Major Histocompatibility Complex
Introduction
The Major Histocompatibility Complex (MHC) is a set of cell surface proteins essential for the acquired immune system to recognize foreign molecules in vertebrates, which in turn determines histocompatibility. The MHC molecules mediate interactions of leukocytes, also called white blood cells (WBCs), with other leukocytes or with body cells. The MHC determines donor compatibility for organ transplant, as well as one's susceptibility to autoimmune diseases.
Structure and Function
MHC Class I
MHC Class I molecules are expressed on the cell surface of all nucleated cells and present peptide fragments derived from intracellular proteins. These peptides are typically 8-10 amino acids in length. The primary function of MHC Class I molecules is to display intracellular proteins to cytotoxic T cells (CD8+ T cells). If these peptides are recognized as foreign, such as those derived from viruses, the T cells will initiate the destruction of the infected cell.
MHC Class II
MHC Class II molecules are expressed only on the surface of antigen-presenting cells (APCs) such as dendritic cells, macrophages, and B cells. They present peptides derived from extracellular proteins that have been phagocytosed and processed within the cell. These peptides are typically 13-18 amino acids in length. The primary function of MHC Class II molecules is to present these peptides to helper T cells (CD4+ T cells), which then activate other immune cells to respond to the pathogen.
MHC Class III
MHC Class III molecules include several other immune system proteins, such as components of the complement system, cytokines, and heat shock proteins. These proteins are not involved in antigen presentation but play various roles in immune responses.
Genetic Organization
The genes encoding MHC molecules are highly polymorphic, meaning they have many different alleles, which allows for a diverse range of peptide presentation. In humans, the MHC genes are located on chromosome 6 and are divided into three regions: Class I, Class II, and Class III. The human MHC is also referred to as the Human Leukocyte Antigen (HLA) system.
HLA Class I Genes
The HLA Class I region contains three primary genes: HLA-A, HLA-B, and HLA-C. These genes encode the alpha chains of the MHC Class I molecules. Each individual inherits one set of these genes from each parent, leading to a high degree of variability in the population.
HLA Class II Genes
The HLA Class II region contains several genes, including HLA-DP, HLA-DQ, and HLA-DR. These genes encode the alpha and beta chains of the MHC Class II molecules. Similar to Class I, the high polymorphism in these genes contributes to the diversity of immune responses.
HLA Class III Genes
The HLA Class III region contains genes that encode components of the complement system (such as C2, C4, and factor B), as well as various cytokines and other immune-related proteins.
Role in Disease
The MHC plays a critical role in the immune system's ability to distinguish self from non-self. However, this same mechanism can sometimes lead to autoimmune diseases, where the immune system mistakenly targets the body's own cells. Certain HLA alleles are associated with an increased risk of autoimmune diseases, such as Type 1 Diabetes, Rheumatoid Arthritis, and Multiple Sclerosis.
Autoimmune Diseases
Autoimmune diseases occur when the immune system attacks the body's own tissues. Specific HLA alleles have been linked to various autoimmune conditions. For example, HLA-B27 is strongly associated with ankylosing spondylitis, while HLA-DR4 is linked to rheumatoid arthritis.
Infectious Diseases
The variability in MHC genes also affects susceptibility to infectious diseases. Certain HLA types can provide resistance or susceptibility to infections. For instance, HLA-B*57:01 is associated with slower progression of HIV infection.
Transplantation
The MHC molecules are critical in organ transplantation, as they are the primary determinants of tissue compatibility. Mismatches in HLA alleles between donor and recipient can lead to transplant rejection. Therefore, HLA typing is a crucial step in the organ matching process.
Graft-Versus-Host Disease
In bone marrow transplants, donor immune cells can attack the recipient's tissues, leading to graft-versus-host disease (GVHD). This condition is influenced by the degree of HLA mismatch between donor and recipient.
Evolutionary Perspective
The high polymorphism of MHC genes is thought to be maintained by balancing selection, where multiple alleles are preserved in the population due to their advantageous effects on immune response. This diversity allows populations to better respond to a wide range of pathogens.
Pathogen-Driven Selection
Pathogens exert selective pressure on MHC genes, as individuals with certain MHC alleles may be better equipped to present pathogen-derived peptides and mount an effective immune response. This co-evolutionary arms race between hosts and pathogens drives the diversity of MHC alleles.
Mate Selection
There is evidence that MHC genes influence mate selection in some species, including humans. Individuals may prefer mates with different MHC alleles to increase the genetic diversity and immune competence of their offspring.
Research and Clinical Applications
Research on MHC molecules has led to significant advancements in immunology and medicine. Understanding MHC function and genetics has implications for vaccine development, cancer immunotherapy, and the treatment of autoimmune diseases.
Vaccine Development
MHC molecules play a crucial role in the immune response to vaccines. Designing vaccines that effectively present antigens via MHC molecules can enhance their efficacy. Research is ongoing to develop vaccines that target specific MHC alleles to improve immune responses.
Cancer Immunotherapy
Cancer cells can evade the immune system by downregulating MHC molecules. Immunotherapies, such as checkpoint inhibitors, aim to enhance the presentation of tumor antigens by MHC molecules, thereby boosting the immune system's ability to target cancer cells.
Autoimmune Disease Treatment
Therapies targeting specific HLA alleles associated with autoimmune diseases are being developed. These treatments aim to modulate the immune response and reduce the attack on self-tissues.
Conclusion
The Major Histocompatibility Complex is a fundamental component of the immune system, playing a critical role in antigen presentation and immune recognition. Its genetic diversity and polymorphism are essential for effective immune responses and have significant implications for disease susceptibility, transplantation, and therapeutic interventions.