Major Histocompatibility Complex (MHC)

Genetics and Biological Significance of the HLA System

The Major Histocompatibility Complex was originally discovered through studies of graft rejection. Consequently, the surface proteins of this family in humans were named Human Leukocyte Antigens (HLA).

The genetic apparatus of this system is located on the short arm of chromosome 6 (region 6p21.31). This expansive region includes over two hundred genes encoding specialized glycoproteins. A key feature of this complex is the extraordinarily high degree of variability (polymorphism) in class I and II genes. A vast array of allele variations forms a unique, individualized set of cell surface markers for each person. The only individuals in the world with an entirely identical histocompatibility profile are identical twins.

Classification and Localization of Molecules

Traditionally, the genes and proteins of this family are divided into three classes based on their functions, structure, and location.

• MHC Class I (represented by HLA-A, HLA-B, HLA-C). These molecules are present on the membranes of virtually all nucleated cells in the body, serving as a molecular "identity card." Exceptions are few: MHC I molecules are absent on erythrocytes (which lack a nucleus), neurons, and syncytiotrophoblast cells.
• MHC Class II (types HLA-DR, HLA-DP, HLA-DQ). Normally, these are located exclusively on professional antigen-presenting cells (APCs), which include macrophages, dendritic cells, and B lymphocytes. Under specific conditions, such as activation by $\gamma$-interferon, their expression can be induced on T lymphocytes, endothelium, and epithelium.
• MHC Class III. Unlike the first two, these genes encode molecules that do not participate in antigen presentation. Their products are soluble immune mediators: complement system components and important cytokines (such as tumor necrosis factor alpha [TNF-$\alpha$] and lymphotoxin).

Molecular Structure

Histocompatibility molecules involved in antigen presentation share a similar structural design with critical differences. The core of the receptor is the antigen-binding cleft (peptide-binding groove).

Structure of MHC Class I Molecules The receptor is formed by two non-covalently linked polypeptide chains. The heavy $\alpha$-chain contains three domains: $\alpha_1$, $\alpha_2$, and $\alpha_3$. The light chain is the $\beta_2$-microglobulin molecule. The peptide-binding groove lies between the $\alpha_1$ and $\alpha_2$ domains. This hypervariable region binds short peptides ranging from 8 to 10 amino acid residues in length.

Structure of MHC Class II Molecules This molecule has a more complex structure, consisting of two full-length polypeptide chains: $\alpha$ and $\beta$. Each chain contributes two domains (forming an $\alpha_1$, $\alpha_2$ and $\beta_1$, $\beta_2$ arrangement). The antigen-binding cleft here is formed cooperatively by both chains (involving the $\alpha_1$ and $\beta_1$ domains). Due to this architecture, the groove capacity is significantly larger, accommodating peptides from 12 to 25 amino acid residues in length.

Mechanisms of Antigen Processing and Presentation

The primary role of MHC is to display what is happening inside or around a cell to the immune system. The process of preparing a foreign protein is called processing, and displaying it on the surface is called presentation.

MHC I Pathway (Endogenous Antigens) Through this pathway, a cell displays what is synthesized internally (e.g., viral proteins during an infection or mutant tumor proteins).

1. Intracellular proteins are degraded in the proteasome into short peptides.
2. Peptides are transported into the endoplasmic reticulum (ER).
3. In the ER, the peptide-MHC I complex is assembled.
4. The finished complex is transported to the cell membrane, where it is recognized by cytotoxic T lymphocytes (CD8+ phenotype). The CD8 coreceptor binds to the invariant $\alpha_3$ domain, stabilizing the contact.

MHC II Pathway (Exogenous Antigens) Used by antigen-presenting cells (APCs) to present pathogens captured from the extracellular environment.

1. The APC engulfs the pathogen via phagocytosis or endocytosis.
2. The pathogen enters a vesicle where it is degraded (processed) into fragments. Simultaneously, MHC II molecules are synthesized in the ER.
3. The antigen fragment binds to the MHC II molecule, and the complex is transported to the membrane.
4. The target of this presentation is a naive $T$ helper cell ($T_H0$) with the CD4+ phenotype.

Upon recognizing the complex, the naive $T$ helper cell becomes activated and differentiates. If it becomes a type 1 $T$ helper ($T_H1$), it secretes cytokines to activate cell-mediated immunity. If it differentiates into a $T_H2$ cell, it releases factors that stimulate the humoral response.