Origin of the terms MHC and HLA
Historically, the study of these surface glycoproteins began with the development of transplantology. Researchers noticed that the rejection of transplanted tissues depends on a mismatch of structures on the cells of the donor and the recipient — foreign tissues were recognized by lymphocytes and destroyed. In general biological English-language literature, the term MHC (Major Histocompatibility Complex) became established.
For humans, the medical abbreviation HLA (Human Leukocyte Antigens) is used more frequently, since these marker proteins were first discovered precisely on leukocytes. It later turned out that the main physiological role of these complexes is not rejection of transplants at all, but participation in immune responses — presenting antigens to the body's own defense cells.
Genetically, this complex is localized on the short arm of chromosome 6. A characteristic feature of MHC genes is colossal variability: each gene has from tens to hundreds (300–500) of allelic variants. Due to this, every person possesses a unique combination of proteins on the cell surface, which forms their unmistakable "biological ID".
Classification of MHC molecules
All products of histocompatibility genes are divided into three major classes, which differ significantly in their localization in the body and functions performed:
- MHC-I (Membrane). Present on the surface of absolutely all somatic cells of the body that have a nucleus. An important exception is erythrocytes — since they are anucleated, class I molecules are absent on their membranes.
- MHC-II (Membrane). Have a strictly limited localization. They are expressed only on the surface of specialized antigen-presenting cells (APCs).
- MHC-III (Soluble). Unlike the first two classes, they do not anchor to cell membranes. These are secretory proteins found in extracellular fluids (this group includes, for example, complement system components).
Antigen-presenting cells and their role
The main task of membrane MHC proteins is the presentation (presenting) of antigenic determinants to T lymphocytes. There is a strict division of labor: MHC-I molecules present antigens to cytotoxic T cells, while MHC-II molecules work exclusively with T helper cells.
Cells on the surface of which MHC-II is expressed are called antigen-presenting cells (APCs). These include:
- Macrophages and their derivatives (interdigitating cells, dendritic cells, Kupffer cells in the liver, Langerhans cells in the skin).
- B lymphocytes.
- Specialized epithelium (e.g., M cells of the gastrointestinal tract, as well as thymic stromal epithelial cells, which are critical for the proper selection of maturing T lymphocytes). Under certain situations, endothelial cells and other epithelial cells can take on this function.
Endogenous presentation pathway (MHC-I)
Any nucleated cell constantly performs immunological "face control", displaying fragments of what is inside its cytoplasm on its surface. This mechanism is called the endogenous presentation pathway. The source of antigens can be the cell's own proteins, proteins of intracellular parasites (e.g., viruses), or tumor markers.
The assembly process of the complex is as follows:
- Processing. Proteins are cleaved not in lysosomes, but in proteasomes — cylindrical non-membrane complexes with protease activity. As a result, long chains are chopped into short peptides (8–11 amino acids long).
- Transport. The resulting short peptides are transported into the endoplasmic reticulum (ER) using a specialized transporter protein — TAP protein.
- Assembly and export. In the rough ER, the peptide enters a special cleft on the MHC-I molecule. The ready "MHC-I + peptide" complex is transported and embedded into the outer cell membrane.
If a normal self-peptide is displayed on the surface, the immune system ignores it. However, if the cell is infected and displays a foreign viral or tumor fragment, it is immediately recognized by lymphocyte receptors and becomes a target for destruction by cytotoxic T cells.
Briefly: answers to topical questions
How does the exogenous pathway of antigen presentation by MHC class II molecules occur?
The exogenous pathway of antigen presentation by MHC class II molecules involves the uptake of foreign proteins and their intracellular processing. The process consists of the following stages:
- Antigen endocytosis — proteins are captured by the cell, enter the endosome, and are cleaved into peptides.
- MHC-II synthesis — molecules are synthesized in the endoplasmic reticulum, with the invariant chain blocking the peptide-binding groove.
- Transport — the complex passes through the Golgi apparatus into vesicles (MIIC granules).
- Fusion and loading — MIIC granules fuse with the late endosome. With the participation of the HLA-DM molecule, the invariant chain remnant (CLIP) is replaced by an exogenous peptide.
- Exocytosis — the formed complex is translocated to the cell membrane for presentation to T-helper cells.
Which other proteins, besides complement system components, belong to class III MHC?
Besides complement system components, sources indicate that class III MHC includes:
- tumor necrosis factors — TNF (LTA, LTB) genes;
- MICB gene.
Class III MHC is not involved in antigen presentation; sources also indicate that class III consists of soluble proteins of extracellular fluids and is not present on cell membranes.
What is the difference in the protein chain structure of class I and class II MHC molecules?
Differences in the structure of class I and class II MHC molecules:
| Characteristic | Class I MHC | Class II MHC |
|---|---|---|
| Symmetry | Asymmetric molecule | Symmetric molecule |
| Polypeptide chains | Heavy α-chain and light chain | Two chains: α and β |
| Domains specified in the source | α1 and α2 | α1, α2, β1, and β2 |
| Formation of the peptide-binding cleft | α1 and α2 domains | α1 and β1 domains |
| Obligate structural component | β2-microglobulin | Source indicates α- and β-chains |
MHC molecules of both classes feature a peptide-binding cleft at the top of the molecule; its lateral walls are formed by α-helix structures.
To easily remember the localization: MHC-I (class I) is basic; it is present on the membranes of all nucleated somatic cells. MHC-II (class II) is "elite"; it is present only on specialized antigen-presenting cells (macrophages, B lymphocytes).
Class and exam questions
Why are MHC-I molecules absent on mature erythrocytes?
Class I antigens are synthesized and expressed only on the surface of nucleated cells. Since mature human erythrocytes lose their nucleus, they lack these membrane complexes as well.
What is the TAP protein and what is its function?
This is a specialized transporter protein that ensures the transport of short cleaved peptides (8–11 amino acids) into the lumen of the endoplasmic reticulum, where they bind to the MHC-I molecule.
Where does protein cleavage occur in the endogenous presentation pathway?
Processing of endogenous (viral, tumor, or self) proteins occurs in proteasomes—non-membrane protein cylinders with high protease activity—rather than in lysosomes.
What else to study on this topic
- Structure and functions of proteasomes
- The role of thymic stromal epithelial cells in T lymphocyte selection
- Features of gastrointestinal M cells
- Mononuclear phagocyte system (Kupffer cells, Langerhans cells)
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