1KLA , 1KLC , 1KLD , 3KFD , 4KV5
32-473: 7040 21803 ENSG00000105329 ENSMUSG00000002603 P01137 P04202 NM_000660 NM_011577 NP_000651 NP_035707 Transforming growth factor beta 1 or TGF-β1 is a polypeptide member of the transforming growth factor beta superfamily of cytokines . It is a secreted protein that performs many cellular functions, including the control of cell growth , cell proliferation , cell differentiation , and apoptosis . In humans, TGF-β1
64-455: A guanine exchange factor , loads ARL14/ARF7 with GTP. Subsequently, ARF7EP interacts with MYO1E which binds itself to actin myofibers. Altogether, this complex contributes to maintain MHC-II loaded vesicles within the immature dendritic cell , impeding its translocation to the cell membrane. One type of MHC class II deficiency, also called bare lymphocyte syndrome , is due to mutations in
96-483: A MHC class II molecule occurs by phagocytosis . Extracellular proteins are endocytosed into a phagosome , which subsequently fuses with a lysosome to create a phagolysosome . Within the phagolysosome, lysosomal enzymes degrade the proteins into peptide fragments . These fragments are then loaded into the peptide-binding groove of the MHC class II molecule. Once loaded, the MHC class II-peptide complexes are transported to
128-582: A chemotactic manner. Furthermore, the expression of monocytic cytokines (such as interleukin(IL)-1 α, IL-1β, and TNF-α ), and macrophage's phagocytic can be increased by the action of TGF-β1. TGF-β1 reduces the efficacy of the MHC II in astrocytes and dendritic cells , which in turn decreases the activation of appropriate helper T cell populations. TGF beta 1 has been shown to interact with: Transforming growth factor beta superfamily The transforming growth factor beta (TGF-β) superfamily
160-499: A class of major histocompatibility complex (MHC) molecules normally found only on professional antigen-presenting cells such as dendritic cells , macrophages , some endothelial cells , thymic epithelial cells , and B cells . These cells are important in initiating immune responses . Antigens presented by MHC class II molecules are exogenous, originating from extracellular proteins rather than cytosolic and endogenous sources like those presented by MHC class I . The loading of
192-465: A conserved family of proteins called SMADs . They play fundamental roles in the regulation of basic biological processes such as growth, development , tissue homeostasis and regulation of the immune system . Proteins from the TGF-beta superfamily are only active as homo- or heterodimer; the two chains being linked by a single disulfide bond. From X-ray studies of TGF-beta-2, it is known that all
224-427: A full-force antibody immune response due to activation of B cells . During synthesis of class II MHC in the endoplasmic reticulum, the α and β chains are produced and complexed with a special polypeptide known as the invariant chain . The nascent MHC class II protein in the rough ER has its peptide-binding cleft blocked by the invariant chain (Ii; a trimer) to prevent it from binding cellular peptides or peptides from
256-418: A multitude of different diseases, one of which being Type I diabetes . HLA class II genes are the most important genes associated with the risk of inheriting Type I diabetes, accounting for about 40-50% of heritability . Alleles of these genes that affect peptide binding to the MHC class II molecules seem to impact Type I diabetes risk the most. Specific allele polymorphisms have been identified to increase
288-401: A transmembrane sequence and a cytoplasmic tail. The α1 and β1 regions of the chains come together to make a membrane-distal peptide-binding domain, while the α2 and β2 regions, the remaining extracellular parts of the chains, form a membrane-proximal immunoglobulin-like domain. The antigen binding groove, where the antigen or peptide binds, is made up of two α-helixes walls and β-sheet. Because
320-524: Is a large group of structurally related cell regulatory proteins that was named after its first member, TGF-β1 , originally described in 1983. They interact with TGF-beta receptors . Many proteins have since been described as members of the TGF-β superfamily in a variety of species, including invertebrates as well as vertebrates and categorized into 23 distinct gene types that fall into four major subfamilies: Transforming growth factor-beta (TGF-beta)
352-414: Is a deficiency in MHC class II molecules B cells are not activated and cannot differentiate into plasma cells which causes them to be deficient in antibodies which are unable to perform as they are expected. The only current form of treatment is a bone-marrow transplant however even this does not cure the disease and most patients do not live past age ten. MHC class II genes and molecules are related to
SECTION 10
#1732791528189384-460: Is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. TGF-beta-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein. These proteins interact with a conserved family of cell surface serine/threonine-specific protein kinase receptors, and generate intracellular signals using
416-576: Is a type of MHC class II deficiency. Like MHC class I molecules, class II molecules are also heterodimers , but in this case consist of two homogenous peptides, an α and β chain, both of which are encoded in the MHC. The subdesignation α1, α2, etc. refers to separate domains within the HLA gene; each domain is usually encoded by a different exon within the gene, and some genes have further domains that encode leader sequences, transmembrane sequences, etc. These molecules have both extracellular regions as well as
448-433: Is also expressed on group 3 innate lymphoid cells . Having MHC class II molecules present proper peptides that are bound stably is essential for overall immune function. Because class II MHC is loaded with extracellular proteins, it is mainly concerned with presentation of extracellular pathogens (for example, bacteria that might be infecting a wound or the blood). Class II molecules interact mainly with immune cells, like
480-602: Is encoded by the TGFB1 gene . TGF-β is a multifunctional set of peptides that controls proliferation , differentiation , and other functions in many cell types. TGF-β acts synergistically with transforming growth factor-alpha (TGF-α) in inducing transformation . It also acts as a negative autocrine growth factor . Dysregulation of TGF-β activation and signaling may result in apoptosis . Many cells synthesize TGF-β and almost all of them have specific receptors for this peptide. TGF-β1, TGF-β2 , and TGF-β3 all function through
512-526: Is then acquired and loaded onto a MHC II molecule. The MHC II molecule then travels to the surface to present the antigen to a helper T cell . MHC II activate helper T cells which help release cytokines and other things which will help induce other cells which help to combat the pathogens outside the cells. Several molecules are involved in this pathway. PIK3R2 and PIP5K1A are two kinases that phosphorylate Phosphatidylinositol (PIP) providing PSD4 with substrates for its GTP loading ability. PSD4 as
544-503: The T helper cell ( CD4 ). The peptide presented regulates how T cells respond to an infection. Stable peptide binding is essential to prevent detachment and degradation of a peptide, which could occur without secure attachment to the MHC molecule. This would prevent T cell recognition of the antigen, T cell recruitment, and a proper immune response. The triggered appropriate immune response may include localized inflammation and swelling due to recruitment of phagocytes or may lead to
576-412: The immune system , and shows different activities on different types of cell, or cells at different developmental stages. Most immune cells (or leukocytes ) secrete TGF-β1. Some T cells (e.g. regulatory T cells ) release TGF-β1 to inhibit the actions of other T cells. Specifically, TGF-β1 prevents the interleukin(IL)-1 - & interleukin-2 -dependent proliferation in activated T cells, as well as
608-522: The plasma membrane by the APCs(antigen presenting cells). In some cells, antigens bind to recycled MHC class II molecules while they are in the early endosomes , while other cells such as dendritic cells internalize antigens via receptor-mediated endocytosis and create MHC class II molecules plus peptide in the endosomal-lysosomal antigen processing compartment which is independent of the synthesis of new MHC class II complexes. These suggest that after
640-469: The plasma membrane via vesicular transport , where they present the antigens to the extracellular environment. In humans, the MHC class II protein complex is encoded by the human leukocyte antigen gene complex (HLA) . HLAs corresponding to MHC class II are HLA-DP , HLA-DM , HLA-DOA , HLA-DOB , HLA-DQ , and HLA-DR . Mutations in the HLA gene complex can lead to bare lymphocyte syndrome (BLS), which
672-474: The activation of quiescent helper T cells and cytotoxic T cells . Similarly, TGF-β1 can inhibit the secretion and activity of many other cytokines including interferon-γ , tumor necrosis factor-alpha (TNF-α), and various interleukins . It can also decrease the expression levels of cytokine receptors, such as the IL-2 receptor to down-regulate the activity of immune cells. However, TGF-β1 can also increase
SECTION 20
#1732791528189704-415: The antigen is internalized, already existent MHC class II complexes on mature dendritic cells can be recycled and developed into new MHC class II molecules plus peptide. Unlike MHC I, MHC II is meant to present extracellular pathogens rather than intracellular. Furthermore, the first step is to acquire the pathogen through phagocytosis. The pathogen is then broken down in a lysosome and a desired component
736-445: The antigen-binding groove of MHC class II molecules is open at both ends while the corresponding groove on class I molecules is closed at each end, the antigens presented by MHC class II molecules are longer, generally between 15 and 24 amino acid residues long. These molecules are constitutively expressed in professional, immune antigen-presenting cells , but may also be induced on other cells by interferon γ . They are expressed on
768-521: The endogenous pathway (such as those that would be loaded onto class I MHC). The invariant chain also facilitates the export of class II MHC from the ER to the Golgi apparatus , followed by fusion with a late endosome containing endocytosed, degraded proteins. The invariant chain is then broken down in stages by proteases called cathepsins , leaving only a small fragment known as CLIP which maintains blockage of
800-606: The epithelial cells in the thymus and on APCs in the periphery. MHC class II expression is closely regulated in APCs by CIITA , which is the MHC class II transactivator. CIITA is solely expressed on professional APCs; however, non-professional APCs can also regulate CIITA activity and MHC II expression. As mentioned interferon γ (IFN γ) triggers the expression of CIITA and is also responsible for converting monocytes which are MHC class II negative cells into functional APCs that express MHC class II on their surfaces. MHC class II
832-525: The expression of certain cytokines in T cells and promote their proliferation, particularly if the cells are immature. TGF-β1 has similar effects on B cells that also vary according to the differentiation state of the cell. It inhibits proliferation, stimulates apoptosis of B cells, and controls the expression of antibody , transferrin and MHC class II proteins on immature and mature B cells. The effects of TGF-β1 on macrophages and monocytes are predominantly suppressive; this cytokine can inhibit
864-459: The genes that code for transcription factors that regulate the expression of the MHC class II genes. It results in the depletion of CD4 T cells and some immunoglobulin isotypes even though there are normal levels of both CD8 Cells and B cells present. Deficient MHC class II molecules are unable to present antigens to T cells and properly activate T cells. T cells are then unable to proliferate, and secrete cytokines which normally participate in
896-520: The immune response. Not only do the deficient MHC class II molecules affect the activation and proliferation of T cells but also the rest of the immune response cascade which includes B cells. Therefore, with this decrease in the number of T cells, the T cells cannot interact and activate the B cells. Normally when B cells are activated they divide, proliferate and differentiate, which includes the differentiation of these cells into plasma cells which are responsible for producing antibodies. However, when there
928-906: The other cysteines are involved in intrachain disulfide bonds. As shown in the following schematic representation, there are four disulfide bonds in the TGF-beta's and in inhibin beta chains, while the other members of this superfamily lack the first bond. where 'C' denotes a conserved cysteine involved in a disulfide bond. Human genes encoding proteins that contain this domain include: AMH ; ARTN ; BMP2 ; BMP3 ; BMP4 ; BMP5 ; BMP6 ; BMP7 ; BMP8A ; BMP8B ; BMP10 ; BMP15 ; GDF1 ; GDF2 ; GDF3 ; GDF5 ; GDF6 ; GDF7 ; GDF9 ; GDF10 ; GDF11 ; GDF15 ; GDNF ; INHA ; INHBA ; INHBB ; INHBC ; INHBE ; LEFTY1 ; LEFTY2 ; MSTN ; NODAL ; NRTN ; PSPN ; TGFB1 ; TGFB2 ; TGFB3 ; MHC class II MHC Class II molecules are
960-401: The peptide binding cleft on the MHC molecule. A MHC class II-like structure, HLA-DM , facilitates CLIP removal and allows the binding of peptides with higher affinities. The stable class II MHC is then presented on the cell surface. After MHC class II complexes are synthesized and presented on APCs they are unable to be expressed on the cell surface indefinitely, due to the internalization of
992-442: The proliferation of these cells and prevent their production of reactive oxygen (e.g. superoxide (O 2 ) ) and nitrogen (e.g. nitric oxide (NO) ) intermediates. However, as with other cell types, TGF-β1 can also have the opposite effect on cells of myeloid origin. For example, TGF-β1 acts as a chemoattractant , directing an immune response to certain pathogens . Likewise, macrophages and monocytes respond to low levels of TGF-β1 in
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1024-406: The same receptor signaling systems. TGF-β1 was first identified in human platelets as a protein with a molecular mass of 25 kilodaltons with a potential role in wound healing . It was later characterized as a large protein precursor (containing 390 amino acids ) that was proteolytically processed to produce a mature peptide of 112 amino acids. TGF-β1 plays an important role in controlling
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