Classification of interferonopathies.
This chapter reviews various interferon (IFN) system disturbances—interferonopathies. The authors describe clinical specifics of type I interferonopathy associated with overexpression of IFNα—which is a rare Mendelian genetic disease. Certain autoimmune diseases (systemic lupus erythematosus (SLE), vasculitis, immune dysregulation syndrome, etc.) are also characterized by overproduction of IFNα. Furthermore the most common interferonopathies are described—deficiencies of IFN, congenital or acquired IFNα/IFNβ and IFNγ deficiencies in children and adults. Deficiency of IFNα/IFNβ associated with severe recurrent viral infections and deficiency of IFNγ cause mycobacterial infection. Interferon-corrective therapy methods are described. The target therapy of type I interferonopathies (biologics) binds IFNα and normalizes the high level of IFNα. From the other side, patients with congenital IFNα deficiencies are needed in replacement IFN therapy. In case of acquired IFNα deficiency, the differentiated interferon-corrective therapy is performed. In both replacement and interferon-corrective therapies, recombinant human IFNα2b in complex with antioxidants (Viferon®) can be used, because their application is safe and has good clinical efficiency and no side effects.
- interferon deficiency
- interferon overexpression
- IFN-corrective therapy
Type I interferonopathies are congenital genetic disorder of the interferon (IFN) system, characterized by certain clinical symptoms resulting from the overproduction of IFNα [1, 2, 3]. In our opinion, the term interferonopathy means a general pathology of the interferon system, congenital or acquired, which includes the following types of disorders of the IFN system:
2. Molecular mechanisms of the induction of type I interferon synthesis
The main role of type I interferons is to control viral infection. The synthesis and secretion of type I IFN is activated when our immune cells come in contact with viruses. Type I IFN is synthesized by epithelial cells, many cells of the immune system, including plasmacytoid dendritic cells (pDC) that recognize foreign or auto nucleic acids. Although both epithelial and pDC synthesize type I IFN simultaneously in different tissues, pDC-derived type I IFN actually exerts various immune responses through its cognate receptors on target cells. This results in modulation of diverse processes such as antigen presentation and activation of adaptive immunological process involving B and T cells . For the synthesis of interferons in the body, cell activation is necessary. Toll-like receptors (TLRs); RIG-like receptors (RLRs), RIG-I; melanoma differentiation-associated protein 5 (MDA5); and cyclic GMP-AMP synthase (cGAS) participate in the recognition of foreign and host nucleic acid sites . The main inducers of the synthesis of type I interferons are double-stranded and single-stranded RNA of viruses, as well as bacterial DNA . RIG-like receptors recognize both single- and double-stranded viral RNAs, whereas cGAS (cyclic GMP-AMP synthase), in contrast, recognizes double-stranded DNA and RNA: DNA duplexes are formed during the replication of retroviruses and catalyze the synthesis of cGMP-AMP, which is the main agonist of the adapter protein—STING. After binding RNA, RIG-I and MDA5 bind the mitochondrial antiviral-signaling (MAVS) adapter protein. Both STING and MAVS stimulate downstream signaling cascades that include multiple kinases and finally lead to phosphorylation of IRF3 and induction of interferon synthesis . Then type I IFN binds to the corresponding IFNAR receptors located on the cell membrane, which leads to the activation of Tyk2 and Jak1 kinases, which undergo phosphorylation and activate signal transduction and transcription activation proteins (STAT1 and STAT2). As a result, a heterotrimeric complex is formed, known as IFN-stimulating gene factor-3 (ISGF3), which includes IFN regulatory factor 9 (IRF9). Janus kinase (Jak) activation is negatively regulated by IFNα-inducible proteins SOCS1 and SOCS3. The binding of ISGF3 promotes interferon-stimulated genes (ISGs), which leads to their transcriptional activation and the collective actions of hundreds of ISGs, resulting in the production of a large number of induced IFN, which inhibits both viral replication and the spread of viruses. Rapid type I IFN secretion and then rapid synthesis induce activity of congenital and adaptive immunity cells by activation of pro-inflammatory cytokines that activate cellular and humoral antiviral immune response  (Figure 1).
3. Interferonopathies classification
During acute viral infection, IFN level is significantly elevated, and more than 70% of cells acquire antiviral status, i.e., they are protected against virus penetration and are able to efficiently neutralize them. Type I IFN has several very important positive effects: direct and indirect antiviral effect, protective antiviral effect, antitumor effect, and immunomodulatory effect. At the same time, it was shown that increased production of IFN can lead to negative consequences similar to autoimmune reactions.
The information presented by several authors about interferon system pathologies is vast and diverse but is not well-systematized. All known defects of IFN system, including type I and II IFN, whether congenital or acquired, including various disorders (deficiency; inadequate response to contact with viruses, bacteria, and mutated or tumor cells; IFN system paralysis; IFN overexpression), are pathologies of IFN system. All those defects of IFN system are collectively known as interferonopathies. There is an urgent need to create a classification of congenital and acquired disorders of the IFN system. We believe that the classification of IFN pathology would help in determining the correct approaches to the differentiated choice of adequate treatment tactics.
3.1 Congenital type I interferonopathies associated with IFNα overexpression
Recently several studies have presented genetic and molecular disorders accompanying rare Mendelian diseases that are associated with type I IFN overexpression resulting from defects in intracellular nucleic acid metabolism, DNAse deficiency, or defects in sensor nucleic acid recognition. Genetic disorders—Mendelian diseases (Aicardi-Goutières syndrome, familial chilblain lupus, spondyenchondromatosis, proteasome-associated autoinflammatory syndrome, Singleton-Merten syndrome)—resulting in inadequately high type I IFN overexpression accompanied by a certain range of clinical disorders are called type I interferonopathies. Interferonopathies have rare pathology; their occurrence varies from 1:10,000 to 1:1,000,000 people. According to the literature, the most common syndrome is Aicardi-Goutières . The frequency of some recently described genetic disorders (e.g., PRAAS2) cannot be counted . Such disorders cause a great number of own nucleic acids in cell cytoplasm to appear. It results in active DNA recognition and pathological overexpression of type I IFN which launch autoimmunity hyperactivation, thus leading to autoimmune inflammation affecting the central and peripheral nervous system. It also results to skin and vessel damage (vasculitis), lung damage, etc. Therefore rapid and efficient immune reaction to alien nucleic acids is positive when it causes type I IFN activation during pathogen invasion and antimicrobial protection. It becomes deleterious when it responds to own DNA which is due to the defect of own nucleic acid metabolism. Some neurological, vascular, and skin symptoms which are typical for type I interferonopathies are reviewed in such multifactorial diseases as exanthematous lupus erythematosus, widespread vasculitis, and autoimmune multiple myositis [6, 7, 18] (Table 2).
|I. Congenital interferonopathies||II. Acquired—secondary interferonopathies|
1.1 Interferon α deficiency (IFNα)
1.2 Interferon β deficiency (IFNβ)
1.3 Interferon γ deficiency (IFNγ)
2.1 IFNα overexpression
2.1.1 Autoinflammatory syndromes and autoimmune diseases (systemic lupus erythematosus (SLE), systemic angiitis, dermatomyositis), Down syndrome
2.1.2 Type I interferonopathies: Aicardi-Goutières syndrome (AGS), familial chilblain lupus (FCL), spondyenchondromatosis, proteasome-associated autoinflammatory syndrome (PRAAS), Singleton-Merten syndrome (SMS)
1.1 IFNα deficiency
1.2 IFNβ deficiency
1.3 IFNγ deficiency
2.1 Blockage IFNα adequate response
2.2 Blockage IFNβ adequate response
2.3 Blockage IFNγ adequate response
3.1 Cytokine storm
|Aicardi-Goutières syndrome||TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SANHD, ADAR, IFIH1||Encephalopathy, muscular dystonia, microcephaly, calcification of the basal ganglia in the substance of the brain, cramps, fever, increased acute phase blood markers, cytopenia, increased levels of interferon in the cerebrospinal fluid|
|Cardiovascular diseases with aortic calcification, osteoporotic manifestations, dental and skeletal abnormalities, psoriatic skin lesions|
|Proteasome-associated autoinflammatory syndromes|
Chronic atypical neutrophilic dermatosis with lipodystrophy
and elevated temperature (CANDLE)
|Erythematous skin lesions, panniculitis, lipodystrophy, arthritis with the development of joint contractures, myalgia, hepatomegaly, splenomegaly, calcification of the basal ganglia in the brain, fever, increased acute phase blood markers|
Recurrent fevers in the first months of life, along with characteristic skin lesions, lipodystrophy, violaceous swollen eyelids, arthralgias, extremity contractures, and delayed physical development as well as systemic inflammation markers have been identified as CANDLE-related clinical manifestations
|STING-associated vasculopathy with onset in infancy (SAVI)||TMEM173||Vasculopathy with the formation of distal gangrene; necrosis; erythematous rash on the face, tip of the nose, and auricles; interstitial lung disease, arthralgia, fever|
|Spondyloenchondrodysplasia (SPENCD)||ACP5||Spondylometaphyseal dysplasia, stunting, calcification of the basal ganglia in the substance of the brain, arthropathy, thrombocytopenia, deficiency of cellular and humoral immunity|
|ISG15 deficiency||ISG15||Calcification of the basal ganglia in the substance of the brain, convulsions, mycobacterial infections|
|USP18 deficiency (pseudo-TORCH syndrome)||USP18||Cerebral hemorrhage and calcification, hepatomegaly, thrombocytopenia|
|Trichohepatoenteric syndrome 2||SKIV2L||Watery diarrhea, brittle and tangled hair, liver damage, mental retardation|
|Retinal vasculopathy with cerebral leukodystrophy (RVCL)||TREX1||The main characteristics of RVCL include the middle-age onset, the progressive visual loss due to retinal vasculopathy (telangiectasias, microaneurysms, and retinal capillary obliteration around the macula), and variable neurological manifestations such as dementia or migraine|
|Familial chilblain lupus||TREX1||Rare monogenic form of cutaneous lupus erythematosus; partly ulcerating acral lesions or painful bluish-red papules located in the fingers, toes, nose, and ears; arthralgias, affecting mainly large joints, without evidence of true arthritis; photosensitivity; or mouth ulcers|
|X-linked reticulate pigmentary disorder (XLPDR)||POLA1||Generalized hyperpigmentation intermingled with small hypomelanotic macules during early childhood, a distinctive face characterized by an upswept frontal hairline and arched eyebrows, as well as severe photophobia, recurrent respiratory infections, and severe gastrointestinal disorders|
3.1.1 Target therapy by biologics in the treatment associated with type I IFN overexpression of type I IFN hyperproduction
Data available on genetic defects of intracellular nucleic acid metabolism greatly facilitate understanding of the mechanisms of insufficient immune activation, which can help in the development of new therapeutic approaches to the treatment of autoinflammatory and autoimmune diseases [1, 2, 3]. The progress in understanding immunopathogenesis mechanism makes it possible to set the exact targets for new therapeutic strategy development [1, 2]. The immune dysregulation syndrome is characterized by a high level of IFNα, a deficiency of regulatory T-lymphocytes, impaired functioning of B cells, and low content of low-density neutrophils. These neutrophils easily form neutrophilic extracellular traps (NET), and the resulting DNA complexes provoke an increase in IFNα synthesis, and then pDC recognizes autoDNA and produces IFNα [10, 11, 19]. These disorders are observed primarily in systemic lupus erythematosus. New approaches in treatment of SLE and other type I interferonopathies have been developed. Monoclonal antibody therapy in type I interferonopathies treatment with SLE is sifalimumab, rontalizumab against IFNα, and anifrolumab against IFNα receptor (IFNAR). Baricitinib (JAK1/JAK2 inhibitor) is currently at clinical studies (phases 2 and 3) in small cohort of patients with interferonopathies [20, 21, 22]. It is also known that treatment with baricitinib decreased disease signs and symptoms and allowed a significant reduction of corticosteroid treatment in patients with CANDLE and SAVI  (Figure 2).
3.2 Congenital interferonopathies associated with type I IFN deficiency
There are genetic defects in the synthesis of IFNα/IFNβ and IFNγ and defects in the receptors for IFNα and IFNγ (IFNAR and IFNGR) including genetic disorders associated with low IFN production according to recent studies. Those genetic defects of IFNs are accompanied by clinical signs of severe recurrent viral and/or mycobacterial infection.
Congenital defects of type I IFN are associated with mutation of genes participating in synthesis of IFNα/IFNβ resulting to deficiency of various molecules (STAT1, UNC93B1, MCM4, TLR3, TRAF3, TRIF, TBK1) and decline level of IFNα/IFNβ. Deficiency of IFNγ, its receptor IFNGR (IFNγR1), and IL-12 plays an important role in IFNγ regulation [12, 24, 25]. Congenital defects of type I IFN have been globally systematized in 2015 by Bousfiha et al. . It has been proven that it causes severe viral and bacterial intracellular infections which are the cause of deaths. Such patients are needed in replacement therapy with recombinant IFNα2b in complex with antioxidants. Congenital defects of IFNγR1 receptor are associated with severe intracellular mycobacterial infections. Combined genetic defects leading to deficiency of IFNα and IFNγ are associated with an autosomal recessive mutation in the STAT1 gene, which causes severe viral and mycobacterial infections [12, 24, 25] (Table 3).
|Predominant susceptibility to viral infection|
|Herpes simplex encephalitis (HSE)||AR (autosomal recessive inheritance):|
AD (autosomal dominant inheritance):
|Dominant clinical phenotype is HSE during primary infection with HSV1, usually between 3 months and 6 years of age|
Specific tests examining the TLR3 pathway marked decrease on the ability of patient’s fibroblasts to produce IFNβ/IFNλ in response to TLR3 agonists and HSV1 infection
|Warts, hypogammaglobulinemia, infection, myelokathexis (WHIM) syndrome||AD: CCXR4||Warts/human papilloma virus infection|
Neutropenia, reduced B cell numbers
|Epidermodysplasia verruciformis||EVER1/TMC6, EVER2/TMC8||Human papilloma virus (group B1) infection and skin cancer|
|CD16 deficiency||Severe viral infections|
|IRF7 deficiency||Severe influenza disease|
|IRF8 deficiency||AR: IRF8||Susceptibility to mycobacteria, |
|RORc deficiency||RORc||Susceptibility to mycobacteria, |
IL-12-IFNγ axis deficiency
Complete AR IFNGR1 and AR IFNGR2
Partial STAT1 LOF (AD), partial IFNGR1, partial IFNGR2, complete IL-12R1, complete IL-12B, complete ISG15, XL CYBB, IRF8, Tyk2, XL NEMO
Serious disseminated BCG and environmental mycobacteria infections (soft tissue, bone marrow, lungs, skin, bones, and lymph nodes),
Usually less severe
3.3 Acquired: secondary interferonopathies
There are secondary acquired disorders in the IFN system, which cause a weakening of antiviral resistance in adults and children . Different viruses can damage synthesis and production of IFN at various interferonogenesis stages. These secondary defects of the type I IFN lead to the occurrence of severe viral infections (herpesviral encephalitis), recurrent acute respiratory viral infections (recARVI), chronic recurrent HSV1 infection, atypical chronic EBV infections, and other atypical cases of virus infection. It was shown that viruses can avoid the effects of IFN and inhibit the action and synthesis of IFN using various molecular mechanisms. Numerous studies demonstrated that a lot of viruses (all herpesviruses, majority of respiratory viruses, hepatitis B and C viruses, etc.) produce proteins capable of inhibiting synthesis and production of IFNα/IFNβ and IFNγ. Viruses can damage each stage of the expression of ISGs  (Figure 3).
Patients with recurrent acute respiratory viral infections and various chronic herpesvirus infections including recurrent herpes viral infections have secondary defects of IFN system. Immunocompromised children of various ages and adults may suffer from recARVI with the frequency of 10 to 16–24 and more times annually; almost in 100% of cases, it is associated with the presence of mono and mixed herpes viral infection. The frequency of recurrent chronic HSV1/HSV2 infection of facial and/or genital location in those patients may reach 16–24 times per year. Epstein-Barr virus may cause atypical virus infection associated with chronic fatigue syndrome .
3.3.1 Differentiated approaches to interferon therapy in patients with secondary interferonopathies
The problem of developing new approaches to the treatment of congenital and acquired defects of the IFN system is very acute [12, 26, 27, 28]. Acquired defects in the IFN system (93–96%) and impaired functioning of neutrophilic granulocytes (NG) are most often detected in patients with recurrent chronic herpes virus infections.
We conducted experiment in vitro to study the effect of recombinant IFNα2b (rIFNα2b) on NG in viral (cells from patients with HSV1/HSV2 infection) and bacterial (model infection by fMLP) infections. The study showed positive regulation of the negatively charged IFNαβR1+IFNγR+TLR4+NG phenotype in patients with various chronic herpesvirus infections under the influence of rIFNα2b in vitro. It was noted that the number of NGs carrying IFNαβR1 and IFNγR and expression density of IFNαβR1 is increasing, wherein expression density of IFNγR and TLR4 is decreased . rIFNα2b modulating effects on CD16+CD66b+CD33+CD11b+NG phenotype transformed by fMLP in experimental model of bacterial process in vitro, to promote remodeling of the pro-inflammatory NG phenotype into anti-inflammatory, have been shown . Thus rIFNα2b has a protective effect on the NG phenotype according to experimental data.
In clinical practice, the use of parenteral IFN to correct disorders in the IFN system is very difficult due to the presence of numerous side effects. One should also bear in mind the inefficiency of short courses of IFN therapy for restoration of the normal IFN system functioning in recARVI, recurrent chronic herpes viral infection of facial or genital location, and papilloma virus infection of the skin and mucosa characterized by recurrent episodes when the frequency of recARVI and/or recurrent attacks of HSV1/HSV2 infection may reach 14–24 and more per year. For over 20 years, we have been developing interferon therapy programs using drugs in Russian production—rectal suppositories and gel of recombinant human IFNα2b (rIFNα2b+aox) in combination with antioxidants (vitamins E and C) (Viferon) [12, 13, 14, 15, 26, 27]. During that period, we managed to demonstrate safety, antiviral, and immunomodulatory efficiency of this kind of IFN therapy, total absence of any side effects that are typical for parenteral IFN therapy, and total absence of antibodies against IFNα2b. Replacement therapy with rIFNα2b + aox is prescribed to patients with primary, genetically preconditioned, congenital or acquired IFN system disorders. In case of primary IFN system disorders, patients need a basic recovery therapy making it possible to eliminate viral antigens as much as possible; and then it is required to select dosage for permanent replacement therapy with rIFNα2b+aox. In case of acquired interferon deficiency, patients are prescribed with differentiated therapy with high, medium, and low doses of rIFNα2b+aox (Figure 4).
At the same time, in case when we had treated the group of patients with combined immunodeficiency (defects of induced production of IFNα and IFNγ and dysfunctions of phagocytic and microbicidal activities of neutrophilic granulocytes) that was associated with recurrent acute respiratory viral infection and different chronic herpes viral coinfections, combined interferon and immunomodulatory therapy was used. The aim was to restore the levels of induced production of IFNα and IFNγ and to reconstruct dysfunctions of phagocytic and microbicidal activities of neutrophilic granulocytes and other deficient chains in antiviral immunity. One group of children, group 1, received an interferon therapy program (rIFNα2b+aox), and patients in group 2 received a program of combined interferon therapy (rIFNα2b+aox) and immunotherapy (glucosaminylmuramyldipeptide). The use of replacement and immunomodulatory mono-rIFNα2b+aox or in combination with immunotherapy (glucosaminylmuramyldipeptide) has helped us to receive very good clinical efficacies and has reached restoration of interferon status and normal functioning of neutrophilic granulocytes (p < 0.05) (Figure 5). At the same time, it is required to take into account both uneven viral infection syndrome manifestation and the rate of IFNα deficiency as well as peculiarities of immune system disorders in case of secondary immune deficiency [12, 13, 14, 15, 27].
Here is an example illustrating the change in clinical, immune, and interferon status in immunocompromised children with recurrent acute respiratory viral infections under the influence of interferonotherapy.
Clinical case. Patient X, 3 years old. The child suffers from repeated acute respiratory viral infections 1–2 times per month (14–16 episodes per year); the duration of the acute period of respiratory viral infection is 7–10 days. The clinical symptoms of the disease were acute rhinitis, acute pharyngitis, acute laryngitis, acute tracheitis, febrile and subfebrile body temperature for 2–4 days, and severe symptoms of intoxication. The duration of the frequent incidence of acute respiratory viral infections is 2 years. The defects of the immune system are a decrease of CD3+CD4+ lymphocytes and CD3+CD8+ lymphocytes; a decrease of immunoregulatory index; neutropenia; a decrease of bacteria absorption and digestion processes by neutrophils; and a decrease of microbicidal activity of neutrophils. We tested spontaneous and Newcastle disease virus-induced IFN production during the incubation of peripheral blood (24 h, t 37°C in 5% CО2). The level of induced IFNα in the patient was 4 IU/ml versus 58 IU/ml in control. The patient was prescribed rIFNα2b+aox therapy with a total duration of 2.5 months.
Local intranasal use of rIFNα2b+aox (Viferon gel, 36,000 IU/g), two to three times a day, 6 weeks.
Systemic rectal application of rIFNα2b+aox suppositories according to a “step-by-step” scheme:
300,000 IU per day, 10 days.
300,000 IU per day three times a week, 2 weeks.
300,000 IU per day two times a week, 2 weeks.
150,000 IU per day two times a week, 2 weeks.
150,000 IU per day once a week, 2 weeks.
Conducted local and systemic interferon therapy led to a reduction in the frequency of acute respiratory viral infections to three episodes per year lasting 5–7 days, proceeding in a milder form. Rehabilitation of immunity parameters occurred after 2.5 months of interferonotherapy, and the level of induced IFNα was normalized to 64 IU/ml.
Summing up the above information, we may conclude that new biological drugs based on mAb are effective and safe, and they are able to neutralize IFNα overexpression in type I interferonopathies, both in Mendelian’s diseases and in autoimmune disorders. At the same time, local and system use of rIFNα2b+aox (Viferon) in congenital and acquired IFN system defects associated with viral infection syndrome, where a differential dosage is selected individually taking into account the rate of deficiency and an adequate, extended course of therapy is optimal because it is associated with positive clinical and immunological effects without any negative and side effects. Our more than 20-year experience has shown that using recIFNα2b+aox in patients with congenital or acquired IFN system defects had demonstrated positive clinical effect and is safe . IFN (rIFNα2b+aox) therapy can be used with very good clinical efficacy in cases of primary or secondary defects of induced production of IFNα and IFNγ. From the other side, it is very important that in patients with a genetic predisposition to the manifestation of autoimmune diseases, primarily vasculitis and systemic lupus erythematosus, we do not recommend to use IFN therapy.