Type 1 interferons

Type I interferons (IFNs) are important messengers of the immune system and play a decisive role in viral infections: they bind to a special receptor on the surface of their target cells, the interferon-alpha/beta receptor (IFNAR).

Interferon alpha (IFN-α), is produced by leukocytes, especially macrophages and dendritic cells. There are 13 human genes for IFN-alpha. A second class, interferon beta (IFN-β), is produced by fibroblasts. There is only one human IFN-beta gene. The genes for IFN-alpha and -beta are located on human chromosome 9 and share many common characteristics. They are therefore classified as type I interferons. Interferon gamma (IFN-γ) is produced by T-cell lymphocytes. There is only one human gene for this interferon on chromosome 12. IFN-gamma differs in many properties from type I interferons and is therefore referred to as type II interferon. The central importance 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 show 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 clinical pictures listed below are summarized under the term type 1 interferonopathies (see also Immunodeficiencies/autoiflammatory diseases/Crow Y, 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 the metabolism and immunological recognition of intracellular nucleic acids. Dysregulation of the type 1 interferon (IFN) axis leads to constitutive type 1 interferon activation, which can have the following molecular consequences:

• impaired negative regulation of type 1 IFN signaling pathways.
• increased or altered sensitivity of nucleic acid sensors
• ligand-independent activation of components of downstream signaling cascades
• Unphysiological accumulation or chemical modification of endogenous nucleic acids
• Pathophysiology PublishedSaturday, August 29, 2020, 1:40 pm

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 peptide. 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