A STUDY OF ANTIGEN PRESENTATION AND PROCESSING

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Molecular Immunology

Seminar 2

Human Leukocyte Antigen System

The human leukocyte antigen (HLA) has the major importance in immune response and it is also known as Major Histopathology Complex (MHC). HLA also plays a key role in various clinical applications i.e. antigens transplantation and numerous diseases. The position of HLA is at the arm of chromosome 6. It is comprises of three major region that includes class I, class II and class III region.

The class I region contains three different genes which includes HLA-A, HLA-B and HLA-C. These genes encode for heavy chains of class I molecules.

The class II region comprises of sub regions series that includes A and B genes which encodes α and β chains respectively. DP gene family is also included that comprises of DPA1 and DPB1 gene which collectively form DP molecules. DR gene family contains single DRA gene and nine DRB (DRB1 to DRB9) genes. The DRA gene encoded α chains binds to various β chains that are encoded by DRB genes. DQ gene family is also a part of class II region that is composed of DQA1 and DQB1 gene that unite to form DQ molecules.

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The class III region is comprised of genes that encodes for complement system (C2, C4, factor B), tumor necrosis factor and hydroxylase etc. The class III region does not contain any gene for HLA.

The Mendelian mode suggests that HLA haplotype are responsible from each parent for the HLA inheritance. Almost all the nucleated cells expresses HLA class I molecules on their surface whereas only B lymphocytes, activated T lymphocytes and antigen presenting cells (dendritic cells, macrophages and monocytes) expresses HLA class II molecules. The peptide binding pockets present in HLA molecules comprises of a limited number of amino acids residue which determines the HLA molecules peptide binding specificity. The binding specificity of class I and class II HLA molecules varies and bind to different peptides.

The antigens which are synthesized within the target cell are called endogenous antigens. These antigens are formed in response to cellular, viral or transformed induced proteins. The endogenous antigens are recognized by class I restricted T cells and binds to form class I molecule peptide complex. This complex is then transported to the surface of target cell and it is than able to recognize by CD8+ T cell receptors. The exogenous antigens are mostly recognized by class II restricted T cells and are then endocytosed and then degraded by the endosomal compartments. The class II molecules also binds to form class II molecule peptide complex and it is then transported to the surface of the target cell to be recognized by the CD4+ T cell receptors. The T lymphocyte and HLA molecule recognition is also enhanced by some accessory molecules present in T cell receptors.

The transplantation can be enhanced by testing of HLA system by the help of different techniques. Complement mediated Microlymphocytotoxicity Technique is an important technique in analyzing HLA system. It provides a standard serological typing of class I and II antigens. Polymerase chain reaction (PCR) is used for the molecular typing of HLA alleles. Two different PCR methods are used for molecular typing i.e. Sequence specific oligonucleotide probe (SSOP) and Sequence specific primer method (SSP). Besides, enzyme linked immunosorbent assay (ELISA) and flow cytometry are used for HLA antibody screening.

The HLA system has the major role in transplantation, that can be organ transplantation or hematopoietic stem cell transplantation. The HLA system is also involve in blood transfusion therapy where it plays a role in cross matching of blood and the components within. Previously HLA typing was also used for parentage testing, however, this technique has now been replaced by many other molecular techniques.

Antigen presentation and processing pathways

Two groups of T cells are involved in the regulation of cell mediated immunity i.e. T helper cells or CD4+ T cells and Cytotoxic T cells or CD8+ T cells. The function of these cells involves the destruction and surveillance of entering pathogens in accordance with antigen presenting cells (APCs). The antigens present in APCs are also combined with other molecules which are collectively known as Major Histocompatibility Complex (MHC). There are two types of MHC namely MHCI and MHC II. Both the MHC binds specifically to receptors present on Helper T cells and Cytotoxic T cells. The binding of MHC with the T cells results in the activation of T cells and it leads to production of antibodies, proliferation or enhance immune response if the same antigen interacts subsequently. There are two pathways for the antigen presentation and processing.

The Endogenous Pathway

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MHC class I molecules are involved in the presentation of antigen on the surface of target cell. These antigens are formed in response to cellular, viral or transformed induced proteins. The endogenous antigens are recognized by MHC I and binds to form class I molecule peptide complex. This complex is then transported to the surface of target cell and it is than able to recognize by CD8+ T cell receptors. As the target cell is infected by the antigen, these proteins become ubiquinated and they are presented to proteosome degradation. Proteosomes break this antigen into peptides which are around nine amino acids long. Then there comes the role of TAP protein which spans the rough endoplasmic reticulum (ER) membrane. TAP transport the peptides in the rough endoplasmic reticulum. The MHC I folding is regulated by chaperons and binding immunoglobulin protein (BiP) which are present in ER. The TAP transport the peptides to the ER binds with this folded MHC I molecule and stabilizing it. This MHC I molecule peptide complex is then transported to the cell surface through golgi apparatus. The Cytotoxic T cells or CD8+ T cells are then able to recognize these molecules and turns immune response accordingly.

The Exogenous Pathway

The exogenous antigens are recognized by antigen presenting cells and are then endocytosed. These endocytosed proteins are then presented to class II MHC molecules and are then endocytosed and then degraded by the endosomal compartments by the action of acid dependent proteases. The class II MHC molecules also binds to the exogenous antigen to form class II molecule peptide complex and it is then transported to the surface of the target cell to be recognized by the CD4+ T cell receptors. The peptide binding cleft of MHC II molecule is blocked an invariant chain in ER, so that it cannot bind to cellular peptides or endogenous pathway's peptides. The MHC II molecules are transported to the vesicle with the help of this invariant chain. There HLA-DM which is MHC II like structure removes the clip and allows the broken peptide in the endosome to be attached. This MHC II peptide complex is then presented to the cell surface to be recognized by T helper cells or CD4+ T cells.