# Interferon type I

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Cytokine

Not to be confused with [Interferon type II](/source/Interferon_type_II).

Protein family

Interferon Type I (α/β/δ...) The molecular structure of human interferon-beta (PDB: 1AU1​). Identifiers Symbol Interferons Pfam PF00143 InterPro IPR000471 SMART SM00076 PROSITE PDOC00225 CATH 1au1 SCOP2 1au1 / SCOPe / SUPFAM CDD cd00095 Available protein structures: PDB ‹ The template below (Protein Data Bank link 3) is being considered for merging with PDBsum link. See templates for discussion to help reach a consensus. › 1b5l :24-187 ‹ The template below (Protein Data Bank link 3) is being considered for merging with PDBsum link. See templates for discussion to help reach a consensus. › 1ovi :24-185 ‹ The template below (Protein Data Bank link 3) is being considered for merging with PDBsum link. See templates for discussion to help reach a consensus. › 2hie :24-186 ‹ The template below (Protein Data Bank link 3) is being considered for merging with PDBsum link. See templates for discussion to help reach a consensus. › 1itf :24-186 ‹ The template below (Protein Data Bank link 3) is being considered for merging with PDBsum link. See templates for discussion to help reach a consensus. › 1au1B:22-187 ‹ The template below (Protein Data Bank link 3) is being considered for merging with PDBsum link. See templates for discussion to help reach a consensus. › 2hif :24-182 ‹ The template below (Protein Data Bank link 3) is being considered for merging with PDBsum link. See templates for discussion to help reach a consensus. › 1wu3I:22-182 IPR000471 PF00143 (ECOD; PDBsum) AlphaFold IPR000471 PF00143

The **type-I interferons** (IFN) are [cytokines](/source/Cytokine) which play essential roles in [inflammation](/source/Inflammation), [immunoregulation](/source/Immunoregulation), tumor cells recognition, and [T-cell](/source/T_cell) responses. In the human genome, a cluster of thirteen functional IFN genes is located at the 9p21.3 cytoband over approximately 400 kb including coding genes for IFNα (*IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17* and *IFNA21*), IFNω (*IFNW1*), IFNɛ (*IFNE*), IFNк (*IFNK*) and IFNβ (*IFNB1*), plus 11 IFN pseudogenes.[1]

Interferons bind to [interferon receptors](/source/Interferon_receptor). All type I IFNs bind to a specific cell surface receptor complex known as the IFN-α receptor ([IFNAR](/source/Interferon-alpha%2Fbeta_receptor)) that consists of [IFNAR1](/source/IFNAR1) and [IFNAR2](/source/IFNAR2) chains.

Type I IFNs are found in all mammals, and homologous (similar) molecules have been found in birds, reptiles, amphibians and fish species.[2][3]

## Sources and functions

IFN-α and IFN-β are secreted by many cell types including [lymphocytes](/source/Lymphocytes) ([NK cells](/source/NK_cells), [B-cells](/source/B-cell) and [T-cells](/source/T-cell)), macrophages, fibroblasts, endothelial cells, osteoblasts and others. They stimulate both [macrophages](/source/Macrophage) and NK cells to elicit an anti-viral response, involving [IRF3](/source/IRF3)/[IRF7](/source/IRF7) antiviral pathways,[4] and are also active against [tumors](/source/Tumor). [Plasmacytoid dendritic cells](/source/Plasmacytoid_dendritic_cells) have been identified as being the most potent producers of type I IFNs in response to antigen, and have thus been coined natural IFN producing cells.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

IFN-ω is released by [leukocytes](/source/Leukocyte) at the site of viral infection or tumors.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

IFN-α acts as a [pyrogenic](/source/Pyrogen_(fever)) factor by altering the activity of thermosensitive [neurons](/source/Neuron) in the [hypothalamus](/source/Hypothalamus) thus causing fever. It does this by binding to [opioid receptors](/source/Opioid_receptor) and eliciting the release of [prostaglandin-E2](/source/Prostaglandin_E2) (PGE2).[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

A similar mechanism is used by IFN-α to reduce pain; IFN-α interacts with the μ-opioid receptor to act as an [analgesic](/source/Analgesic).[5]

In mice, IFN-β inhibits immune cell production of growth factors, thereby slowing tumor growth, and inhibits other cells from producing vessel-producing growth factors, thereby blocking [tumor angiogenesis](/source/Angiogenesis#Tumor_angiogenesis) and hindering the tumour from connecting into the blood vessel system.[6]

In both mice and human, negative regulation of type I interferon signaling is known to be important. Few endogenous regulators have been found to elicit this important regulatory function, such as SOCS1 and [Aryl Hydrocarbon Receptor Interacting Protein](/source/AH_receptor-interacting_protein) (AIP).[7]

## Mammalian types

The mammalian types are designated IFN-α (alpha), IFN-β (beta), IFN-κ (kappa), IFN-δ (delta), IFN-ε (epsilon), IFN-τ (tau), IFN-ω (omega), and IFN-ζ (zeta, also known as limitin).[8][9] Of these types, IFN-α, IFN -ω, and IFN-τ can work across species.[10]

### IFN-α

The IFN-α proteins are produced mainly by [plasmacytoid dendritic cells](/source/Plasmacytoid_dendritic_cell) (pDCs). They are mainly involved in innate immunity against viral infection. The genes responsible for their synthesis come in 13 subtypes that are called [IFNA1](/source/IFNA1), [IFNA2](/source/IFNA2), [IFNA4](/source/IFNA4), [IFNA5](/source/IFNA5), [IFNA6](/source/IFNA6), [IFNA7](/source/IFNA7), [IFNA8](/source/IFNA8), [IFNA10](/source/IFNA10), [IFNA13](/source/IFNA13), [IFNA14](/source/IFNA14), [IFNA16](/source/IFNA16), [IFNA17](/source/IFNA17), [IFNA21](/source/IFNA21). These genes are found together in a cluster on chromosome 9. By comparison, in other species such as mice, mouse IFN-α genes were first isolated and characterized in 1982 by Shaw in the Weissmann lab at the University of Zurich. There are 14 mouse IFN-α genes and they are found in a cluster on chromosome 4.[11][12]

IFN-α is also made synthetically as [medication](/source/Medication) in hairy cell leukemia. The [International Nonproprietary Name](/source/International_Nonproprietary_Name) (INN) for the product is [interferon alfa](/source/Interferon_alfa). The [recombinant](/source/Recombinant_DNA) type is [interferon alfacon-1](/source/Interferon_alfacon-1). The [pegylated](/source/PEGylation) types are [pegylated interferon alfa-2a](/source/Pegylated_interferon_alfa-2a) and [pegylated interferon alfa-2b](/source/Pegylated_interferon_alfa-2b).

[Recombinant feline interferon omega](/source/Recombinant_feline_interferon_omega) is a form of [cat](/source/Cat) IFN-α (not ω) for veterinary use.[10]

### IFN-β

The IFN-β proteins are produced in large quantities by [fibroblasts](/source/Fibroblasts) and play a key role in the innate immune response through their antiviral activity. Only one type of IFN-β, IFN-β1 ([IFNB1](/source/IFNB1)), has been confirmed. A second gene, IFNB3, was reported,[13] but this symbol was never adopted by the [HUGO Gene Nomenclature Committee](/source/HUGO_Gene_Nomenclature_Committee). A third gene once designated IFN-β2 was later identified as [IL-6](/source/Interleukin-6).

### IFN-ε, -κ, -τ, -δ and -ζ

IFN-ε, -κ, -τ, and -ζ appear, at this time, to come in a single isoform in humans, *[IFNK](/source/IFNK)*. Only ruminants encode IFN-τ, a variant of IFN-ω. So far, IFN-ζ is only found in mice, while a structural homolog, IFN-δ is found in a diverse array of non-primate and non-rodent placental mammals. Most but not all placental mammals encode functional IFN-ε and IFN-κ genes.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*].

### IFN-ω

IFN-ω, although having only one functional form described to date (*[IFNW1](/source/IFNW1)*), has several [pseudogenes](/source/Pseudogene): *[IFNWP2](https://www.genenames.org/tools/search/#!/genes?query=IFNWP2)*, *[IFNWP4](https://www.genenames.org/tools/search/#!/genes?query=IFNWP4)*, *[IFNWP5](https://www.genenames.org/tools/search/#!/genes?query=IFNWP5)*, *[IFNWP9](https://www.genenames.org/tools/search/#!/genes?query=IFNWP9)*, *[IFNWP15](https://www.genenames.org/tools/search/#!/genes?query=IFNWP15)*, *[IFNWP18](https://www.genenames.org/tools/search/#!/genes?query=IFNWP18)*, and *[IFNWP19](https://www.genenames.org/tools/search/#!/genes?query=IFNWP19)* in humans. Many non-primate placental mammals express multiple IFN-ω subtypes.

### IFN-ν

Not to be confused with [Interferon gamma](/source/Interferon_gamma) or [IFN-γ](/source/IFN-%CE%B3).

This subtype of type I IFN was recently described as a pseudogene in human, but potentially functional in the domestic cat genome. In all other genomes of non-feline placental mammals, IFN-ν is a pseudogene; in some species, the pseudogene is well preserved, while in others, it is badly mutilated or is undetectable. Moreover, in the cat genome, the IFN-ν promoter is deleteriously mutated. It is likely that the IFN-ν gene family was rendered useless prior to mammalian diversification. Its presence on the edge of the type I IFN locus in mammals may have shielded it from obliteration, allowing its detection.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

## Interferon type I in cancer

### Therapeutics

From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by the [US Food and Drug Administration](/source/US_food_and_drug_administration) (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and [pegylated](/source/Pegylated) IFNα for clinical use; e.g., IFNα2a ([Roferon-A](/source/Roferon_A), Roche), IFNα2b ([Intron-A](/source/Intron_A), Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of [hairy cell leukemia](/source/Hairy_cell_leukemia), [melanoma](/source/Melanoma), [renal cell carcinoma](/source/Renal_cell_carcinoma), [Kaposi's sarcoma](/source/Kaposi's_sarcoma), [multiple myeloma](/source/Multiple_myeloma), follicular and non-Hodgkin lymphoma, and [chronic myelogenous leukemia](/source/Chronic_myelogenous_leukemia). Human IFNβ (Feron, Toray ltd.) has also been approved in Japan to treat [glioblastoma](/source/Glioblastoma), [medulloblastoma](/source/Medulloblastoma), [astrocytoma](/source/Astrocytoma), and [melanoma](/source/Melanoma).[\[1\]](https://doi.org/10.1016/j.neo.2021.08.004)

### Copy number alteration of the interferon gene cluster in cancer

A large individual patient data meta-analysis using 9937 patients obtained from cBioportal indicates that copy number alteration of the IFN gene cluster is prevalent among 24 [cancer](/source/Cancer) types. Notably deletion of this cluster is significantly associated with increased mortality in many cancer types particularly [uterus](/source/Uterus_cancer), [kidney](/source/Kidney_cancer), and [brain](/source/Brain_tumor) cancers. The Cancer Genome Atlas [PanCancer](/source/Pan-cancer_analysis) analysis also showed that copy number alteration of the IFN gene cluster is significantly associated with decreased [overall survival](/source/Overall_survival). For instance, the overall survival of patients with brain [glioma](/source/Glioma) reduced from 93 months (diploidy) to 24 months. In conclusion, the copy number alteration of the IFN gene cluster is associated with increased [mortality](/source/Mortality_rate) and decreased [overall survival](/source/Overall_survival) in cancer.[1]

## Use of Interferon type I in therapeutics

### In cancer

From the 1980s onward, members of type-I IFN family have been the standard care as immunotherapeutic agents in cancer therapy. In particular, IFNα has been approved by the [US Food and Drug Administration](/source/US_food_and_drug_administration) (FDA) for cancer. To date, pharmaceutical companies produce several types of recombinant and [pegylated](/source/Pegylated) IFNα for clinical use; e.g., IFNα2a ([Roferon-A](/source/Roferon_A), Roche), IFNα2b ([Intron-A](/source/Intron_A), Schering-Plough) and pegylated IFNα2b (Sylatron, Schering Corporation) for treatment of [hairy cell leukemia](/source/Hairy_cell_leukemia), [melanoma](/source/Melanoma), [renal cell carcinoma](/source/Renal_cell_carcinoma), [Kaposi's sarcoma](/source/Kaposi's_sarcoma), [multiple myeloma](/source/Multiple_myeloma), follicular and non-Hodgkin lymphoma, and [chronic myelogenous leukemia](/source/Chronic_myelogenous_leukemia). Human IFNβ ([Feron](/source/Feron), Toray ltd.) has also been approved in Japan to treat [glioblastoma](/source/Glioblastoma), [medulloblastoma](/source/Medulloblastoma), [astrocytoma](/source/Astrocytoma), and [melanoma](/source/Melanoma).[1]

#### Combinational therapy with [PD-1/PD-L1 inhibitors](/source/PD-1_and_PD-L1_inhibitors)

By combining [PD-1/PD-L1 inhibitors](/source/PD-1_and_PD-L1_inhibitors) with type I interferons, researchers aim to tackle multiple resistance mechanisms and enhance the overall anti-tumor immune response. The approach is supported by preclinical and clinical studies that show promising synergistic effects, particularly in [melanoma](/source/Melanoma) and [renal carcinoma](/source/Renal_cell_carcinoma). These studies reveal increased infiltration and [activation of T cells](/source/T_cell_activation) within the [tumor microenvironment](/source/Tumor_microenvironment), the development of [memory T cells](/source/Memory_T_cell), and prolonged patient survival.[14]

### In viral infection

Due to their strong antiviral properties, recombinant type 1 IFNs can be used for the treatment for persistent viral infection. Pegylated IFN-α is the current standard of care when it comes to chronic Hepatitis B and C infection.[15]

### In multiple sclerosis

Currently, there are four FDA approved variants of IFN-β1 used as a treatment for relapsing [multiple sclerosis](/source/Multiple_sclerosis).[16] IFN-β1 is not an appropriate treatment for patients with progressive, non-relapsing forms of multiple sclerosis.[17] Whilst the mechanism of action is not completely understood, the use of IFN-β1 has been found to reduce brain lesions, increase the expression of anti-inflammatory cytokines and reduce T cell infiltration into the brain.[18][19]

## Side effects of type I interferon therapy

One of the major limiting factors in the efficacy of type I interferon therapy are the high rates of side effects. Between 15% - 40% of people undergoing type 1 IFN treatment develop major depressive disorders.[20] Less commonly, interferon treatment has also been associated with anxiety, lethargy, psychosis and parkinsonism.[21] Mood disorders associated with IFN therapy can be reversed by discontinuation of treatment, and IFN therapy related depression is effectively treated with the selective serotonin reuptake inhibitor class of antidepressants.[22]

## Interferonopathies

Interferonopathies are a class of hereditary auto-inflammatory and autoimmune diseases characterised by upregulated type 1 interferon and downstream interferon stimulated genes. The symptoms of these diseases fall in a wide clinical spectrum, and often resemble those of viral infections acquired while the child is in utero, although lacking any infectious origin.[23] The aetiology is largely still unknown, but the most common genetic mutations are associated with nucleic acid regulation, leading most researchers to suggest these arise from the failure of antiviral systems to differentiate between host and viral DNA and RNA.[24]

## Non-mammalian types

Avian type I IFNs have been characterized and preliminarily assigned to subtypes (IFN I, IFN II, and IFN III), but their classification into subtypes should await a more extensive characterization of avian genomes.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

Functional lizard type I IFNs can be found in lizard genome databases.[*[citation needed](https://en.wikipedia.org/wiki/Wikipedia:Citation_needed)*]

Turtle type I IFNs have been purified (references from 1970s needed). They resemble mammalian homologs.

The existence of amphibian type I IFNs have been inferred by the discovery of the genes encoding their receptor chains. They have not yet been purified, or their genes cloned.

Piscine (bony fish) type I IFN has been cloned first in zebrafish.[25][26] and then in many other teleost species including salmon and mandarin fish.[27][28] With few exceptions, and in stark contrast to avian and especially mammalian IFNs, they are present as single genes (multiple genes are however seen in polyploid fish genomes, possibly arising from whole-genome duplication). Unlike amniote IFN genes, piscine type I IFN genes contain introns, in similar positions as do their orthologs, certain interleukins. Despite this important difference, based on their 3-D structure these piscine IFNs have been assigned as Type I IFNs.[29] While in mammalian species all Type I IFNs bind to a single receptor complex, the different groups of piscine type I IFNs bind to different receptor complexes.[30] Until now several type I IFNs (IFNa, b, c, d, e, f and h) has been identified in teleost fish with as low as only one subtype in green pufferfish and as many as six subtypes in salmon with an addition of recently identified novel subtype, IFNh in mandarin fish.[27][28]

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## External links

- [Interferon+Type+I](https://meshb.nlm.nih.gov/record/ui?name=Interferon+Type+I) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- ["Interferon"](https://web.archive.org/web/20160705115457/http://druginfo.nlm.nih.gov/drugportal/name/Interferon). *Drug Information Portal*. U.S. National Library of Medicine. Archived from [the original](https://druginfo.nlm.nih.gov/drugportal/name/interferon) on July 5, 2016.

v t e Cell signaling: cytokines By family Chemokine CCL CCL1 CCL2/MCP1 CCL3/MIP1α CCL4/MIP1β CCL5/RANTES CCL6 CCL7 CCL8 CCL9 CCL11 CCL12 CCL13 CCL14 CCL15 CCL16 CCL17 CCL18/PARC/DCCK1/AMAC1/MIP4 CCL19 CCL20 CCL21 CCL22 CCL23 CCL24 CCL25 CCL26 CCL27 CCL28 CXCL CXCL1/KC CXCL2 CXCL3 CXCL4 CXCL5 CXCL6 CXCL7 CXCL8/IL8 CXCL9 CXCL10 CXCL11 CXCL12 CXCL13 CXCL14 CXCL15 CXCL16 CXCL17 CX3CL CX3CL1 XCL XCL1 XCL2 TNF TNFA Lymphotoxin TNFB/LTA TNFC/LTB TNFSF4 TNFSF5/CD40LG TNFSF6 TNFSF7 TNFSF8 TNFSF9 TNFSF10 TNFSF11 TNFSF13 TNFSF13B EDA Interleukin Type I (grouped by receptor subunit) γ chain IL2/IL15 IL4/IL13 IL7 IL9 IL21 β chain IL3 IL5 GMCSF IL6 like/gp130 IL6 IL11 IL27 IL30 IL31 +non IL OSM LIF CNTF CTF1 IL12 family/IL12RB1 IL12 IL23 IL27 IL35 Other IL14 IL16 IL32 IL34 Type II IL10 family IL10/IL22 IL19 IL20 IL24 IL26 Interferon type III IL28/IFNL2+3 IL29/IFNL1 Interferon I IFNA1 IFNA2 IFNA4 IFNA5 IFNA6 IFNA7 IFNA8 IFNA10 IFNA13 IFNA14 IFNA16 IFNA17 IFNA21 IFNB1 IFNK IFNW1 II IFNG Ig superfamily IL1 family: IL1A/IL1F1 IL1B/IL1F2 1Ra/IL1F3 IL1F5 IL1F6 IL1F7 IL1F8 IL1F9 IL1F10 33/IL1F11 18/IL1G IL17 family IL17/IL25 (IL17A) Other Hematopoietic KITLG Colony-stimulating factor SPP1 MIF By function/ cell proinflammatory cytokine IL1 TNFA Monokine Lymphokine Th1 IFNγ TNFβ Th2 IL4 IL5 IL6 IL10 IL13 Category Commons

v t e Cytokine receptor modulators Chemokine See here instead. CSF Erythropoietin Agonists: ARA-290 Asialo erythropoietin Carbamylated erythropoietin CNTO-530 Darbepoetin alfa Epoetin alfa Epoetin beta Epoetin delta Epoetin epsilon Epoetin gamma Epoetin kappa Epoetin omega Epoetin theta Epoetin zeta Erythropoietin (EPO) Erythropoietin-Fc Methoxy polyethylene glycol-epoetin beta (CERA/Mircera) Peginesatide Pegol sihematide (EPO-018B) G-CSF (CSF3) Agonists: Filgrastim Granulocyte colony-stimulating factor Lenograstim Leridistim Lipegfilgrastim Nartograstim Pegfilgrastim Pegnartograstim GM-CSF (CSF2) Agonists: Ecogramostim Granulocyte-macrophage colony-stimulating factor Milodistim Molgramostim Regramostim Sargramostim Antibodies: Mavrilimumab Namilumab Otilimab M-CSF (CSF1) Agonists: Cilmostim Interleukin 34 Lanimostim Macrophage colony-stimulating factor Mirimostim Kinase inhibitors: Agerafenib SCF (c-Kit) See here instead. Thrombopoietin Agonists: Eltrombopag Pegacaristim Promegapoietin Romiplostim Avatrombopag Lusutrombopag Thrombopoietin (THPO, MGDF) Interferon IFNAR (α/β, I) Agonists: Albinterferon Interferon alpha (interferon alfa, IFN-α) Interferon alfa (IFNA1, IFNA2, IFNA4, IFNA5, IFNA6, IFNA7, IFNA8, IFNA10, IFNA13, IFNA14, IFNA16, IFNA17, IFNA21) Interferon alfa 2a Interferon alfa 2b Interferon alfa n1 Interferon alfacon-1 Interferon alpha-n3 Interferon beta (IFN-β) (IFNB1, IFNB3) Interferon beta 1a Interferon beta 1b Interferon kappa (IFN-ε/κ/τ/ζ, IFNK) Interferon omega (IFN-ω, IFNW1) Peginterferon alfa-2a Peginterferon alfa-2b Antibodies: Anifrolumab Faralimomab MEDI-545 Rontalizumab Sifalimumab Decoy receptors: Bifarcept IFNGR (γ, II) Agonists: Interferon gamma (IFN-γ) Interferon gamma 1b Antibodies: Emapalumab Fontolizumab IFNLR (λ, III) See IL-28R (IFNLR) here instead. Interleukin See here instead. TGFβ See here instead. TNF See here instead. Others JAK (inhibitors) JAK1 Abrocitinib Baricitinib Deuruxolitinib Filgotinib Momelotinib Oclacitinib Peficitinib Ruxolitinib Tofacitinib (tasocitinib) Upadacitinib JAK2 Atiprimod AZD-1480 Baricitinib CHZ868 Cucurbitacin I (elatericin B, JSI-124) CYT387 Deuruxolitinib Lestaurtinib NSC-7908 NSC-33994 Pacritinib Peficitinib Ruxolitinib SD-1008 Tofacitinib (tasocitinib) JAK3 Cercosporamide Decernotinib (VX-509) Peficitinib Ritlecitinib TCS-21311 Tofacitinib (tasocitinib) WHI-P 154 ZM-39923 ZM-449829 TYK2 Deucravacitinib Others Additional cytokines: Cardiotrophin 1 (CT-1) FMS-like tyrosine kinase 3 ligand (FLT3L) Leukemia/leukocyte inhibitory factor (LIF) Oncostatin M (OSM) Thymic stromal lymphopoietin (TSLP) Additional cytokine receptor modulators: Emfilermin Lestaurtinib Midostaurin Quizartinib Sorafenib Sunitinib

[Portals](https://en.wikipedia.org/wiki/Wikipedia:Contents/Portals):
- [Biology](https://en.wikipedia.org/wiki/Portal:Biology)
- [Medicine](https://en.wikipedia.org/wiki/Portal:Medicine)
- [Viruses](https://en.wikipedia.org/wiki/Portal:Viruses)

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Adapted from the Wikipedia article [Interferon type I](https://en.wikipedia.org/wiki/Interferon_type_I) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Interferon_type_I?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.