MHC Molecules- Definition, Properties, Class, Types, Pathways

The major histocompatibility complex (MHC) is a group of genes that encode proteins that play a crucial role in the immune system. These proteins are called MHC molecules or transplantation antigens, because they are responsible for the rejection or acceptance of transplanted organs or tissues between individuals. MHC molecules are also involved in the recognition and presentation of foreign antigens to T cells, which are a type of white blood cells that mediate cellular immunity.

MHC molecules are glycoproteins that are embedded in the plasma membrane of various cells. They have two main functions:

• To bind and display peptide fragments derived from the degradation of proteins inside or outside the cell. These peptides can be self-peptides (from the host cell) or non-self-peptides (from pathogens or foreign substances).
• To interact with T cell receptors (TCRs) on the surface of T cells and co-receptors (CD4 or CD8) that determine the type and function of T cells. The binding of MHC molecules and TCRs triggers an immune response against the source of the peptide.

There are two main types of MHC molecules: class I and class II. Class I MHC molecules are expressed on almost all nucleated cells and present endogenous peptides (from inside the cell) to cytotoxic T cells (CD8+ T cells) that can kill infected or abnormal cells. Class II MHC molecules are expressed mainly on antigen-presenting cells (APCs), such as macrophages, dendritic cells, and B cells, and present exogenous peptides (from outside the cell) to helper T cells (CD4+ T cells) that can activate other immune cells and produce cytokines.

In humans, the MHC genes are located on chromosome 6 and are also known as human leukocyte antigens (HLA). The HLA genes are divided into three classes: class I, class II, and class III. Class I and class II genes encode the α and β chains of class I and class II MHC molecules, respectively. Class III genes encode other proteins involved in immune functions, such as complement components and inflammatory cytokines.

The HLA genes are highly polymorphic, meaning that there are many different alleles (variants) for each gene in the population. This results in a great diversity of MHC molecules that can bind and present different peptides to T cells. The polymorphism of HLA genes is also important for transplant compatibility, as matching HLA types between donor and recipient can reduce the risk of rejection.

The HLA genes are inherited as a block or a haplotype from each parent, meaning that each individual has two sets of HLA genes (one from each parent). The haplotypes are usually conserved within families or ethnic groups, but can vary widely between different populations. The haplotypes can also influence the susceptibility or resistance to certain diseases, as some HLA alleles may confer protection or predisposition to certain pathogens or autoimmune disorders.

The structure of MHC molecules consists of two domains: a peptide-binding domain and an immunoglobulin-like domain. The peptide-binding domain is formed by two α helices on top of a β sheet that create a groove or a cleft where the peptide binds. The immunoglobulin-like domain is involved in the interaction with TCRs and co-receptors. The structure of class I and class II MHC molecules differs in the number and origin of their chains, the size and shape of their peptide-binding groove, and their distribution and expression on different cell types.

The function of MHC molecules is to present peptides to T cells in a specific and restricted manner. This means that T cells can only recognize peptides that are bound to self-MHC molecules (MHC restriction) and that match their TCR specificity (antigen specificity). This ensures that T cells can distinguish between self and non-self antigens and mount an appropriate immune response against foreign invaders or abnormal cells.

The human leukocyte antigens (HLA) complex is a set of genes located on the short arm of chromosome 6 that encode cell-surface proteins involved in the regulation of the immune system. The HLA complex is also known as the human version of the major histocompatibility complex (MHC) found in many animals.

The HLA complex consists of three classes of genes: class I, class II, and class III.

• Class I genes (HLA-A, HLA-B, and HLA-C) encode glycoproteins that are expressed on the surface of nearly all nucleated cells and present endogenous peptide antigens to CD8+ cytotoxic T cells. Class I molecules also interact with natural killer (NK) cells and some nonclassical MHC molecules, such as HLA-G and HLA-E, that have specialized functions in immune regulation.
• Class II genes (HLA-DP, HLA-DQ, and HLA-DR) encode glycoproteins that are expressed mainly on antigen-presenting cells (APCs), such as B cells, macrophages, dendritic cells, and Langerhans cells, and present exogenous peptide antigens to CD4+ helper T cells. Class II molecules can also be induced on other cell types by interferon-gamma.
• Class III genes encode various proteins that are involved in inflammation and complement activation, such as C2, C4, factor B, tumor necrosis factor (TNF)-alpha, lymphotoxin, and heat shock proteins.

The HLA genes are highly polymorphic, which means that they have many different alleles in the population, allowing them to recognize a wide range of antigens and fine-tune the adaptive immune response. Each individual inherits a set of alleles from each parent, forming a haplotype. The HLA haplotypes are usually inherited as a block with little recombination.

The HLA system plays a crucial role in immune defense against pathogens, organ transplant rejection, autoimmune diseases, cancer, and mate selection. The HLA system is also used for tissue typing, paternity testing, forensic identification, and disease association studies.

The human leukocyte antigen (HLA) complex is a set of genes located on chromosome 6 that encode for the major histocompatibility complex (MHC) molecules in humans. MHC molecules are cell surface proteins that bind and present peptide antigens to T cells, initiating an immune response. The HLA complex can be divided into three classes based on the structure, function and distribution of the MHC molecules: Class I, Class II and Class III.

Class I HLA

Class I HLA molecules consist of a heavy chain (α) and a light chain (β2-microglobulin) that are non-covalently associated. The heavy chain is encoded by one of the three highly polymorphic genes: HLA-A, HLA-B or HLA-C. The light chain is encoded by a non-polymorphic gene on chromosome 15. The heavy chain has three extracellular domains (α1, α2 and α3), a transmembrane domain and a cytoplasmic tail. The α1 and α2 domains form a peptide-binding groove that can accommodate peptides of 8-10 amino acids in length. The α3 domain interacts with the CD8 co-receptor on cytotoxic T cells (Tc cells).

Class I HLA molecules are expressed on the surface of almost all nucleated cells, including platelets. They present endogenous antigens, such as viral or tumor-derived peptides, to Tc cells. The endogenous antigens are generated by the proteasome in the cytosol and transported to the endoplasmic reticulum (ER) by the transporter associated with antigen processing (TAP). There, they bind to the newly synthesized class I HLA molecules with the help of chaperone proteins such as tapasin, calreticulin and ERp57. The class I HLA-peptide complexes then exit the ER and travel to the cell surface via the Golgi apparatus.

Class II HLA

Class II HLA molecules consist of two non-covalently associated chains: an α chain and a β chain. Both chains are encoded by polymorphic genes within the HLA-D region. There are three main types of class II HLA molecules: HLA-DR, HLA-DQ and HLA-DP. Each type has several alleles that can form different combinations of α and β chains. The α and β chains have two extracellular domains each (α1, α2 and β1, β2), a transmembrane domain and a cytoplasmic tail. The α1 and β1 domains form a peptide-binding groove that can accommodate peptides of 13-18 amino acids in length. The β2 domain interacts with the CD4 co-receptor on helper T cells (Th cells).

Class II HLA molecules are expressed mainly on antigen-presenting cells (APCs), such as B cells, dendritic cells, macrophages and activated T cells. They present exogenous antigens, such as bacterial or parasitic peptides, to Th cells. The exogenous antigens are internalized by endocytosis or phagocytosis and degraded by endosomal or lysosomal proteases in vesicles called endosomes or phagosomes. The class II HLA molecules are synthesized in the ER and associate with an invariant chain (Ii) that blocks their peptide-binding groove. The Ii-class II HLA complexes then exit the ER and travel to the Golgi apparatus, where they fuse with vesicles containing the processed antigens. In these vesicles, the Ii is cleaved by proteases, leaving a small fragment called CLIP that is displaced by the exogenous peptides with the help of an exchange factor called HLA-DM. The class II HLA-peptide complexes then exit the vesicles and travel to the cell surface.

Class III HLA

Class III HLA genes are located between class I and class II genes on chromosome 6. They encode for several proteins that are not involved in antigen presentation but have other immune functions. These proteins include components of the complement system (C2, C4A, C4B and factor B), cytokines (TNF-α and TNF-β) and heat shock proteins (HSP70). These proteins play roles in inflammation, immune regulation and stress response.

The HLA complex of genes encodes different types of glycoproteins that have important roles in the immune system. These glycoproteins are classified into three classes: class I, class II and class III.

• Class I HLA genes encode glycoproteins that are expressed on the surface of almost all nucleated cells. The main function of these glycoproteins is to present endogenous peptide antigens to CD8+ T cells, which are cytotoxic T cells that can kill infected or abnormal cells. The class I HLA genes include HLA-A, HLA-B and HLA-C. Each gene has multiple alleles that can produce different variants of the glycoprotein. The class I HLA glycoprotein consists of a heavy chain (α) and a light chain (β2-microglobulin). The heavy chain has three domains: α1, α2 and α3. The α1 and α2 domains form a cleft that binds the peptide antigen, while the α3 domain interacts with the CD8 co-receptor on the T cell. The light chain is non-polymorphic and stabilizes the heavy chain.
• Class II HLA genes encode glycoproteins that are expressed mainly on antigen-presenting cells (APCs), such as B cells, dendritic cells and macrophages. These glycoproteins present exogenous peptide antigens to CD4+ T cells, which are helper T cells that can activate other immune cells. The class II HLA genes include HLA-DR, HLA-DQ and HLA-DP. Each gene has two subtypes: α and β. Each subtype has multiple alleles that can produce different variants of the glycoprotein. The class II HLA glycoprotein consists of two chains: an α chain and a β chain. Both chains have two domains: α1 and α2 for the α chain, and β1 and β2 for the β chain. The α1 and β1 domains form a cleft that binds the peptide antigen, while the β2 domain interacts with the CD4 co-receptor on the T cell.
• Class III HLA genes encode proteins that are not involved in antigen presentation, but have other immune functions. These proteins include components of the complement system (C2, C4 and factor B), which are involved in inflammation and opsonization; and cytokines (TNF-α and TNF-β), which are involved in cell signaling and regulation. The class III HLA genes are located between the class I and class II regions on chromosome 6.

The gene products of the HLA complex are essential for the recognition and elimination of foreign antigens by the adaptive immune system. They also contribute to the diversity and specificity of the immune response by allowing different combinations of alleles to be expressed by different individuals. However, they also pose a challenge for organ transplantation, as mismatched HLA molecules can trigger rejection by the recipient`s immune system.

• In humans, the MHC molecules are divided into three types, Class I, Class II and Class III.
• Each type of MHC molecule has a different structure, function and distribution in the body.
• The main role of MHC molecules is to present peptide fragments of antigens to T cells for recognition and activation.

Class I MHC Molecule

• Class I MHC molecules are coded from three different locations called A, B and C and these molecules are expressed on the surface of nearly all nucleated cells .
• Class I MHC molecules consist of two polypeptide chains: an α chain that is embedded in the membrane and a β chain that is non-covalently attached to the α chain.
• The α chain has three domains: α1, α2 and α3. The α1 and α2 domains form a peptide-binding groove that can accommodate peptides of 8-11 amino acids, typically from endogenous antigens. The α3 domain interacts with the CD8 co-receptor on cytotoxic T cells.
• Class I MHC molecules present peptides from intracellular or endogenous pathogens, such as viruses, to CD8+ cytotoxic T cells . This triggers the killing of the infected cells by the cytotoxic T cells.
• Class I MHC molecules are synthesized in the endoplasmic reticulum (ER) and transported to the cell surface via the Golgi apparatus. The peptides that bind to class I MHC molecules are generated by proteasomes in the cytosol and transported to the ER by a transporter associated with antigen processing (TAP).

Class II MHC Molecule

• Class II MHC molecules are coded from several loci in the D region, such as DR, DQ and DP, and these molecules are expressed only on antigen-presenting cells (APCs), such as B cells, dendritic cells and macrophages .
• Class II MHC molecules are heterodimers of two non-covalently linked polypeptide chains: an α chain and a β chain. Both chains have two domains: α1 and α2 for the α chain, and β1 and β2 for the β chain.
• The α1 and β1 domains form a peptide-binding groove that can accommodate peptides of 13-20 amino acids, typically from exogenous antigens. The β2 domain interacts with the CD4 co-receptor on helper T cells.
• Class II MHC molecules present peptides from extracellular or exogenous pathogens, such as bacteria, parasites or toxins, to CD4+ helper T cells . This triggers the activation and differentiation of the helper T cells into various subsets that secrete cytokines and provide help to other immune cells.
• Class II MHC molecules are synthesized in the ER and transported to endocytic vesicles where they encounter the peptides that bind to them. The peptides that bind to class II MHC molecules are generated by lysosomal enzymes in endocytic vesicles after phagocytosis or endocytosis of extracellular antigens. An invariant chain prevents binding of self-peptides to class II MHC molecules in the ER and is later degraded by proteases in endocytic vesicles.

Class III MHC Molecule

• Class III MHC molecules are coded in the region between class I and class II genes. They do not have any involvement in antigen presentation.
• Class III MHC molecules encode several different proteins, some with immune functions, such as components of the complement system (C2, C4A, C4B and factor B) and molecules involved in inflammation (tumor necrosis factors α and β) .
• Some heat shock proteins are also classified as class III MHC molecules .

The expression of MHC molecules varies depending on the cell type and the class of MHC. MHC class I molecules are present on the surface of almost all nucleated cells, except for neurons and striated muscle cells . They are especially abundant on lymphocytes, where they can reach up to 10,000 molecules per cell. MHC class II molecules, on the other hand, are restricted to antigen-presenting cells (APCs) such as B cells, dendritic cells, and macrophages, as well as thymic epithelial cells . These cells can express up to 100,000 MHC class II molecules per cell. Some non-APCs, such as endothelial and epithelial cells, can also express MHC class II molecules when stimulated by cytokines like interferon-gamma. MHC class III molecules are not cell surface molecules, but rather soluble proteins that are involved in the complement system and inflammation. They include components such as C2, C4, factor B, and tumor necrosis factors.

The distribution of MHC molecules reflects their different roles in antigen presentation and immune recognition. MHC class I molecules present endogenous antigens (derived from inside the cell) to CD8+ cytotoxic T cells, which can then eliminate infected or abnormal cells . MHC class II molecules present exogenous antigens (derived from outside the cell) to CD4+ helper T cells, which can then activate other immune cells and mediate various immune responses . MHC class III molecules do not present antigens, but rather participate in the activation of the complement system and the regulation of inflammation.

The expression of MHC molecules can be modulated by various factors, such as cytokines, infection, stress, and hormones. For example, interferons can increase the expression of both MHC class I and II molecules, enhancing the antigen presentation capacity of the cells. Some pathogens can also evade immune recognition by downregulating or altering the expression of MHC molecules on infected cells. Therefore, the distribution of MHC molecules is not static, but rather dynamic and responsive to the changing environment.

MHC molecules are essential for the adaptive immune system to recognize and eliminate foreign antigens, such as those derived from pathogens or tumor cells. MHC molecules bind to peptide fragments of antigens and present them on the cell surface for recognition by T cells. T cells are a type of lymphocyte that can activate other immune cells or directly kill infected or abnormal cells.

However, T cells do not recognize antigens alone; they also require the presence of self-MHC molecules on the antigen-presenting cell (APC). This phenomenon is known as MHC restriction. MHC restriction means that a T cell can only interact with an antigen when it is bound to a specific MHC molecule that matches the T cell receptor (TCR). For example, CD8+ cytotoxic T cells can only recognize antigens bound to class I MHC molecules, while CD4+ helper T cells can only recognize antigens bound to class II MHC molecules.

MHC restriction is important for several reasons:

• It ensures that T cells are tolerant to self-antigens and do not attack healthy cells. During T cell development in the thymus, T cells undergo positive and negative selection based on their affinity for self-MHC molecules and self-peptides. Only T cells that can bind to self-MHC molecules with moderate affinity (positive selection) and do not bind to self-peptides with high affinity (negative selection) are allowed to mature and exit the thymus. This process eliminates potentially autoreactive T cells that could cause autoimmune diseases.
• It increases the diversity and specificity of the T cell repertoire. Because there are many different alleles of MHC genes in the population, each individual inherits a unique set of MHC molecules from their parents. These MHC molecules can bind to a wide range of peptide antigens and present them to T cells. Therefore, each individual has a different set of T cells that can recognize different antigens bound to their own MHC molecules. This increases the chances of finding a matching T cell for any given antigen and enhances the immune response.
• It prevents viral escape and tumor evasion. Some viruses and tumor cells can evade the immune system by downregulating or mutating their own antigens, making them less recognizable by T cells. However, if they also downregulate or mutate their own MHC molecules, they will lose the ability to present any antigen to T cells and become more susceptible to natural killer (NK) cells, which can detect and kill cells that lack MHC molecules.

MHC restriction is a key feature of the adaptive immune system that enables T cells to discriminate between self and non-self antigens and mount a specific and effective response against foreign invaders.

Antigen presentation and processing are the essential steps that enable the T cells of the adaptive immune system to recognize and respond to foreign antigens. Antigens are molecules that can elicit an immune response, such as proteins from viruses, bacteria, parasites or tumor cells. However, T cells cannot directly interact with antigens; they need to be presented by specialized molecules called major histocompatibility complex (MHC) molecules. MHC molecules are glycoproteins that bind to peptide fragments derived from antigens and display them on the surface of antigen-presenting cells (APCs), such as macrophages, dendritic cells and B cells. T cells have receptors (TCRs) that can recognize the specific combination of MHC and peptide, and also have co-receptors (CD4 or CD8) that can bind to the MHC molecule. This interaction triggers the activation and differentiation of T cells into effector and memory cells that can carry out various immune functions, such as cytotoxicity, cytokine production and antibody production.

There are two major classes of MHC molecules: class I and class II. Class I MHC molecules present endogenous antigens, which are derived from proteins synthesized inside the cell. These antigens are usually associated with intracellular pathogens, such as viruses, or abnormal cells, such as tumor cells. Class I MHC molecules are expressed on almost all nucleated cells and can be recognized by CD8+ cytotoxic T cells (CTLs), which can kill the infected or abnormal cells. Class II MHC molecules present exogenous antigens, which are derived from proteins taken up by the cell from the extracellular environment. These antigens are usually associated with extracellular pathogens, such as bacteria, parasites or toxins. Class II MHC molecules are expressed mainly on APCs and can be recognized by CD4+ helper T cells (Th cells), which can provide help to other immune cells, such as B cells or macrophages.

The process of antigen presentation and processing involves six discrete steps:

1. Acquisition of antigen: This step involves the uptake of antigen by the cell. For class I MHC molecules, this means the synthesis of endogenous proteins in the cytosol. For class II MHC molecules, this means the ingestion of exogenous proteins by endocytosis or phagocytosis.
2. Tagging of antigen: This step involves the marking of antigen for degradation. For class I MHC molecules, this means the attachment of ubiquitin molecules to endogenous proteins in the cytosol. For class II MHC molecules, this means the lowering of pH and activation of proteases in endosomes or phagosomes.
3. Degradation of antigen: This step involves the breakdown of antigen into smaller peptides. For class I MHC molecules, this means the cleavage of ubiquitinated proteins by proteasomes in the cytosol. For class II MHC molecules, this means the cleavage of exogenous proteins by lysosomal enzymes in endolysosomes.
4. Transport of peptide: This step involves the movement of peptide fragments to the site of MHC loading. For class I MHC molecules, this means the translocation of peptides from the cytosol to the endoplasmic reticulum (ER) by transporter associated with antigen processing (TAP) proteins. For class II MHC molecules, this means the fusion of endolysosomes with vesicles containing newly synthesized MHC molecules.
5. Loading of peptide: This step involves the binding of peptide fragments to MHC molecules. For class I MHC molecules, this means the association of peptides with α and β chains of MHC molecules in the ER with the help of chaperone proteins. For class II MHC molecules, this means the exchange of peptides with invariant chain (Ii) fragments that occupy the peptide-binding groove of MHC molecules in vesicles with the help of HLA-DM proteins.
6. Display of peptide: This step involves the expression of peptide-MHC complexes on the cell surface. For both class I and class II MHC molecules, this means the transport of peptide-MHC complexes from vesicles to the plasma membrane by secretory pathways.

By following these steps, antigen presentation and processing ensure that T cells can survey a wide range of antigens from different sources and locations and mount an appropriate immune response against them.

: Major Histocompatibility Complex (MHC) Molecules Characteristics : Antigen Presentation Pathway: Class I MHC molecules (Cytosolic pathway) : Antigen Presentation Pathway: Class II MHC molecules (Endocytic Pathway)

The antigen presentation pathway refers to the process by which MHC molecules bind to peptide antigens and display them on the cell surface for recognition by T cells. Depending on the source and location of the antigen, different MHC molecules and pathways are involved.

Class I MHC molecules (Cytosolic pathway)

Class I MHC molecules present endogenous or intracellular antigens, such as those derived from viral or tumor proteins. These antigens are synthesized in the cytosol and degraded by proteasomes, which are cylindrical protein complexes that cleave proteins into smaller peptides. The peptides are then transported into the endoplasmic reticulum (ER) by a transporter associated with antigen processing (TAP), which consists of two subunits, TAP1 and TAP2. In the ER, the peptides bind to the peptide-binding groove of newly synthesized class I MHC molecules, which are composed of an α chain and a β2-microglobulin chain. The class I MHC-peptide complex then exits the ER and travels to the Golgi apparatus and then to the plasma membrane via secretory vesicles. On the cell surface, the complex is recognized by CD8+ cytotoxic T cells, which have T cell receptors (TCRs) that are specific for both the peptide and the MHC molecule. The CD8 co-receptor binds to the α3 domain of the class I MHC molecule and stabilizes the interaction. The recognition of the complex triggers the activation and proliferation of cytotoxic T cells, which can then kill the infected or abnormal cells.

Class II MHC molecules (Endocytic pathway)

Class II MHC molecules present exogenous or extracellular antigens, such as those derived from bacteria, parasites, or toxins. These antigens are taken up by antigen-presenting cells (APCs), such as macrophages, dendritic cells, or B cells, via endocytosis or phagocytosis. The antigens are enclosed in endosomes, which fuse with lysosomes to form endolysosomes. In these compartments, the antigens are degraded by proteolytic enzymes into smaller peptides. The class II MHC molecules are synthesized in the ER and associated with an invariant chain, which blocks the peptide-binding groove and prevents binding of self-peptides. The invariant chain-MHC complex then exits the ER and travels to the Golgi apparatus and then to another vesicle. In this vesicle, the invariant chain is cleaved by proteases and only a small fragment called CLIP (class II-associated invariant chain peptide) remains attached to the MHC molecule. The vesicle containing the class II MHC-CLIP complex then fuses with the endolysosome containing the antigenic peptides. In this fusion site, an exchange factor called HLA-DM facilitates the removal of CLIP and the binding of a foreign peptide to the class II MHC molecule. The class II MHC-peptide complex then exits the endolysosome and travels to the plasma membrane via secretory vesicles. On the cell surface, the complex is recognized by CD4+ helper T cells, which have TCRs that are specific for both the peptide and the MHC molecule. The CD4 co-receptor binds to the β2 domain of the class II MHC molecule and stabilizes the interaction. The recognition of the complex triggers the activation and proliferation of helper T cells, which can then secrete cytokines and provide help to other immune cells.

We are Compiling this Section. Thanks for your understanding.