated interferon signature (upregulation of interferon-stimulated genes) in the blood (Baechler EC et al. 2003).

Major type I interferon producers are plasmacytoid dendritic cells, which are particularly activated in patients with SLE (Vallin H et al. 1999; Lande R et al. 2007).

The monogenic and polygenic clinical pictures listed below are summarized under the term type 1 interferonopathies (see also Immunodeficiencies/autoiflammatory diseases/CrowY, 2011):

• Aicardi-Goutières syndrome: Mutations in the genes: TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, IFIH1 (autosomal recessive inheritance)
• Retinal vasculopathy with cerebral leukodystrophy: mutation in the TREX1 gene (autosomal dominant inheritance)
• Familial chilblain lupus: mutations in the genes TREX1, SAMHD1 (autosomal dominant inheritance)
• STING-associated vasculopathy: mutation in the STING gene (autosomal dominant inheritance)
• Systemic lupus erythematosus: Mutations in the genes TREX1, RNASEH2A-C, DNASE1, DNASE1L3, IFIH1 (multifactorial inheritance)
• Spondyloenchondrodysplasia: mutation in the ACP5 gene (autosomal recessive inheritance)
• Singleton-Merten syndrome: mutation in the IFIH1 and RIGI genes (autosomal dominant inheritance)
• MSMD due to complete ISG15 defect: mutation in the ISG15 gene (autosomal recessive inheritance)
• CANDLE syndrome: mutation in the PSMB8 gene (autosomal recessive inheritance)
• Pseudo-TORCH syndrome3: mutation in the STAT2 gene

Pathogenetically, type 1 interferonopathies are based on disturbances in metabolism and in the immunological recognition of intracellular nucleic acids. The dysregulation of the type-1 interferon (IFN) axis leads to a constitutive type-1 interferon activation which can lead to the following molecular consequences:

• disturbed negative regulation of type 1 IFN signalling pathways.
• increased or altered sensitivity of nucleic acid sensors
• Ligand independent activation of components of downstream signal cascades
• unphysiological accumulation or chemical modification of endogenous nucleic acids

Type 1 interferons(IFN-α and IFN-β) act as essential effector cytokines of the immune response to pathogenic germs. The production of type 1 interferons (type 1 IFN) is induced by receptors of the innate immune system that detect pathogenic danger signals. Activation of the type 1 IFN signaling cascade results in the transcriptional induction of hundreds of IFN-stimulated genes, the interaction of which places the host organism in an antiviral state with the aim of eliminating infected cells and limiting the spread of infection. Uncontrolled activation of type 1 IFN can have negative consequences for the host organism, as it promotes inadequate inflammatory processes and the loss of immunological tolerance.

Our current understanding of the molecular pathogenesis of type 1 interferonopathies suggests that an immunomodulatory intervention that counteracts inadequate type 1 IFN activation could be therapeutically effective (see below for the individual clinical pictures)

1. Aicardi J et al (1984) A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15:49-54
2. Atianand MK et al (2013) Molecular basis of DNA recognition in the immune system. J Immunol 190:1911-1918
3. Baechler EC et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610-2615
4. Crow YJ (2011) Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 1238:91-98
5. Crow YJ et al (2015) Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol 15:429-440
6. Günther C et al (2016) Type I interferonopathies. Z Rheumatol 75: 134-140
7. Iwasaki A et al (2010) Regulation of adaptive immunity by the innate immune system. Science 327:291-295
8. Lande R et al (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptides. Nature 449:564-569
9. Lee-Kirsch MA et al (2013) Aicardi-Goutieres syndrome: a model disease for systemic autoimmunity. Clin Exp Immunol 175:17-24
10. Ronnblom LE et al (1991) Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 115:178-183
11. Vallin H et al (1999) Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-alpha) production acting on leucocytes resembling immature dendritic cells. Clin Exp Immunol 115:196-202
12. Yang YG, Lindahl T, Barnes DE (2007) Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873-886