Origin of the Terms MHC and HLA
Historically, the study of these surface glycoproteins began with the development of transplantation. Researchers noticed that the rejection of grafted tissues depends on mismatched structures on donor and recipient cells—foreign tissues were recognized by lymphocytes and destroyed. In general biological English-language literature, the term MHC (Major Histocompatibility Complex) became standard.
For humans, the medical abbreviation HLA (Human Leukocyte Antigens) is more commonly used, as these marker proteins were first discovered on leukocytes. Later, it turned out that the primary physiological role of these complexes is not transplant rejection at all, but rather 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 their colossal variability: each gene has dozens to hundreds (300–500) of allelic variants. Consequently, every individual possesses a unique combination of cell-surface proteins, forming their distinct "biological passport".
Classification of MHC Molecules
All products of histocompatibility genes are divided into three major classes, which differ significantly in their bodily localization and functions:
- MHC Class I (Membrane-bound). Present on the surface of virtually all nucleated somatic cells of the body. A notable exception is erythrocytes—since they lack nuclei, class I molecules are absent from their membranes.
- MHC Class II (Membrane-bound). Have a strictly limited localization. They are expressed exclusively on the surface of specialized antigen-presenting cells (APCs).
- MHC Class III (Soluble). Unlike the first two classes, they are not anchored 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 primary task of membrane-bound MHC proteins is the presentation of antigenic determinants to T lymphocytes. There is a strict division of labor: MHC class I molecules present antigens to cytotoxic T cells (CD8+ T cells), whereas MHC class II molecules work exclusively with helper T cells (CD4+ T cells).
Cells that express MHC class II on their surface 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 conditions, endothelial cells and other epithelial cells can also assume this function.
Endogenous Antigen Presentation Pathway (MHC Class I)
Every nucleated cell continuously performs an immunological "checkpoint," displaying fragments of its cytoplasmic contents on its surface. This mechanism is known as the endogenous pathway of presentation. The sources of antigens include the cell's own proteins, proteins from intracellular parasites (such as viruses), or tumor markers.
The assembly process proceeds as follows:
- Processing. Proteins are cleaved not in lysosomes, but in proteasomes—cylindrical, non-membranous complexes with protease activity. As a result, long chains are cut into short peptides (8–11 amino acids long).
- Transport. The resulting short peptides are transported into the lumen of the endoplasmic reticulum (ER) via a specialized transporter protein—the TAP protein.
- Assembly and Export. In the rough ER, the peptide enters a specialized binding groove on the MHC class I molecule. The completed "MHC class I + peptide" complex is transported and integrated into the outer cell membrane.
If a normal self-peptide is displayed, 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 targeted for destruction by cytotoxic T cells.