The immune system is a defence mechanism which allows complex organisms, Homo sapiens included, to survive and fight back in response to infections by pathogens. There are a wide range of harmful microorganisms, such as viruses, bacteria, prions, fungi and other parasites, with a rapid adaptive capability to escape host defence tools. On the other hand, evolution has provided the host with an elaborate network of cells, tissues and organs for detecting and neutralizing an infection. The immune system has been classified into two subsystems, the innate immune system and the adaptive immune system . Innate immunity acts as an early defence against invading microorganisms and triggers the activation of the more advanced adaptive immunity. A key property of the immune system is the ability to distinguish between host cells (self) and pathogenic antigens (non-self); alterations in the induction or in the maintenance of self tolerance may lead to inflammatory and then autoimmune diseases or cancer.
Phylogenetically speaking, innate immunity is the more ancient arm of the defence system and is present in many eukaryotic organisms such as plants and animals. It consists of cellular and biochemical defence mechanisms pre-existing the infection, ready for rapid and immediate action in recognizing the pathogenic agent. The main components of the innate immune system are: physical and chemical barriers, white blood cells (neutrophils, macrophages and natural killer cells), blood proteins (antimicrobial peptides and the complement cascade) and numerous other molecules called cytokines which regulate and coordinate many activities of innate immune cells. Some components are functioning constantly, even before the infection, such as the physiological barriers active against the entrance of the pathogens; while other elements are usually inactive, but promptly triggered in the presence of antigens. The main three physiological barriers of the human body are the skin, the mucosal surfaces in the intestinal tract and the surfaces of the respiratory apparatus; while a typical chemical barrier is the low stomach pH, which usually inhibits microbial growth. Despite these barriers, pathogens may enter the body and are then recognised in tissues or in the circulatory system by the main effector cells of innate immunity: neutrophils, eosinophils, basophils, mononuclear phagocytes, dendritic cells (DCs) and natural killer (NK) cells. These cells, in particular macrophages and NK cells, release cytokines which activate the phagocytes stimulating the inflammatory response. Antimicrobial peptides and the complement cascade are humoral components of innate immunity and help to enhance the response. However, many harmful microorganisms have developed several strategies to avoid or evade innate immunity. In this kind of infection, therefore, the innate immune system can only keep the pathogenic agent under control until the activation of a more specific and specialised adaptive immunity . The components of innate immunity recognise particular structures of microbial organisms which are not expressed by host cells. These elements are called pathogen associated molecular patterns (PAMPs) which are sensed by a wide variety of pattern recognition receptors (PRRs) expressed by several cells of the innate immune system such as macrophages and dendritic cells, but also epithelial cells and fibroblasts .
PRRs are connected to the transduction of intracellular signaling pathways which induce the activation of the immune response and inflammation after the detection of PAMPs. They are responsible for the rapid and aspecific first-line response to harmful microorganism infections in order to block or contain them; while the adaptive immune system requires up to 5 days for producing a more selective and robust response. The signaling pathways downstream of PRRs lead to the activation of transcription factors which bind the promoter region of immune genes. Nuclear factor κB (NF-κB) and the interferon regulatory factors (IRFs) are the main transcription factors involved in the upregulation of immune proteins, such as cytokines and IFNs. The production of several pro-inflammatory cytokines is controlled by NF-κB, for example TNFα and CCL5 (also known as RANTES); while type I IFN induction is regulated by IRFs, such as IRF-3 and IRF-7 .
PRRs are commonly classified in five main families: Toll-like receptors (TLRs), Retinoic acid Inducible gene-1 (RIG-I)-like receptors (RLRs), Nod-like receptors (NLRs), C-type lectin-like receptors (CLRs) and Absent in melanoma 2 (AIM2)-like receptors (ALRs) (see Figure1).
Figure 1: Pattern Recognition Receptors (PRRs)
The Interferon Response
IFNs are cytokines secreted by infected cells and the first molecules of this big family were discovered by Isaacs and Lindenmann in 1957. These polypeptides carry out several functions in the control of microbial infections, starting from the creation of an intrinsic anti-pathogen state in infected cells through the induction of the innate immune response and finally the activation of the adaptive immune system. In humans, the IFNs have been classified in three classes differentiated by their receptor complexes.
Type I interferons are the largest class which includes IFNα, IFNβ, IFNε, IFNκ and IFNω, all clustered on chromosome 9. Two members of this class, IFNα and IFNβ, have been well characterized and are upregulated in response to stimulation of PRRs. There are various isoforms of IFNα encoded by 14 distinct genes and they are mainly produced in haematopoietic cells, in particular plasmacytoid dendritic cells. On the contrary IFNβ is encoded by a single gene and is widely produced in most of the human tissues. Type I IFNs activate the STAT-dependent pathway which can induce the expression of many IRFs, such as IRF1, IRF7, IRF8 and IRF9, and several interferon stimulated genes (ISGs) (see Figure 2) .
IFNγ is the only member of the type II IFN class. Its production is strictly confined to immune cells and plays a crucial role in the regulation of both the innate and adaptive systems, whereas the receptor is commonly expressed in many cell types of the human.
IFNλ1, IFNλ2, IFNλ3, also known as IL-29, IL-28A ad IL-28B respectively, and IFNλ4 are members of the most recently discovered third class of IFNs and their genes are clustered on human chromosome 19. Type III IFN receptor is strictly expressed on the plasma membrane of epithelial cells.
Figure 2: The interferon response
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