Capture Process And Presentation Of Exogenous Antigen Biology Essay

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Abstract:

Dendritic cells acts as a presenter of antigen. During the entry of an antigen into the host body DCs capture them and further taken for the presentation. This process involves many pathways depending upon the type of antigen captured. If an endogenous antigen is captured then it activates MHC class I molecules but if an exogenous antigen is captured MHC class II molecules get activated. Antigen is captured by the endosomal activity by immature dendritic cells and protein degradation is carried out. Immature DCs undergo maturation to perform processing of antigen. To process the captured antigen it undergoes binding with MHC molecules to form a peptide antigen MHC complex. The processed antigen is then delivered into the cytosol of the lymph and presented to T-Helper cells. Many advances are carried out to understand the heterogeneity, origin and signals involved in DCs maturation and migration. Exploitation of the T-cells in their therapeutic applications and responses can be seen in future.

Introduction:

Dendritic cells are Antigen presenting cells (APCs) present in small amount in different organs and are derived from bone marrow [1]. Major function of these cells is to protect immune system from antigens by capturing and presenting it to the CD4+ T-cells. Peptides are produced by degrading proteins and are carried to MHC class II proteins for transportation and presentation. Degradation involves peptide factors like HLA-DM or H-2M [4]. DCs show MHC class II pathway for the presentation of exogenous antigen. MHCs are the domain proteins that have 4 extracellular domain of which 2 forms a grove. Activation of the naive cells either in vitro or in vivo conditions can be done by dendritic cells [3]. Immature and mature DCs play a major role in the antigen presentation. Haematopoietic stem cells are characterized into immature DCs. Immature dendritic cells are found in the surface areas like mucosal membrane or skin [2]. These are responsible for capturing the antigen effectively. After maturation mature DCs are moved to secondary lymphoid organs which will present the captured antigen to the cytotoxic T-cells. To induce antigen specific immune responses exosomes are produced by mature DCs.

Main body:

Presentation of antigens by DCs involves different steps like uptake and process.

Uptake and recognition of antigen:

Antigens are captured by endocytic pathways. These pathways can be explained in three steps: 1.Macropinocytosis, 2.receptor mediated endocytosis and 3.phagocytosis [Lecture notes by Eric Hewitt]. Catabolism of antigen and maturation of MHC class II takes place in the same parts of lysosyme system.

Fig.1: Endocytic pathway in capturing antigens [5]

Macropinocytosis requires surface ruffling. For this large vesicles are formed from plasma membrane of 1-5µm diameter. In surface ruffling cells are suspended and are breakdown into particles by lysosomes [6]. After this the macropinosomes are moved into the cell. Receptors required for endocytosis and phagocytosis are: C-type lectin receptors- DEC-205 and Mannose receptor, Fc receptors- Fcε-RI and Fcγ-RI binds to antibodies and immune complexes are internalized by these. Heat shock protein peptides internalize HSP-peptide complexes.

In receptor mediated endocytosis ligand is bound to a receptor at clathrin-coated pit on plasma membrane and forms an endosome..

In phagocytosis particles or antigens are taken in by the cell. This uptake of antigen is mediated by receptors. Phagocytosis is mediated by the engagement of receptors [Lecture notes by Eric Hewitt]. Dendritic cell can phagocytose all Fungi, bacteria, yeast and can also phagocytose necrotic and apoptotic bodies [7].

Processing of Captured antigen:

Exogenous antigen after capturing and targeting to sites processed to the binding of MHC and is expressed on the surface of a cell. DCs initiate immune response by capturing antigen at periphery and move them to secondary lymphoid organs [8]. Immature dendritic cell when passes from antigen captured epidermis to the presenting lymph node through afferent lymphatic vessels it gets mature and becomes an effective and efficient APC [9]. During antigen processing native proteins are converted into MHC peptides. Basic cellular proteolytic mechanisms are used by antigen processing pathways. Endocytic pathway is limited. Disulphide bonds in the proteins are reduced before they get digested in the endosomes. IFN-γ induced lysosomal thiol reductase (GILT) is involved in the endosomal digestion in the antigen-processing pathway. Bacterial products and inflammatory cytokines stimulate DC maturation. Due to the change in biosynthesis (increase) and internalization (reduce) class II surface molecules level increases in maturing DCs. Exposure of DCs for inflammatory stimulus is because of rapid loading of antigenic peptides. Ligation of CD40 enhances the maturation of DCs. On maturation of DCs, B and T cells gets attracted by chemokine release and also synthesis of MHC class II molecules is observed [10]. Antigens are bound on the surface of the MHC molecules by surface-exchange mechanism [16]. IL-10 can enhance reduce the IL-12 production resulting in the decrease of DCs [13]. For further processing and presentation of antigens to the T-cells, they are firstly bound to the MHC molecules by means of processing of an invariant chain [Figure 3]. It includes the synthesis of class II α and β MHC molecules on rough endoplasmic reticulum by forming a heterodimer and are moved to lumen where invariant chain, another polypeptide (Ii) binds to it. Invariant chain is then transported to the endosome of golgi apparatus. Transfer of class II MHC from Golgi to MIIC (vesicular MHC class II compartment) is directed by Ii. MIIC is degraded at low pH for longer duration [11]. CLIP (Class II associated invariant chain peptide) is a short fragment that associates with peptide binding site to separate Ii from class II MHC. A heterodimer of class II MHC α: β is formed by the invariant chain. HLA-DM is the peptide factor involved in the removal of CLIP and also in the binding of other peptides. MHC class II molecules moves between endosomal proteins and membrane to pick a new antigen for destroying [12].

Fig.3: Processing of an invariant chain [17]

After limited proteolysis of antigen and invariant cells, the antigen derived peptide will bind to the MHC molecule and forms peptide-MHC complex.

Fig.2: Processing of an exogenous antigen [15]

Presentation of exogenous antigen:

Presentation of antigen of class II MHC molecule by mature dendritic cells is carried by high-protease activity. T-cells recognise pathogens by the peptides formed from proteins which are in the complexes of MHC molecules and peptides [14]. For further degradation invariant chain peptides are released to lysosome along with other antigenic peptides. This peptide-class-II-MHC complex is released from the endocytic vesicular compartment and set free to the cell surface for the recognition of T-Helper cell. Peptides released are complexed with the T-cell receptors (TCR) and also the CD4 molecules binds to the CD4 receptor on MHC molecules [18].

Fig.2: Presentation of antigens to T-Helper cells [12]

Conclusion:

The role of dendritic cells in the immune system is well explained and elaborated till date. But their molecular mechanisms and functions are still in dark and many experiments are going on to reveal them. Information about antigen processing and pathways at the biochemical level is not appreciable. Still more information is required not only on the structural description of antigens but also to explain the processing of antigen pathways. At present research is going on to explain the functions of DCs in vivo to extend its knowledge and trails in the clinical area. It seems to be not much time is required to achieve the goal of application of DCs in the human's immunotherapy in the coming days.

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