The Major Histocompatibility Complex, or MHC, is a group of genes that construct proteins found on the surface of our cells. These proteins are fundamental to the adaptive immune system, acting as a cellular billboard. They display fragments of proteins from within the cell, allowing immune cells to monitor the cell’s health. This system enables the immune system to detect foreign invaders like viruses and bacteria. In humans, this set of genes is referred to as the Human Leukocyte Antigen (HLA) system.
MHC Class I Structure
MHC Class I molecules are present on the surface of almost all nucleated cells. The structure of a Class I molecule consists of two separate protein chains. One is a long, heavy chain known as the alpha (α) chain, which anchors the molecule into the cell’s membrane. This α chain is folded into three distinct domains: α1, α2, and α3.
The second component is a smaller protein called beta-2 microglobulin (β2m). Unlike the alpha chain, β2m does not span the cell membrane and instead associates with the α3 domain. The primary function of β2m is to stabilize the complex, ensuring the alpha chain maintains its correct shape for transport to the cell surface.
A key feature of the MHC Class I molecule is its peptide-binding groove, which is formed by the α1 and α2 domains of the heavy chain. This groove holds small protein fragments, called peptides, for presentation to the immune system. The structure of this groove has “closed” ends, forming a defined pocket that holds peptides between 8 and 10 amino acids in length.
MHC Class II Structure
MHC Class II molecules have a more limited distribution than their Class I counterparts, found on specialized immune cells. These cells are known as professional antigen-presenting cells (APCs) and include macrophages, dendritic cells, and B cells. Their primary role is to patrol for external threats, engulf them, and present fragments to initiate a targeted response.
The structure of an MHC Class II molecule is composed of two transmembrane chains of similar size, an alpha (α) chain and a beta (β) chain. Both chains are anchored in the cell membrane, and each is folded into two domains: the α chain has α1 and α2 domains, and the β chain has β1 and β2 domains.
In the Class II molecule, the peptide-binding groove is formed by the interaction of the α1 and β1 domains. This collaborative structure results in a groove that is “open” at both ends. This open configuration allows the molecule to bind and present longer peptides than Class I molecules, accommodating fragments that are 13 to 18 amino acids in length.
Structural Differences and Functional Implications
The architectural differences between MHC Class I and Class II molecules directly determine their distinct roles. The closed-ended peptide-binding groove of the Class I molecule is suited for presenting endogenous antigens. These are protein fragments that originate from within the cell itself. If a cell is infected with a virus, fragments of these proteins are loaded into the Class I groove and displayed as a signal to cytotoxic T cells, which eliminate the infected cell.
This system also allows the immune system to detect and destroy cancerous cells. Malignant transformation often involves mutations leading to the production of abnormal proteins. Peptides from these mutated proteins can be presented by MHC Class I molecules, flagging the cancerous cell for destruction by the immune system.
Conversely, the open-ended groove of MHC Class II molecules is designed to accommodate peptides from exogenous antigens. When an antigen-presenting cell engulfs a bacterium, it breaks the pathogen down into smaller pieces. These peptide fragments are then loaded onto MHC Class II molecules and presented on the APC’s surface for helper T cells.
Upon recognizing the presented peptide, helper T cells become activated and orchestrate a broader immune response. They can help activate B cells to produce antibodies that target the pathogen and enhance the activity of other immune cells. The ability of the open groove to bind longer peptides increases the likelihood of an effective response.
Genetic Basis of MHC Diversity
The variability in MHC molecules across the human population stems from the genes that code for them. In humans, these genes are on chromosome 6 and are referred to as the Human Leukocyte Antigen (HLA) complex. The HLA genes are the most polymorphic in the human genome, meaning they exist in a vast number of different versions, or alleles, which is an evolutionary advantage.
This polymorphism ensures that as a population, humanity possesses a wide repertoire of MHC molecules. Each variant can bind and present a different set of peptide fragments. When a new pathogen emerges, this diversity increases the probability that some individuals will have MHC molecules capable of effectively presenting peptides from that pathogen, allowing for a successful immune response.
The high degree of variation in MHC molecules is also the primary reason for tissue rejection in organ transplantation. The immune system of an organ recipient recognizes the donor’s MHC molecules as foreign. This triggers an immune attack against the transplanted organ, a process known as graft rejection. To minimize this risk, doctors perform tissue typing to match the HLA profiles of the donor and recipient.