Interferon

Some studies I've been reading lately. Interferon has been and is currently being both praised and vilified in regards to the genesis of various autoimmune disease. One such article is from July 2024, published with NBC News titled Scientists say they have identified a root cause of lupus- one that could pave the way for new treatments. It's essentially interferon imbalance. What could be causing imbalance/excess/deficiency in interferons leading to wayward immune response? A 2018 paper called Type 1 and 2 interferon receptors differentially regulate type 1 diabetes susceptibility in male versus female non-obese diabetic mice explained attempting to decipher these puzzling, conflicting interferon papers well: "The role of interferons, either pathogenic or protective, during autoimmune diabetes remains controversial...The role of interferon-gamma in type 1 diabetes progression is perplexing...despite the diverse results among the published studies, two essential findings demonstrate that interferon signaling and/or interferon-inducible genes are required for type 1 diabetes incidence." It seemed like every paper I read, the next contradicted it. But I wanted to post this because it allowed me to close out a lot of tabs on my phone and I believe that the research is important and hopefully leading us somewhere more definitive in the future.

The 1998 paper Ingested Interferon-alpha suppresses Type 1 diabetes in non-obese diabetic mice states: "Because multiple sclerosis and Type 1 diabetes share several features of immunopathogenesis, we decided to determine whether murine ingested interferon-alpha inhibits insulitis and suppresses diabetes in non-obese diabetic mice...The natural history of the development of Type 1 diabetes includes a pre-symptomatic stage between the occurrence of insulitis and the onset of symptomatic hyperglycemia, and provides a broad therapeutic window for intervention between T cell islet infiltration and beta cell numbers falling below that required to maintain normoglycemia. Ingested interferon-alpha may be an ideal treatment for Type 1 diabetes before or immediately after diagnosis."

Dr. Teresa Rodriguez-Calvo, author of the 2021 study Relationship between type 1 diabetes, interferon response and viral infection is first step toward preventative therapies explained: "We found in the pancreas of people with type 1 diabetes that several molecules produced in response to interferons have a negative impact on insulin production and they induce inflammation, attracting immune cells with capacity to kill insulin producing beta cells. Our data also suggest that the detection of these molecules in the pancreas is associated to viral infections...Our current goal is to further characterize these immune responses and to investigate how they can be controlled. We also want to study how the immune system recognizes viral proteins as well as self-proteins during the course of type 1 diabetes, to be able to stop the immune attack to beta cells."

The 2017 paper Type 1 Interferon is a Catastrophic Feature of the Diabetic Islet Microenvironment states: "Association of type 1 interferon with type 1 diabetes reported in previous studies together with our current findings makes a strong case that these cytokines play some role in the complexity of the diabetes puzzle...While the pleiotropic actions of type 1 interferons are designed to strengthen the immune response to viral pathogens, this response proves detrimental in the case of autoimmunity where the immune response is misdirected toward self and in this way can promote beta cell death in type 1 diabetes."

The 2004 paper Autoimmunity is a type I interferon-deficiency syndrome corrected by ingested type I interferon via the GALT system states: "In multiple sclerosis and insulin-dependent diabetes mellitus at the target organ, and in rheumatoid arthritis as a regulator of other pro-inflammatory cytokines, interferon-gamma is the nexus of inflammation in autoimmunity. Ingested type I interferons counteract type II interferons, overcome the relative lack of type I interferon activity, and ameliorate autoimmunity. The administration of type I interferons (alpha/beta) via the gut offers an exciting alternative to systemic application for overcoming the type I interferon immunodeficiency in autoimmunity. Successful use of ingested type I interferons in three separate prototypical autoimmune diseases suggests a broad anti-inflammatory therapeutic profile for this technology."

The authors of the 2022 study Type 1 interferon regulates proteolysis by macrophages to prevent immunopathology following viral infection said: "Our body's immune response is trying to fight off the virus infection, but there's a risk of damaging innocent healthy tissue in the process. Type 1 interferons regulate the immune response to only target tissues that are infected," adding: "This applies not just to COVID-19, but also other highly infectious viruses such as flu and Ebola, which can cause tremendous and often life-threatening damage to the body's organs." See the 2022 ScienceDaily article "Type 1 interferon stops immune system 'going rogue' during viral infections."

The 2021 paper Interferon system deficiencies exacerbating severe pandemic virus infections found: "An emerging concept is that genetic and non-genetic deficiencies in interferon system components lead to uncontrolled virus replication and severe illness in a subset of people. Intriguingly, new findings suggest that individuals with autoantibodies neutralizing the antiviral function of interferon are at increased risk of severe COVID-19."

The 2024 paper Reserve drug as first-line management: Topical interferon alpha 2b for vernal keratoconjuntivitis states: "Patients were treated with topical interferon alpha 2b eye drop four times a day dosing for 6 weeks...Eye drop interferon alpha 2b is a safe and effective option as first-line monotherapy for VKC. No side effects and recurrence were observed for 6 months."

The 2023 study Type 1-type 2 interferon imbalance in dry eye disease found: "The mRNA expression levels of interferon alpha and interferon beta were significantly lower and that of interferon gamma was significantly higher in dry eye disease patients compared to healthy controls...The presence of an imbalance between type 1 and type 2 interferons in dry eye disease patients suggests newer pathogenic processes in dry eye disease, plausible ocular surface infection susceptibility in dry eye disease patients, and potential therapeutic targets in the management of dry eye disease...It is noteworthy that the immunomodulatory role of interferon alpha was explored using recombinant interferon alpha to improve the lacrimal gland function in patients with Sjogren's syndrome and for the management of immune-mediated keratoconjunctivitis sicca in dogs. Further, recombinant interferon alpha is also being used in the management of uveitis...Augmenting type 1 interferon status would plausibly bring about dampening of inflammation and reduction in ocular surface pain or discomfort and prevent infectious keratoconjunctivitis in patients with dry eye disease. Using conjunctival impression cytology samples, we reported that trehalose eye drops significantly enhanced interferon alpha, while reducing interferon gamma expression in the ocular surface of healthy volunteers." 

The eye drop iVIZIA contains trehalose and can be found at grocery/drug stores and online.

The 2024 study Ectoine Enhances Mucin Production Via Restoring Interleukin-13/Interferon-gamma Balance in a Murine Dry Eye Model concluded: "Our findings demonstrate that topical ectoine significantly reduces corneal damage, and enhances goblet cell density and mucin production through restoring imbalanced interleukin-13/interferon gamma signaling in murine dry eye model. This suggests therapeutic potential of natural osmoprotectant ectoine for dry eye disease." 

Optase Allegro is a new eye drop that contains 2% Ectoin (a brand name for Ectoine) - available at Walgreens and online. In Canada, Bausch & Lomb's Soothe Allergy + Dry Eye is available.

The 2021 study Comparison of the Safety and Efficacy of Interferon Alpha-2a and Cyclosporine-A when Combined with Glucocorticoid in the Treatment of Refractory Behcet's Uveitis: A Randomized Controlled Prospective Study found: "Compared to cyclosporine-A plus corticosteroid, interferon-alpha 2a plus corticosteroid appears to induce a better treatment response, a significantly greater improvement in visual acuity, and more stable remission of intraocular inflammation in a 12-month study period."

The 2019 paper Toxoplasma gondii effector TgIST blocks type 1 interferon signaling to promote infection states: "Toxoplasma gondii infects a wide range of animals, including humans, where it can form chronic persistent infections for the life of the host. We demonstrate that the parasite T. gondii secretes an effector protein called TgIST that traffics to the host cell nucleus, binds to STAT1/STAT2 heterodimers, and blocks signaling through type 1 interferon. TgIST globally blocks induction of interferon-stimulated genes normally up-regulated by interferon-beta, including those involved in innate defense pathways. Type 1 interferon is important for control of chronic infection by T. gondii in the central nervous system, and the ability of the parasite to modulate this pathway contributes to chronic persistence."

The 2024 paper Mutual regulations between Toxoplasma gondii and type 1 interferon notes: "Although interferon 2 (interferon-gamma) has long been recognized as an essential anti-T.gondii immune effector, much less is known about the role of type 1 interferon (IFN-1) in host defense against this parasite. Since its first discovery, IFN-1 has been extensively studied for decades for their antiviral activity. However, increasing evidence suggests that IFN-1 also plays an important role in limiting the infection of T. gondii, particularly in chronic infections which take place in the brain. Meanwhile, when facing the deadly killing of the IFN-1, T. gondii secretes proteins that hijack the host immunity to assist in successful immune escape...Interferons are crucial for orchestrating the immune response that limits the parasite's growth. However, T. gondii has developed sophisticated mechanisms to combat the immune defenses mediated by these interferons, enabling it to evade the host's immune surveillance and persist within the host cells...TgIST was firstly found to block interferon gamma-dependent transcription...however, a recent study has shown that TgIST blocks IFN-1 signaling to promote infection...As one of the most successful parasites in the world, T. gondii develops a series of strategies to fight against host defense. To neutralize IFN-1 signaling, it secretes ROP18 and ROP16 to inhibit the IFN-1 production pathway, and produces TgIST and TgNSM at the same time to deactivate ISGs downstream of IFN-1, thus protecting T. gondii from host elimination...These diverse proteins originating from different strains of T. gondii exert varying effects on IFN-1, potentially explaining the differences in virulence among distinct strains of T. gondii." See the 1988 paper Interferon-gamma: The major mediator of resistance against Toxoplasma gondii: "The fact that an antibody to interferon-gamma can eliminate resistance to acute Toxoplasma infection in mice suggests that this lymphokine is an important mediator of host resistance to this parasite."

The 2005 paper The role of interferon-gamma on immune and allergic responses found: "Interferon-gamma, the principal Th1 effector-cytokine, has shown to be crucial for the resolution of allergic-related immunopathologies. In fact, reduced production of this cytokine has been correlated with severe asthma."

The 2007 study Systemic Production of Interferon-alpha by garlic in humans noted: "The chronic eating of garlic was found to maintain interferon-alpha at high levels for at least 7 days...consumption of garlic resulted in stimulated synthesis of nitric oxide and, in turn, interferon-alpha in humans, which could be beneficial in viral or proliferative diseases."

The 2020 paper Artemisinin inhibits the replication of flaviviruses by promoting the type 1 interferon production states: "In summary, our in vitro and in vivo study provides the first evidence that artemisinin inhibits the replication of flaviviruses by enhancing the host type 1 interferon response upon viral infection." 

This made me think of a study I just had to dig out of an old binder from a year or two ago that suggests dried whole-plant Artemisia annua from which artemisinin is derived may be more beneficial therapeutically than the isolate. The 2015 study Dried whole-plant Artemisia annua slows evolution of malaria drug resistance and overcomes resistance to artemisinin noted: "In our previous study, we reported that antimalarial activity of whole-plant Artemisia annua was at least five times more effective than an equivalent dose of pure artemisinin. Here we also show that dried whole-plant material of Artemisia annua is more effective in killing malaria parasites resistant to artemisinin and that whole-plant is more resilient than pure artemisinin and may actually delay the onset of resistance. Although the exact mechanisms still need to be identified, the antimalarial activity of whole-plant against artemisinin-resistant parasites can be explained by increased bioavailability of artemisinin, synergism among artemisinin and other A. annua constituents, and/or the presence of other compounds in A. annua that may have antimalarial activity independent from artemisinin."

The 2020 study Nutraceuticals have potential for boosting the type 1 interferon response to RNA viruses including influenza and coronavirus states: "Ingestion of spirulina or of spirulina extracts enriched in phycocyanin may have potential for boosting type 1 interferon response in the context of RNA virus infection. Oral administration of cold-water spirulina extract rich in phycocyanin has been found to decrease mortality in influenza-infected mice."

Sunlight is also a stimulator of interferon responses that could prove useful for fighting infections. In recent studies, however, including 2020's The early local and systemic Type 1 interferon responses to UVB light exposure are cGAS dependent, 2015's UV light potentiates STING (Stimulator of Interferon Genes)-dependent innate immune signaling through deregulation of ULK1, and 2020's Acute skin exposure to UV light triggers neutrophil-mediated kidney inflammation, lupus patients are advised to avoid sunlight because it worsens their already hyper-active interferon response.