Type I interferons (IFN) are the body’s main line of defense against viruses and pathogenic microorganisms. However, IFN-I responses to infection can be both beneficial and harmful to the body. Dysregulation of the IFN-I system can cause autoimmune diseases-interferonopathy and systemic lupus erythematosus (SLE).

All type I interferons transmit a signal through the IFN-alpha receptor (IFNAR) and cause the cell to express specific genes that form an interferon signature (IFNGS). Interferon-stimulated genes are present in some patients with SLE and other autoimmune diseases, such as myositis, Sjogren’s syndrome, systemic sclerosis, and rheumatoid arthritis. Recent data also indicate that IFN-I signaling is a crucial factor in the inflammatory process in non-autoimmune diseases, such as solid tumors and myocardial infarction.

Protective functions of type I interferons

Plasmacytoid dendritic cells (pDC) are the leading producers of interferon during the antiviral immune response. IFN-I expression is triggered by nucleic acid-sensing pattern recognition receptors, such as TLR (DNA and RNA sensor), RIG-I (RNA sensor), and cGAS (DNA sensor).

Although type I interferons transmit a signal through the same IFNAR receptor, IFN-I subtypes (for example, IFN-α and IFN-β) can perform both separate and overlapping functions in the body’s defense. Their role in a particular context is determined by differences in time, interferon signal strength, and the source of the IFN-I subtype. For example, cGAS stimulation preferentially elicits an IFN-β response, whereas TLR stimulation preferentially increases IFN-α expression.

Type I interferons:

  • Stimulate the maturation of dendritic cells into antigen-presenting cells.
  • Regulate the survival, activation, and differentiation of B cells and T cells, contributing to the further production of PDC interferon.
  • Trigger the differentiation of B cells into a separate pro-inflammatory subpopulation of plasma cells secrete the ISG15 protein. ISG15 regulates antiviral activity, increases the production of IFN-gamma by lymphocytes, and suppresses the IFN-I response.

Impaired interferon type I function is a sign of SLE and other diseases caused by IFN.

IFN-I in autoimmune diseases

SLE and interferonopathy

Systemic lupus erythematosus is a chronic inflammatory autoimmune disease that affects the microcirculatory bed’s connective tissue and blood vessels. SLE can be caused by genetic, hormonal, and environmental factors. Dysregulation of IFN-I is a critical factor in the pathogenesis of SLE.

Interaction of IFN-I with immune cells may contribute to the pathogenesis of lupus:

Target Cell Effects of IFN-I
NK cells Increase the ability to destroy malignant, infected, and abnormal cells.
CD4+ T cells Increase the survival of T-helper cells, promote their differentiation, increase the expression of the interleukin 12 receptor (IL-12R), and stimulate the formation of memory cells.
CD8+ cytotoxic T cells Increase cytotoxicity, slow down apoptosis.
Regulatory T cells Inhibit the activity of Treg, which regulate the strength and duration of the immune response.
Th17 T cells Promote the differentiation of T helper cells in T17 and the production of IL-17. T17 plays a vital role in the development of autoimmune diseases.
Macrophages Enhance the intracellular destruction of pathogens and the expression of costimulating molecules.
Dendritic cells Accelerates dendritic cell maturation and antigen presentation.
pDC Increases the production of IFN-I entering the lymph nodes.
B cells Stimulate plasma cell differentiation, antibody isotype switching, enhance antibody production, memory cell formation, and ISG15 secretion in plasma cells.
Neutrophils Promote the release of mitochondrial DNA, which activates the synthesis of endogenous interferon.
Endothelial cells Trigger apoptosis, disrupts regeneration.
Microglia Helps to reduce the number of synapses.

Up to 87% of children and adults with SLE have IFNGS. It remains unclear how IFNGS is related to disease progression. However, it has recently been shown that IFN assessment can predict SLE development in at-risk individuals. Alternative biomarkers of IFN-I activity include IFN-α and the Siglec-1 protein, expressed exclusively on resident dendritic cells originating from monocytes and resident tissue macrophages. The IFN-α response is increased in the risk group and patients with SLE. Higher levels of Siglec-1 are associated with kidney disease in SLE. Other gene signatures, such as plasmablasts and neutrophils, may better correlate with SLE disease activity at the individual level.

The primary source of IFN-I in lupus patients is most likely pDC, although the role of other IFN-producing nuclear cells, including macrophages, cannot be excluded. The cells of patients with SLE constantly produce IFN-I, which causes tissue damage. Also, patients with SLE have impaired clearance of dead cells. Therefore, in these patients, endogenous nucleic acids accumulate in the extracellular and intracellular space, which leads to hyperreactivity of the immune system and predisposes patients with SLE to an increased inflammatory response to subsequent viral infection.

In SLE, the expression of mobile genetic elements — DNA sequences can change their position within the genome-is disrupted. Therefore, mobile genetic factors can activate TLR and cytosolic receptors that perceive nucleic acid and trigger the production of IFN-I.

Both endosomal and cytosolic nucleic acid receptors are involved in the pathogenesis of SLE. However, it remains unknown whether excessive activation of one receptor type is sufficient to stimulate disease activity. In newborn mice, infection with the lymphocytic choriomeningitis RNA virus (LCMV) causes lupus-like disease at the age of 2-5 months via the endosomal TLR receptor and cytosolic mitochondrial antiviral signaling (MAVS), which depends on the production of IFN-I. LCMV-induced lupus depends on the pDC and the endosomal TLR receptor. MAVS signaling alone is not enough to cause lupus-like symptoms. Recent evidence suggests that exogenous (e.g., viral) or endogenous cytosolic RNA can activate the cGAS DNA sensor, triggering the release of mitochondrial DNA and the production of IFN-β.

IFN-I and anti-nucleic acid antibodies can alter the behavior of cells relative to damaged DNA. Neutrophils primed with IFN-I and exposed to TLR-activating autoantibodies retain and displace oxidized mitochondrial DNA, which causes pDC to produce IFN-I. Spontaneous activation of MAVS in the lymphocytes of patients with SLE correlates with mitochondrial oxidative stress and elevated serum levels of IFN-I.

The genetic background increases the expression of IFN-I and contributes to the risk of SLE. A global study using genomic data from more than 27,000 people, including 11,590 patients with SLE, confirmed that the risk of SLE has both hereditary and ancestral-independent factors. Swedish scientists have demonstrated that patients with SLE and elevated levels of the STAT4 T-cell protein (the STAT4 risk allele) have increased T-cell sensitivity to interleukin 12 (IL-12) and IFN-α. Moreover, healthy individuals with a variant of the risk allele have average sensitivity to IL-12, which can become lupus if the cells of these individuals are exposed to IFN-α. The presence of the PNP risk allele was associated with IFN-I-dependent increased mRNA expression in B cells obtained from SLE patients.

Sjogren’s syndrome

Sjogren’s syndrome is an autoimmune disease that primarily affects the exocrine glands. Dysregulation of the IFN-I system is a crucial factor in inflammation. However, the effects of IFN-I in Sjogren’s syndrome may be specific to the subtype. IFN-β may reduce the expression of pro-inflammatory mediators in peripheral blood mononuclear cells of patients with Sjogren’s syndrome.

As with SLE, patients with Sjogren’s syndrome can be divided into those who have or do not have IFNGS. Patients with an interferon signature have increased expression of B-cell activation factor (BAFF) and more common autoantibodies to the Sjogren syndrome-associated antigen A (SSA, also called anti-Ro / SSA) and B (SSB, also called anti-La / SSB), compared to patients without an interferon signature.

Patients can also be divided into groups based on the presence or absence of the type II interferon signature. In a phase 2 study evaluating the effect of the anti — BAFF-belimumab antibody, exocrine inflammation in patients with Sjogren’s syndrome, low numbers of natural killer cells in blood and saliva were the only predictor of response to belimumab. The authors suggested that there may be two groups of patients with Sjogren’s syndrome: one with a predominant IFN-I-BAFF-B-cell axis (i.e., responding to belimumab), and the other with a predominant IFN-II-NK-cell axis (not responding).

Systemic sclerosis

Systemic sclerosis is an atypical autoimmune disease in which both inflammatory (e.g., vasculopathy) and non-inflammatory (e.g., cutaneous and visceral fibrosis) processes contribute to clinical manifestations.

Cutaneous pDC and IFN-I dysregulation are involved in the clinical manifestations of systemic sclerosis, including fibrosis, and IFNGS is present in more than 68% of patients. pDC in the skin of patients with systemic sclerosis abnormally express the TLR8 receptor, which is responsible for the secretion of pDC protein CXCL4, also called platelet factor 4. TLR8 and TLR9 cause pDC to produce IFN-I, and under the influence of CXCL4, interferon production increases. Abnormal TLR8 expression and subsequent secretion of both CXCL4 and IFN-α pDC may partially explain why lupus and systemic sclerosis have different clinical manifestations. Targeting the pDC, rather than a specific IFN, could be a more practical approach to treating patients with systemic sclerosis.

Myositis

Idiopathic inflammatory myopathies are systemic autoimmune diseases, the main target of the muscles and the skin. These include polymyositis and dermatomyositis.

Muscle biopsies of patients with dermatomyositis are characterized by a large number of pDC, noticeable IFNGS, and a great content of mixovirus resistance protein 1, whose expression depends on IFN-I. It highlights the potential role of IFN-I in stimulating disease activity. In addition, IFNGS and levels of regulated IFN-I chemokines in the blood correlate with disease activity in patients with dermatomyositis. IFN-β is the predominant subtype of IFN-I in the serum of patients with dermatomyositis and connects with IFNGS. According to these data, severe dermatomyositis can be triggered by IFN-β therapy in multiple sclerosis (MS). Although IFN-β is predominant, IFN-α is also involved in the pathogenesis of dermatomyositis. IFN-α stimulates the growth of a population of immature transitional B cells with pro-inflammatory properties in juvenile dermatomyositis.

Rheumatoid arthritis

Rheumatoid arthritis is a chronic inflammatory autoimmune disease that primarily affects the joints, but as a systemic infection has extra-articular manifestations: it affects the eyes, heart, lungs and other organs.

In rheumatoid arthritis, levels of pDC and IFN-α/β are elevated in the synovial membrane. Up to 50% of patients with rheumatoid arthritis have IFNGS in the peripheral blood. Baseline IFN-I activity, quantified by IFN-I protein and IFNGS expression, may predict clinical response to TNF antagonists and lack of response to rituximab in patients with rheumatoid arthritis. However, IFNGS may not reflect rheumatoid arthritis disease activity, and whether there is a causal relationship between IFNGS and the pathogenesis of rheumatoid arthritis is currently unclear. A British study confirmed this: the pDC of patients with early rheumatoid arthritis who had not previously taken medication expressed genes indicating increased immune tolerance.

Patients with autoimmune regulator deficiency

An autoimmune regulator (AIRE) is a protein that regulates gene expression so that the correct cell expresses genes at the right time in the right amount. AIRE eliminates self-reactive T cells that can cause autoimmune disease. AIRE deficiency causes autoimmune polyendocrine syndrome type 1 (APS-1). With APS-1, the functions of several endocrine or non-endocrine glands are disrupted. Individuals with AIRE deficiency have auto-reactivity to autoantigens, including those commonly associated with multiple sclerosis, SLE, type I diabetes, and rheumatoid arthritis. At the same time, the last two diseases occur less frequently in people with AIRE deficiency than one might expect.

Serum studies of patients with APS-1 and the control group have shown that in addition to the general loss of T-cell tolerance, patients with APS-1 have two types of B-cell dysregulation:

1. Diverse or separate reactivity to up to 100 different gene products, many of which are regulated by AIRE;

2. overall reactivity to steroidogenic enzymes and individual cytokines, none of which are regulated by AIRE.

Notably, highly effective antibodies to IFN-α were present in almost all patients, preventing the transmission of signals through the IFNAR receptor. Antibodies to IFN-α negatively correlated with the prevalence of type I diabetes mellitus in patients with such signs of insulin-dependent diabetes as antibodies to glutamate decarboxylase GAD65 and GAD67. Thus, specific autoantibodies can actively limit certain diseases in individuals with AIRE deficiency.

Interestingly, the presence of antibodies against IFN-α does not predispose patients with APS-1 to severe viral infections. It may mean that the antiviral defense is preserved and works through IFN-β or other IFN.

Interferon type I in non-autoimmune diseases

Tuberculosis

Mycobacterium tuberculosis infection is the leading cause of death from infectious diseases. In most people, M. Tuberculosis infection is controlled by the immune response, with CD4+ T cells, IL-12, IFN-γ, and TNF being the most critical factors. It remains unclear why some people are not protected from developing active tuberculosis (TB).

Patients with active TB can be distinguished from patients with latent by the presence in peripheral blood cells of increased expression of IFN-I-stimulated genes and reduced expression of IFNG and TBX21 genes. The IFNG gene encodes interferon-gamma, which triggers a cellular response to viral and microbial infections. TBX21 is responsible for the Th1 cells ‘ production of interferon-gamma. The presence of IFN-I-stimulated genes correlates with X-ray evidence of active tuberculosis and decreases with successful treatment. These data and the results of studies of tuberculosis in mice confirm the role of type I interferons in the pathogenesis of tuberculosis.

Different strains of M. tuberculosis cause different IFN-I responses:

  • Recognition of one particular strain by the TLR4 receptor was associated with IFN-β production and increased virulence, with lung pathology observed at an early stage of infection.
  • Specific strains of M. tuberculosis may differ in their ability to cause mitochondrial stress, the generation of reactive oxygen species, and the release of mitochondrial DNA into the cytosol.
  • The release of mitochondrial DNA contributes to the fact that the cGAS receptor and the STING gene (an interferon response stimulator) trigger the production of IFN-β after infection with M. tuberculosis.

The impact of IFN-I on TB depends on the context:

  • In mouse models of tuberculosis, IFN-I triggers the production of the immunosuppressive cytokine IL-10, decreases the production of protective cytokines such as IL-1, and impairs the macrophage response to IFN-II (IFN-γ). This prevents Th1 cells from enhancing the adaptive immune response, increases the bacterial load, and decreases survival. Research links:
  • Virulence of Mycobacterium tuberculosis in mice is determined by the inability to trigger a Th1 immune response and is associated with IFN-α/β.
  • The hypervirulent Beijing M. tuberculosis strain enhances the regulation of IFN-I and increases the expression of negative regulators of the Jak-Stat pathway.
  • Intranasal administration of Poly-IC exacerbates tuberculosis in mice by recruiting pathogen-releasing monocytes and macrophages into the lungs.
  • Influenza A virus impairs control of coinfection with Mycobacterium tuberculosis in a type I interferon receptor-dependent pathway.
  • TPL-2 – ERK1 / 2 signaling contributes to the body’s resistance to intracellular bacterial infection due to the negative regulation of IFN-I production.
  • IFN-I triggers IL-10 production in an IL-27-independent manner and blocks the IFN-γ response to produce IL-12 and kill Mycobacterium tuberculosis in infected macrophages.
  • In contrast to the data obtained in mice, several clinical studies of M. tuberculosis have reported the positive effects of IFN-I administration:
  • Aerosol interferon alfa, combined with antimycobacterial therapy faster than antimycobacterial therapy alone, reduced the manifestations of tuberculosis: fever, the number of M. tuberculosis in sputum and abnormalities on computed tomography images.
  • Two out of five patients after treatment with recombinant interferon alpha-2b had sputum smear, and culture-negative results showed clinical improvement and smear-negative after therapy but remained culture positive. The other two patients had no response.
  • In addition, under conditions of low IFN-γ or decreased IFN-γ signaling, low levels of IFN-I can support the function of classically activated protective macrophages by inhibiting the expression of the Arg1 gene (an essential regulator of innate and adaptive immune responses) and the associated transformation of protective macrophages into alternatively activated, less effective ones.

Understanding the mechanisms responsible for the switch from acute to the persistent expression of IFN-I in chronic M. tuberculosis infection may be informative for autoimmune diseases such as SLE, in which activation of the latent Epstein-Barr virus has been proposed as a factor that can induce autoimmunity in genetically predisposed person.

HIV infection

HIV infection caused by retroviruses leads to progressive depletion of T cells and dysfunction of the immune system.

During chronic retroviral infections, sustained production of type I interferon causes hyperactivation of the immune system and chronic inflammation, all of which increase the severity of the disease. Thus, in Asian macaques infected with the simian immunodeficiency virus (SIV), the level of interferon is chronically elevated, which leads to the progression of the disease. However, SIV only increases interferon levels during acute infection in African green monkeys, and the condition does not progress.

The biological effect of type I interferons in chronic viral inflammation varies and depends on the IFN subtype:

Type I interferon plays opposite roles in acute and chronic HIV infection. HIV enters plasmacytoid dendritic cells and triggers the production of IFN-I. In acute HIV infection, interferon contributes to the suppression of HIV replication and activation of the antiviral response of T cells. However, in chronic HIV infection, sustained production of IFN-I depletes T cells.

Treating HIV infection saves the T cell population and improves virus clearance or control.

Antiretroviral drugs, which inhibit HIV replication, treat HIV infection. During treatment, the level of virus in the blood and other tissues falls below detectable levels. However, cells with HIV DNA persist in tissues, and if antiviral treatment is stopped, viral replication is restored within 2 weeks.

Since HIV causes a sustained production of type I interferon, which depletes T cells, scientists have proposed blocking the IFN-I receptor (IFNAR) in addition to antiretroviral therapy. Blockade of IFNAR in HIV-1-infected mice abolished immune hyperactivation, prevented T-cell depletion, and restored the antiviral immune response. In addition, IFNAR blockade reduced the size of the HIV-1 reservoir and delayed viral replication after antiretroviral therapy was discontinued.

Interestingly, in studies of chronic HIV infection showing that IFN-I depletes T cells, scientists did not distinguish between interferon-beta and interferon-alpha responses. Recently, German scientists have investigated IFN-alpha-14 for the treatment of HIV. IFN-alpha-14 effectively suppressed HIV replication. In addition, combination therapy with antiretrovirals and IFN-alpha-14 reduced viral load in mice with chronic HIV infection.

In 2022, German scientists showed that mice do not develop immune system hyperactivation when chronically infected with the Friend retrovirus but deplete T-killers. Unlike IFN-beta, which led to immune dysfunction, treatment with IFN-alpha-11 triggered the expression of antiviral interferon-stimulated genes (ISG), suppressed viral replication, and restored depleted killer T cells. The study was published in the Frontiers in Immunology journal. Details of the study are available in the article “Interferon-Alpha-11 to Treat Immunodeficiency Virus“.

Oncology

Low levels of IFN-I in the tumor have an anti-cancer effect. Through T-cells, they activate adaptive immunity. However, higher levels are adequate by suppressing the formation of new blood vessels.

Conventional cancer treatments, such as radiation therapy, chemotherapy, and epigenetic drugs, can activate the IFN-I system and stimulate the immune response to cancer. Genotoxic cancer therapy leads to breaks in genomic DNA, which, in turn, can act as a stimulus for the cGAS pattern recognition receptor and trigger IFN signaling.

Recent evidence suggests that IFN-I signaling may also play a detrimental role in the immune microenvironment of the tumor:

  • For patients with IFNGS-positive breast cancer tumors, chemotherapy is more likely to be ineffective than for patients with IFNGS-negative tumors.
  • In breast cancer cells, activation of the RIG-I receptor followed by the expression of interferon-stimulated genes may increase therapeutic resistance, progression, and metastasis in breast cancer.
  • Relapse after radiation therapy and treatment with anti-cytotoxic T-lymphocyte-associated protein 4 is associated with prolonged IFN-I signaling in mice.

Thus, IFN can have a positive or negative effect on cancer growth, and this effect depends on various factors, including treatment, the type of cancer, the tumor microenvironment, and the level of IFN stimulation.

Read more about the role of interferons in cancer here.

Myocardial infarction

Coronary atherosclerosis develops asymptomatically until acute myocardial infarction causes chest pain, forcing patients to seek medical attention. In the first few days after a heart attack, the death of cardiomyocyte cells is followed by a sterile inflammatory reaction, which eventually turns into fibrosis. Understanding the mechanisms of pathological ventricular remodeling is an area of intensive research.

DAMP Molecules-molecular patterns associated with damage – are released from damaged cells or die due to injury or infection. In myocardial infarction with double-stranded DNA breaks, DAMPS are released, which contribute to the inflammatory response by triggering the IFN-I system.

In a mouse model of myocardial ischemia, IFNGS dependent on the interferon regulatory factor IRF3 was elevated in cardiac macrophages 4 days after infarction. cGAS and IFNAR receptors were needed for the expression of interferon-stimulated genes. It means that endogenous nucleic acids are the trigger of the IFN-I response. Their DNA was released by damaged cardiomyocytes and absorbed by macrophages. After a heart attack, survival rates improved in IRF3-deficient or IFNAR-deficient mice. Administration of an anti-IFNAR antibody within 48 hours of myocardial ischemia reduced the inflammatory response and ventricular dilatation and improved heart function compared to mice that did not receive treatment. Thus, IFN-I drugs may be helpful in the period of acute post-myocardial ischemia.

Conclusions

SLE occurs due to a violation of the regulation of IFN-I. Clinical trial data confirm that exposure to the IFN-I pathway is a practical therapeutic approach.

Anifrolumab-an all-human monoclonal antibody against IFNAR-plus standard of care neutralized IFNGS, reduced SLE activity compared to placebo, and was well tolerated by SLE patients in a phase 2b trial.

Baricitinib, a JAK inhibitor, reduced SLE activity in the Phase 2 study, as well as improved symptoms, reduced corticosteroid dosage, and neutralized IFNGS in patients with other types I interferonopathies, including infantile chronic atypical neutrophil dermatosis with lipodystrophy, fever, and STING-related vasculopathy.

The presence of IFNGS may predict the clinical response to treatment, but patients without strong IFNGS remain an important subpopulation with clinically significant disease activity.

To date, no serious treatment-related side effects have been observed in patients receiving therapy directed against IFN-I. This is intriguing since the IFN-I system is fundamental to both innate and acquired immunity.

Depletion of pDC may be a more selective approach to controlling excess IFN-I production in autoimmune diseases because other IFN-producing cell populations will be conserved. Currently, a humanized monoclonal antibody to antigen 2 of dendritic blood cells – BIIB059 is being developed to treat SLE. A phase 1 study showed a favorable safety profile, decreased expression of IFN-stimulated genes and decreased activity of skin diseases.

More research is needed to identify the mechanisms of triggering the IFN-I response and response in autoimmune and non-autoimmune inflammatory diseases, especially in determining IFN-I production factors and the effect of these cytokines on T-cell populations. The sustained production of IFN-I in chronic infections contrasts with the transient and well-controlled response in acute viral infections but may be mechanically similar to the dysregulation observed in the IFN-I system in autoimmune diseases caused by IFN.

The role of IFN-I in cancer and chronic infections is complex and depends on the context: sometimes they are friends, and sometimes they are enemies. Given the prevalence of cancer and chronic diseases of tuberculosis and HIV, drugs that affect the type I interferon system can save people’s health worldwide.

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Type I interferons in host defence and inflammatory diseases

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