User:Kinkreet/Immunology/Antigen Processing and Presentation

There are three main types of antigen presenting cells (APCs) - macrophages and dendritic cells of the innate immune system, and B lymphocytes of the adaptive immune system.

The cell must be able to distinguish between sytosolic pathogens and extracellular/vesicular pathogens, and respond to it differently - if the pathogen is in the cytosol, then it indicate that the cell is itself infected, and thus must be degraded; on the other hand, if the pathogen is in vesicles, the cell itself is not infected and thus should break down the pathogen and present to other cells to mount an immune response, while it can carry its effector functions.

Cytosolic pathogens
Antigens from cytosolic pathogens binds to MHC Class I molecules and are presented to CD8+ cytotoxic T cells, which when bound induces cell death on the presenting cell. The mechanism used is the same as used in housekeeping by the cell. Short-lived nascent proteins, Defective ribosomal products (DRiPs, prematurely terminated polypeptides and misfolded polypeptides produced from translation of bona fide mRNAs in the proper reading frame ) and antigens from pathogens are polyubiquinated and targeted to the 26S proteasome, where 99% of them would get degraded by aminopeptidases. The remaining 1% of those peptides are transported into the ER by the ABC transporters-associated with antigen processing (TAP, encoded in the same locus as the MHC molecules) and is degraded by ER-resident aminopeptidases. The remnants of the degradation (8–11 residues in length) from both the proteasome and the ER are loaded onto the peptide binding groove of MHC I heterodimers on the ER membrane by chaperone proteins such as BiP, calreticulin and ERp57. The loaded MHC I complex are translocated to the cell surface via the Golgi apparatus. CD8+ cytotoxic T cells will recognise the MHC-antigen complex, and with a co-stimulatory signal, will proliferate and destroy the infected cell.

Proteasome
The proteasome is an ATPdependent, multisubunit protease which is used to degrade intracellular proteins, both pathogenic and self, to create antigens. Normally, the proteasome is inefficient in creating antigens, but can change its subunit composition so it is more suited to its purpose; the altered proteasome is often referred to as the immunoproteasome.

The proteasome is made up of a 20S cylindrical core containing the enzymatic activity, capped on both ends by 19S regulator complexes, each made up of a base and a lid. The base of the regulator complex consists of 6 ATPases and two other subunits, they are thought to recognises ubiquitin-tagged proteins and unfold and feed them into the 20S core; the function of the 8 non-ATPase subunits of the lid is unknown. The 20S core is made up of four stacked rings, each ring contains 7 related proteins. The proteins are split into two groups (α and β) based on their sequence similarity. The outer rings are made up of the 7 α subunits (α1-α7), and the middle two rings are made up of the 7 β subunits (β1-β7). Three of the β subunits - β1, β2 and β5 - each have two active sites each to which it can perform its proteolytic activity; they seem to have a preference to cleave after acidic, basic or hydrophobic residues, respectively.

Extracellular pathogens are degraded inside endocytic vesicles and bind to MHC Class II molecules, which are recognised by CD4+ helper T cells. There are two types of TH cells - TH1 inflammatory T cells and TH2 cells. CD4+ TH1 cells bind to macrophages and activates its cytotoxic functions; CD4+ TH1 and TH2 cells bind to B cells t o activate them and promote thier differentiation into plasma cells, which secretes antibodies to opsonize extracellular pathogens and toxins.