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Exogenous/Endocytic pathway of antigen processing and presentation:
The pathway is called exogenous as it processes and presents exogenous antigens, that is the antigens generated outside the cells such as bacteria. The process is also called the endocytic pathway as the internalized antigens are processed in different endocytic compartments or endosomes. It involves MHC-class II molecules for antigen presentation and the presented antigens are recognized by CD4+ T helper cells. MHC class II molecules are expressed by Antigen-presenting cells (APCs), such as dendritic cells (DC), macrophages and B cells. APCs can internalize antigens by phagocytosis, endocytosis, or both. For example, Macrophages internalize antigens by both processes and B-cells internalize antigens by receptor-mediated endocytosis.
As mentioned, once an antigen is internalized, it is degraded into peptides within different endocytic compartments. The internalized antigen moves through three increasingly acidic compartments:
1. early endosomes (pH 6.0–6.5)
2. late endosomes, or endolysosomes (pH 5.0–6.0) and
3. lysosomes (pH 4.5–5.0).
In these compartments, using different hydrolytic enzymes under the influence of acidic pH, the antigen is degraded into oligopeptides of about 13 – 18 residues, which is ideal for class II MHC molecule binding. For example, lysosomes contain a unique collection of more than 40 acid-dependent hydrolases, including proteases, nucleases, glycosidases, lipases, phospholipases, and phosphatases.
Similar to class I MHC molecules, class II MHC molecules are also synthesized within the rough endoplasmic reticulum. Since antigen-presenting cells express both class one and class II MHC molecules, some mechanisms must exist to prevent class II MHC molecules from binding to peptides generated by the cytosolic pathway. Therefore, When a class II MHC molecule is newly synthesized, its peptide binding cleft is blocked by a protein called invariant chain, so that, binding of any endogenously derived peptide is prevented. In addition to stabilizing the class II MHC, the invariant chain also helps in directing the complex towards endocytic compartments. Through the Golgi complex, the class II MHC-invariant chain complex moves through different endocytic compartments. Due to acidic pH, proteases cathepsin S and cathepsin L are activated and digest the invariant chain, leaving a short fragment of invariant chain termed CLIP (for class II-associated invariant chain peptide). CLIP physically occupies the peptide-binding groove of the class II MHC molecule, presumably preventing any premature binding of the antigenic peptide. Later, the CLIP is exchanged for an antigenic peptide derived from a protein degraded in the endosomal pathway. This process requires the chaperone HLA-DM. Once a peptide has bound, the peptide–class II complex is transported to the plasma membrane, where the neutral pH appears to enable the complex to assume a compact, stable form. Peptide is bound so strongly in this compact form that it is difficult to replace a class II–bound peptide on the membrane with another peptide at physiologic conditions.
References
[ Ссылка ]
Kelly, J., 1992. Immunology: by Janis Kuby, WH Freeman.
