Interferons

Interferon (IFN) is a cytokine with antiviral properties (it interferes with viral infections) and various roles in immunoregulation. The different types are type I IFN (IFN-ɑ and IFN-β), type II IFN (IFN-ɣ), and type III IFN (IFN-ƛ). Type I IFNs have been extensively studied; these proteins bind to cell-surface receptors when triggered by a viral infection. After stimulation, pathways are activated to produce proteins (e.g., ribonuclease) that inhibit viral replication. An antiviral state is created in both infected and uninfected cells. Type I IFN also has antitumor properties. The antiviral activity of type II IFN (IFN-ɣ) is not as potent as that of type I, but IFN- ɣ is crucial in macrophage activation. The recently discovered IFN-ƛ is noted to have activity against intestinal viruses. With a wide range of biologic effects, interferons are used in therapy for malignancies, infections, and other immune-related conditions (e.g., multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis).

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Overview

Definition

Interferons are a group of proteins belonging to a class of signaling molecules known as cytokines and are released by a variety of cells during the inflammatory response.

General functions

  • Antiviral proteins (so named because they were found to interfere with viral replication) 
  • Important immunoregulatory proteins affecting cell growth, differentiation, gene transcription Transcription Transcription of genetic information is the first step in gene expression. Transcription is the process by which DNA is used as a template to make mRNA. This process is divided into 3 stages: initiation, elongation, and termination. Stages of Transcription, and translation Translation Translation is the process of synthesizing a protein from a messenger RNA (mRNA) transcript. This process is divided into three primary stages: initiation, elongation, and termination. Translation is catalyzed by structures known as ribosomes, which are large complexes of proteins and ribosomal RNA (rRNA). Stages and Regulation of Translation
Interferons

Interferons:
Interferons are cytokines that are released by cells infected with a virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview, leukocytes, and other immune cells. To limit the infection, responses of cells to interferon include inhibition of protein synthesis, activation of immune cells, and induction of apoptosis.

Image: “Interferons” by OpenStax. License: CC BY 4.0

Types of Interferons

Type I interferons

  • Primarily includes interferon (IFN)-α and IFN-β
  • Most extensively studied
  • Produced by almost all cells, such as fibroblasts, leukocytes, and plasmacytoid dendritic cells (triggered by viral stimulation of pattern recognition receptors)
  • Functions:
    • Prevent viral replication inside cells (creating an antiviral state in both infected and uninfected cells)
    • Increases expression of class I MHC molecules on virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview-infected cells
    • Possesses antitumor responses
    • Induces inhibition of angiogenesis
    • Regulates cell survival and apoptosis

Type II interferon

  • Also known as IFN-γ 
  • Produced by T lymphocytes T lymphocytes T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells, natural killer (NK) cells, and macrophages
  • IL-12 and IL-2 trigger release of IFN-γ from T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells.
  • Functions:
    • ​​Up-regulates class I and II MHC molecules and promotes the differentiation of naive helper T cells T cells T cells, also called T lymphocytes, are important components of the adaptive immune system. Production starts from the hematopoietic stem cells in the bone marrow, from which T-cell progenitor cells arise. These cells migrate to the thymus for further maturation. T Cells into Th1 cells
    • Important role in macrophage activation (↑ phagocytosis, ↑ microbial killing) and antigen presentation
    • Antiviral activity is not as potent as that for type I IFN.
Type iv hypersensitivity_dendritic cells are releasing il-12-lpr

Dendritic cells release IL-12, which activates CD4 Th1 cells. These Th1 cells produce IL-2, stimulating production of more Th1 T-cell subsets. Th1 cells also release IFN-γ, which activates macrophages and activates fibroblasts to cause angiogenesis and fibrosis. If these macrophages are persistently stimulated by pathogens such as Mycobacterium Mycobacterium Mycobacterium is a genus of the family Mycobacteriaceae in the phylum Actinobacteria. Mycobacteria comprise more than 150 species of facultative intracellular bacilli that are mostly obligate aerobes. Mycobacteria are responsible for multiple human infections including serious diseases, such as tuberculosis (M. tuberculosis), leprosy (M. leprae), and M. avium complex infections. Mycobacterium and Schistosoma Schistosoma Schistosomiasis is an infection caused by Schistosoma, a trematode. Schistosomiasis occurs in developing countries with poor sanitation. Freshwater snails are the intermediate host and are transmitted to humans through skin contact with contaminated fresh water. The clinical presentation occurs as a result of the host's immune response to antigens from the eggs. Schistosoma/Schistosomiasis, granulomas are formed.

Image by Lecturio.

Type III interferon

  • More recently discovered
  • Also known as IFN-ƛ
  • Functions:
    • Mucosal immunity
    • Defense against intestinal viruses (e.g., rotavirus Rotavirus Rotavirus belongs to the Reoviridae family and is a non-enveloped, double-stranded RNA virus. Transmission occurs through the fecal-oral route. Rotavirus is a common cause of severe gastroenteritis in children. Severe infections can result in dehydration and death. Reoviridae: Rotavirus, norovirus Norovirus Norovirus is a nonenveloped, single-stranded, positive-sense RNA virus belonging to the Caliciviridae family. Norovirus infections are transmitted via the fecal-oral route or by aerosols from vomiting. The virus is one of the most common causes of nonbacterial gastroenteritis epidemic worldwide. Symptoms include watery and nonbloody diarrhea, nausea, vomiting, and low-grade fever. Norovirus)

Description of types of interferons

Table: Characteristics of types of interferons
Other designation Chromosomal location Cell of origin
IFN-ɑ Intron-A 9p22 Leukocytes
IFN-β IFN-b2 9p21 Fibroblasts
IFN-ɣ Macrophage activating factor: immune-interferon 12q14 Lymphocytes, macrophages, NK cells NK cells A specialized subset of T-lymphocytes that exhibit features of innate immunity similar to that of natural killer cells. They are reactive to glycolipids presented in the context of the major histocompatibility complex (MHC) class I-like molecule, CD1D antigen. Lymphocytes, dendritic cells
IFN-ƛ IL-28A, IL-28B, IL-29, IFNA14 19q13.13 Epithelial cells

Effects of Interferons

Induction

  • Strong inducers of IFN include:
    • Type I IFN:
      • Viruses
      • Double-stranded RNA RNA Ribonucleic acid (RNA), like deoxyribonucleic acid (DNA), is a polymer of nucleotides that is essential to cellular protein synthesis. Unlike DNA, RNA is a single-stranded structure containing the sugar moiety ribose (instead of deoxyribose) and the base uracil (instead of thymine). RNA generally carries out the instructions encoded in the DNA but also executes diverse non-coding functions. RNA Types and Structure
    • Type II IFN:
      • Antigens, mitogens
      • Other interferons
      • Cytokines (e.g., IL-2)
      • NK receptors
    • Type III IFN: viruses
  • When induced (e.g., viral entry to a cell), the infected cell or an NK or a T cell produces IFN, sending signals to other cells.
  •  IFN binds to a specific cell-surface receptor in the uninfected cell:
    • Type I IFN (IFN-ɑ, IFN-β): both bind to the same receptors (IFNAR1 and IFNAR2)
    • IFN-ɣ: binds to IFGNR1 and IFNGR2
    • IFN-ƛ: binds to a set of receptors (which are shared with IL-10, IL-28A, IL-28B, and IL-29)

Effects

  • After binding to the receptor → JAK, STAT signaling pathways activated
  • Genes are instructed to produce proteins that inhibit viral replication. 
    • Ribonuclease: degrades mRNA
    • Protein kinase: inhibits protein synthesis (by phosphorylating eukaryotic Eukaryotic Eukaryotes can be single-celled or multicellular organisms and include plants, animals, fungi, and protozoa. Eukaryotic cells contain a well-organized nucleus contained by a membrane, along with other membrane-bound organelles. Cell Types: Eukaryotic versus Prokaryotic initiation factor 2 (eIF-2))
    • Oligo(A) synthetase: Oligo(A) activates ribonuclease.
  • When the virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview tries to infect the cell, the enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes perform their functions.
  • The cell dies from the effects (without producing progeny virus Virus Viruses are infectious, obligate intracellular parasites composed of a nucleic acid core surrounded by a protein capsid. Viruses can be either naked (non-enveloped) or enveloped. The classification of viruses is complex and based on many factors, including type and structure of the nucleoid and capsid, the presence of an envelope, the replication cycle, and the host range. Virology: Overview), ultimately restricting the spread of infection.
  • IFNs have overlapping biologic effects during the early phase of infection, leading to:
    • Antiviral activity
    • Antiproliferative activity (other genes are also also down-regulated)
    • Immunoregulatory activity (immune cells such as macrophages are activated)
  • The IFNs also have unique functions that have differing effects (e.g.,  IFN-β is used for treatment of multiple sclerosis Multiple Sclerosis Multiple sclerosis (MS) is a chronic inflammatory autoimmune disease that leads to demyelination of the nerves in the CNS. Young women are more predominantly affected by this most common demyelinating condition. Multiple Sclerosis, whereas IFN-γ can exacerbate the condition).

Interferons and Diseases

Interferons as treatment

Table: Interferons as treatment
Interferon Condition(s) treated
Interferon-α
  • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and C
  • Papillomavirus ( condylomata acuminata Condylomata Acuminata Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts))
  • Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia
  • Kaposi’s sarcoma
  • Recurrence of melanoma Melanoma Melanoma is a malignant tumor arising from melanocytes, the melanin-producing cells of the epidermis. These tumors are most common in fair-skinned individuals with a history of excessive sun exposure and sunburns. Melanoma
  • Essential thrombocythemia Essential thrombocythemia Essential thrombocythemia (ET) is a type of myeloproliferative neoplasm characterized by the clonal thrombocytosis linked to somatic mutations involving Janus kinase 2 (JAK2), calreticulin (CALR), and myeloproliferative leukemia virus oncogene (MPL). Patients can be asymptomatic or present with vasomotor symptoms. Essential Thrombocythemia
Interferon-β Multiple sclerosis
Interferon-γ
  • Chronic granulomatous disease Chronic Granulomatous Disease Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. Chronic Granulomatous Disease (CGD)
  • Osteopetrosis

Evading interferons

  • Viruses have developed mechanisms of evading interferons by:
    • Inhibiting IFN synthesis
    • Inhibiting the effects of the antiviral proteins/ enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes
    • Blocking IFN signaling
    • Producing decoys to molecules that induce interferon signaling 
    • Encapsidating the genome
  • Some examples include:
    • Hepatitis B Hepatitis B Hepatitis B virus (HBV) is a partially double-stranded DNA virus, which belongs to the Orthohepadnavirus genus and the Hepadnaviridae family. Most individuals with acute HBV infection are asymptomatic or have mild, self-limiting symptoms. Chronic infection can be asymptomatic or create hepatic inflammation, leading to liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis B Virus and HIV block IFN synthesis.
    • Hepatitis C Hepatitis C Hepatitis C is an infection of the liver caused by the hepatitis C virus (HCV). The infection can be transmitted through infectious blood or body fluids and may be transmitted during childbirth or through IV drug use or sexual intercourse. Hepatitis C virus can cause both acute and chronic hepatitis, ranging from a mild to a serious, lifelong illness including liver cirrhosis and hepatocellular carcinoma (HCC). Hepatitis C Virus reduces interferon-induced gene production.

Clinical Relevance

  • Viral hepatitis: viral infection of the liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver that causes inflammation Inflammation Inflammation is a complex set of responses to infection and injury involving leukocytes as the principal cellular mediators in the body's defense against pathogenic organisms. Inflammation is also seen as a response to tissue injury in the process of wound healing. The 5 cardinal signs of inflammation are pain, heat, redness, swelling, and loss of function. Inflammation and damage. Interferon is used as part of the treatment of 2 primary hepatitis viruses: B and C. Management of acute hepatitis is typically supportive, whereas for chronic infection, options such as interferon and oral antiviral agents are available. Interferon-ɑ inhibits protein synthesis via antiviral proteins/ enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes. The medication can cause flu-like symptoms and elevated liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver enzymes Enzymes Enzymes are complex protein biocatalysts that accelerate chemical reactions without being consumed by them. Due to the body's constant metabolic needs, the absence of enzymes would make life unsustainable, as reactions would occur too slowly without these molecules. Basics of Enzymes.
  • Multiple sclerosis (MS): chronic inflammatory autoimmune disease leading to demyelination of the CNS. The clinical presentation of MS varies depending on the site of lesions, but neurologic symptoms affecting vision, motor functions, sensation, and autonomic function are typically seen. Interferon-β is an option among disease-modifying therapies for relapsing MS. Flu-like symptoms and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver dysfunction are adverse effects.
  • Chronic granulomatous disease Chronic Granulomatous Disease Chronic granulomatous disease (CGD), as the name implies, is a chronic disorder that is characterized by granuloma formation. This disorder is a consequence of defective phagocytic cells that are unable to produce bactericidal superoxide because of a defect in nicotinamide adenine dinucleotide phosphate (NADPH), the oxidase responsible for the respiratory burst in phagocytic leukocytes. Chronic Granulomatous Disease (CGD): genetic condition characterized by recurrent severe bacterial and fungal infections and granuloma formation. Defective nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway ( NADPH NADPH Nicotinamide adenine dinucleotide phosphate. A coenzyme composed of ribosylnicotinamide 5'-phosphate (nmn) coupled by pyrophosphate linkage to the 5'-phosphate adenosine 2. Pentose Phosphate Pathway) oxidase (responsible for the respiratory burst) in neutrophils and macrophages leads to impaired phagocytosis. Infections commonly affect the lung, skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Structure and Function of the Skin, lymph nodes, and liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver. Prophylactic treatment includes IFN-ɣ. Side effects include fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever and myalgias.
  • Hairy cell leukemia Hairy cell leukemia Hairy cell leukemia (HCL) is a rare, chronic, B-cell leukemia characterized by the accumulation of small mature B lymphocytes that have "hair-like projections" visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow (causing fibrosis), and red pulp of the spleen, leading to cytopenias. Hairy Cell Leukemia: rare, chronic B-cell leukemia characterized by the accumulation of small mature B lymphocytes B lymphocytes B lymphocytes, also known as B cells, are important components of the adaptive immune system. In the bone marrow, the hematopoietic stem cells go through a series of steps to become mature naive B cells. The cells migrate to secondary lymphoid organs for activation and further maturation. B Cells that have hair-like projections visible on microscopy. The abnormal cells accumulate in the peripheral blood, bone marrow Bone marrow Bone marrow, the primary site of hematopoiesis, is found in the cavities of cancellous bones and the medullary canals of long bones. There are 2 types: red marrow (hematopoietic with abundant blood cells) and yellow marrow (predominantly filled with adipocytes). Composition of Bone Marrow (causing fibrosis), and spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen. Interferon-ɑ is part of the treatment regimen, as it inhibits cell growth and interferes with oncogene and surface antigen expression.

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