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Home , Innate immune system

Companion Notes to WE#6; Weichhart et al; 2008 The innate ; is an important subsystem of the overall system that comprises the cells and mechanisms that defend the host from by other organisms. The cells of the innate system recognize and respond to in a generic way, but, unlike the , the system does not confer long-lasting or protective immunity to the host. Innate immune systems provide immediate defense against infection, and are found in all classes of and animal life. The major functions of the innate immune system include: • Recruiting immune cells to sites of infection, through the production of chemical factors, including specialized chemical mediators, called • Activation of the complement cascade to identify , activate cells, and promote clearance of antibody complexes or dead cells • Identification and removal of foreign substances present in organs, tissues, the blood and lymph, by specialized white blood cells • Activation of the adaptive immune system through a process known as Acting as a physical and chemical barrier to infectious agents.

Prolonged , Chronic inflammation, a progressive shift in the type of cells present at the site of inflammation, such as mononuclear cells, and is characterized by simultaneous destruction and healing of the tissue from the inflammatory process. It is useful to differentiate between inflammation and , as there are many pathological situations where inflammation is not driven by microbial invasion - for example, atherosclerosis, type III hypersensitivity, trauma, and ischaemia. There are also pathological situations where microbial invasion does not result in classic inflammatory response—for example, parasitosis, which leads to an eosinophilia.

Antigen-presenting cell (APC) is a cell that displays antigen complexed with major histocompatibility complexes (MHCs) on their surfaces; this process is known as antigen presentation. T cells may recognize these complexes using their receptors (TCRs). These cells process antigens and present them to T-cells. Almost all cell types can serve as some form of APC, and APCs are found in a large variety of tissue types. Professional antigen-presenting cells, including , B cells, and dendritic cells, specialize in presenting foreign antigen to T helper cells, while other cell types can present antigen originating inside the cell to cytotoxic T cells. In addition to the MHC family of proteins, Antigen presentation relies on other specialized signaling molecules on the surfaces of both APC’s and T cells. The APC’s are vital for an effective adaptive immune response, as the functioning of both cytotoxic and helper T cells are dependent on APCs. Antigen presentation allows for the extreme specificity of adaptive immunity and can contribute to immune responses against both intracellular and extracellular pathogens. It is also involved in defense against tumors.

Dendritic cells (DCs) are one of the APC’s of the mammalian immune system. Their main function is to process antigen material and present it on the cell surface to the T cells of the immune system. They act as messengers between the innate and the adaptive immune systems.

1 DC are present in those tissues that are in contact with the external environment, such as the and the inner lining of the nose, , and intestines. They can also be found in an immature state in the blood. Once activated, they migrate to the lymph nodes where they interact with T cells and B cells to initiate and shape the adaptive immune response.

Macrophages engulfs and digests cellular debris, foreign substances, microbes, cancer cells, and anything else that does not have the types of proteins specific of healthy body cells on its surface in a process called . These large are found in essentially all tissues, where they patrol for potential pathogens by amoeboid movement. Besides phagocytosis, they play a critical role in nonspecific defense (innate immunity) and also help initiate specific defense mechanisms (adaptive immunity) by recruiting other immune cells such as . They are important APC’s to T cells. In humans, dysfunctional macrophages cause severe diseases such as chronic granulomatous disease that result in frequent infections. Beyond increasing inflammation and stimulating the immune system, macrophages also play an important anti-inflammatory role and can decrease immune reactions through the release of cytokines. Macrophages that encourage inflammation are called M1 macrophages, whereas those that decrease inflammation and encourage tissue repair are called M2 macrophages. This difference is reflected in their ; M1 macrophages have the unique ability to metabolize arginine to the "killer" molecule NO, whereas M2 macrophages have the unique ability to metabolize arginine to the "repair" molecule ornithine. They can be identified by their expression of specific of proteins such as CD14, CD40, CD11b, CD64, F4/80 (mice)/EMR1 (human), M, MAC-1/MAC-3 and CD68.

Monocytes are a type of leukocytes. They are the largest of all leukocytes and are precursors to macrophages, dendritic cells and foam cells. They are part of the innate immune system of including all mammals, , reptiles, and . They are amoeboid in shape, having agranulated cytoplasm. have unilobar nuclei, which, makes them one of the types of mononuclear leukocytes (containing azurophil granules). The archetypal idea of the nucleus is that it is bean-shaped or kidney-shaped, although the most important distinction is that it is not deeply furcated into lobes, as occurs in polymorphonuclear leukocytes. Monocytes constitute 2% to 10% of all leukocytes in the human body. They play multiple roles in immune function. Such roles include: (1) replenishing resident macrophages under normal states, and (2) in response to inflammation signals, monocytes can move quickly (approx. 8–12 hours) to sites of infection in the tissues and divide/differentiate into macrophages and dendritic cells to elicit an immune response. Half of them are stored in the spleen and change into macrophages after entering into the tissue spaces, and in can transform into foam cells.

Neutrophil (PMN) are the most abundant type of granulocytes and the most abundant (40% to 75%) type of white blood cells in most mammals. They form an essential part of the innate immune system. Functionality varies in different animals. They are formed from stem cells in the bone marrow. They are short-lived and highly motile, or mobile, as they can enter parts of tissue where other cells/molecules wouldn't be able to enter otherwise. may be subdivided into segmented neutrophils and banded neutrophils (or bands). They form part of the polymorphonuclear cell family (PMNs) together with and . The name derives from staining characteristics on hematoxylin and eosin (H&E)

2 histological or cytological preparations. Whereas basophilic white blood cells stain dark blue and eosinophilic white blood cells stain bright red, neutrophils stain a neutral pink. Normally, neutrophils contain a nucleus divided into 2–5 lobes. Neutrophils are a type of and are normally found in the bloodstream. During the beginning (acute) phase of inflammation, particularly as a result of bacterial infection, environmental exposure, and some cancers, neutrophils are one of the first-responders of inflammatory cells to migrate towards the site of inflammation. They migrate through the blood vessels, then through interstitial tissue, following chemical signals such as Interleukin-8 (IL-8), C5a, fMLP and B4 in a process called . Neutrophils are recruited to the site of injury within minutes following trauma, and are the hallmark of acute inflammation; however, due to some pathogens being indigestible, they can be unable to resolve certain infections without the assistance of other types of immune cell. Neutrophils undergo a process called chemotaxis, which allows them to migrate toward sites of infection or inflammation. Cell surface receptors allow neutrophils to detect chemical gradients of molecules such as interleukin-8 (IL-8), gamma (IFN-γ), , C5a, and Leukotriene B4, which these cells use to direct the path of their migration. Neutrophils have a variety of specific receptors, including ones for complement, cytokines like interleukins and IFN-γ, , , and other proteins. They also express receptors to detect and adhere to endothelium and Fc receptors for opsonin.

3 T helper cells (Th cells) are a type of T cell that play an important role in the immune system, particularly in the adaptive immune system. They help the activity of other immune cells by releasing T cell cytokines. These cells help suppress or regulate immune responses. They are essential in B cell antibody class switching, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages. + + Th cells express the surface protein CD4 and are referred to as CD4 T cells. Such CD4 T cells are generally treated as having a pre-defined role as helper T cells within the immune system. For example, when an APC expresses an antigen on MHC class II, a CD4+ cell will aid those cells through a combination of cell to cell interactions (e.g. CD40 and CD40L) and through cytokines. Nevertheless, there are rare exceptions; for example, sub-groups of regulatory T cells, natural killer cells, and cytotoxic T cells express CD4. All of the latter CD4+ T cell groups are not considered T helper cells.

During an immune response the APC’s carry out endocytosis of typically bacteria or , which undergoes processing, then travel from the infection site to the lymph nodes. Once at the lymph nodes, the APC begin to present antigen peptides that are bound to Cl ss II MHC, allowing CD4+ T cells that express the specific TCR’s against the peptide/MHC complex to activate. When a Th cell encounters and recognizes the antigen on an APC, the TCR-CD3 complex binds strongly to the peptide-MHC complex present on the surface of professional APCs. CD4, a co-receptor of the TCR complex, also binds to a different section of the MHC molecule. These interactions bring these proteins closer together, allowing the intracellular kinases present on the TCR, CD3 and CD4 proteins to activate each other via phosphorylation. With the assistance of a phosphatase present on the intracellular section of CD45 (common leukocyte antigen), these molecules activate major Th cell intracellular pathways. These active pathways are known as Signal 1 of T cell activation, as it is the first and primary pro-activation signal in a Th cell. Upon subsequent encounters with a given antigen, memory T cells are re-activated using the same TCR pathways. The binding of the antigen-MHC to the TCR complex and CD4 may also help the APC and the Th cell adhere during Th cell activation, but the integrin protein LFA-1 on the T cell and ICAM on the APC are the primary molecules of adhesion in this cell interaction.

T helper 17 cells (Th17) are a subset of pro-inflammatory T helper cells defined by their production of interleukin 17 (IL-17). They are related to T regulatory cells and the signals that cause Th17s to differentiate actually inhibit Treg differentiation. However, Th17’s are developmentally distinct from Th1 and Th2 lineages. Th17 cells play an important role in maintaining mucosal barriers and contributing to clearance at mucosal surfaces, but they have also been implicated in autoimmune and inflammatory disorders. The loss of Th17 cell populations at mucosal surfaces has been linked to chronic inflammation and microbial translocation.

Dictionary Addendum of Terms CD40; Cluster of differentiation 40, CD40 is a protein found on antigen presenting cells and is required for their activation. The binding of CD154 (CD40L) on TH cells to CD40 activates APC’s and induces a variety of downstream effects. The protein receptor encoded by this gene is a member of the TNF-receptor superfamily. This receptor has been found to be essential in mediating a broad variety of immune and inflammatory responses including T cell-dependent immunoglobulin class switching, memory 4 B cell development, and germinal center formation. AT-hook transcription factor AKNA is reported to coordinately regulate the expression of this receptor and its ligand, which may be important for homotypic cell interactions. The TNFR-receptor associated factor adaptor proteins TRAF1,TRAF2, TRAF6 and possibly TRAF5 interact with this receptor serve as mediators of the signal transduction.

Interlukins; are a group of cytokines, secreted proteins and signal molecules. The function of the immune system depends in a large part on interleukins, and rare deficiencies of a number of them have been described, all featuring autoimmune diseases or immune deficiency. The majority of interleukins are synthesized by helper CD4 T cell, as well as through monocytes, macrophages, and endothelial cells. They promote the development and differentiation of T and B lymphocytes, and hematopoietic cells. • Interleukin 10 (IL-10) is a protein that inhibits the synthesis of a number of cytokines, including IFN-gamma, IL-2, IL-3, TNF, and GM-CSF produced by activated macrophages and by helper T cells. In structure, IL-10 is a protein of about 160 amino acids that contains four conserved cysteines involved in disulphide bonds. IL-10 is highly similar to the Human herpesvirus 4 (Epstein-Barr ) BCRF1 protein, which inhibits the synthesis of gamma-interferon and to Equid herpesvirus 2 (Equine herpesvirus 2) protein E7. It is also similar, but to a lesser degree, with human protein mda-7, a protein that has antiproliferative properties in human melanoma cells. Mda-7 contains only two of the four cysteines of IL-10. • Interleukin 12 (IL-12) is a disulphide-bonded heterodimer consisting of a 35kDa alpha subunit and a 40kDa beta subunit. It is involved in the stimulation and maintenance of Th1 cellular immune responses, including the normal host defense against various intracellular pathogens, such as , Toxoplasma, virus, and Human immunodeficiency virus 1 (HIV). IL-12 also has an important role in enhancing the cytotoxic function of NK cells and role in pathological Th1 responses, such as in inflammatory bowel disease and multiple sclerosis. Suppression of IL-12 activity in such diseases may have therapeutic benefit. • Interleukin-23 (IL-23) is a heterodimeric composed of an IL-12p40 subunit that is shared with IL-12 and the IL-23p19 subunit. A functional receptor for IL-23 (the IL-23 receptor) has been identified and is composed of IL-12R β1 and IL-23R. The role of IL-12 had blocked the activity of IL-12p40, and were therefore not as specific as thought. Studies which blocked the function of IL-12p35 did not produce the same results as those targeting IL-12p40 as would have been expected if both subunits formed part of IL-12 only.

NF-kB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls transcription of DNA, cytokine production and cell survival. NF-κB is found in almost all animal cell types and is involved in cellular responses to stimuli such as , cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. NF-κB plays a key role in regulating the immune response to infection (κ light chains are critical components of immunoglobulins). Incorrect regulation of NF-κB has been linked to cancer, inflammatory and autoimmune diseases, , viral infection, and improper immune development. NF-κB has also been implicated in processes of synaptic plasticity and memory.

5 Signal transducer and activator of transcription 3 (STAT3); is a transcription factor, which in humans is encoded by the STAT3 gene. It is a member of the STAT protein family. STAT3 is a member of the STAT protein family. In response to cytokines and growth factors, STAT3 is phosphorylated by receptor-associated Janus kinases (JAK), form homo- or heterodimers, and translocate to the where they act as transcription activators. Specifically, STAT3 becomes activated after phosphorylation of tyrosine 705 in response to such ligands as , epidermal growth factor (EGF), IL- 5 and IL-6. Additionally, activation of STAT3 may occur via phosphorylation of serine 727 by Mitogen-activated protein kinases (MAPK) and through c-src non-receptor tyrosine kinase. STAT3 mediates the expression of a variety of genes in response to cell stimuli, and thus plays a key role in many cellular processes such as cell growth and . STAT3- deficient mouse embryos cannot develop beyond embryonic day 7, when gastrulation begins. It appears that at these early stages of development, STAT3 activation is required for self- renewal of embryonic stem cells (ESCs). Indeed, LIF, which is supplied to murine ESC cultures to maintain their undifferentiated state, can be omitted if STAT3 is activated through some other means. STAT3 is essential for the differentiation of the Th17 helper T cells, which have been implicated in a variety of autoimmune diseases.

TSC; Tuberous sclerosis proteins 1 and 2; also known as TSC1 (hamartin) and TSC2 (tuberin), form a protein-complex. The encoding two genes are TSC1 and TSC2. The complex is known as a tumor suppressor. Mutations in these genes can cause tuberous sclerosis complex. The TSC1 and TSC2 proteins form a heterodimeric complex which acts as an important integrator of different signaling pathways controlling mTOR signaling, by regulating especially mTORC1 activity. TSC2 contains a GTPase Activating Protein (GAP) domain, which has been shown to stimulate the GTPase activity of the small GTPase Rheb, which is – in its GTP bound form – an activator of mTORC1. TSC1 does not have a GAP domain but it acts as a stabilizer of TSC2 by protecting it from degradation. The activity of the TSC1-TSC2 complex is regulated by phosphorylation of different Ser and Thr sites mediated by the following Pathways: • PI3K-Akt signalling: Akt inhibits TSC1-TSC2 by phosphorylating TSC2 on 2-5 sites. However the molecular mechanism is yet unknown since the GAP activity of TSC2 is not remarkably influenced by these phosphorylation events. • Low energy levels and stress: The AMP-dependent protein kinase AMPK phosphorylates and thereby activates TSC1-TSC2 by phosphorylating at least 2 residues of TSC2. • Hypoxia: The HIFα induces REDD1 at low oxygen levels. REDD1 has been shown to activate TSC1-TSC2 by neutralization of AKT dependent inhibition. • ERK-RSK signalling: When it is activated by ERK, RSK phosphorylates and inhibits TSC1- TSC2. TSC2 has 3 phosphorylation sites for RSK. Two of them are also substrates of Akt.

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