Major Histocompatibility Complex (MHC)

• MHC is a collection of genes on chromosome six.
• In humans, the MHC genes are organized into regions encoding three classes of molecules.
• Every mammal possesses the gene arrangement that contributes to the MHC.
• The MHC gene cluster organizes intracellular recognition and determination of self and non-self.
• MHC participates in the initial development of both humoral and cell-mediated immune responses.

MHC Classes

• MHC class one molecules are encoded by the A, B, and C loci in humans and are expressed in a wide range of cell types.
• MHC class two molecules are encoded by the DP, DQ, and DR regions in humans.
• Class two molecules contain two different polypeptide chains.
• Class one and two molecules have common structural features and roles in antigen processing and presentation.
• Class three encodes molecules critical for a new function but have little in common with class one and two regions.
• Class three includes complement fragments C4, C2, factor B, and several cytokines, most notably TNF proteins.
• HLA-A, HLA-B, and HLA-C are the classical MHC class I molecules in humans, encoded by the MHC class I region on chromosome 6.
• These molecules present endogenous peptides to CD8+ cytotoxic T cells.
• MHC Class I molecules are found on the surface of almost all nucleated cells (except red blood cells), and play a central role in immune surveillance.
• HLA-A presents a variety of intracellular peptides to CD8+ T cells.
• HLA-B plays a key role in presenting peptides that help the immune system identify infected or abnormal cells.
• HLA-C is often more involved in regulating natural killer (NK) cells.
• Key Point: HLA-A, HLA-B, and HLA-C molecules help the immune system differentiate between self and non-self by presenting peptides from intracellular sources to cytotoxic T cells.
• They enable CD8+ T cells to detect and kill infected or abnormal cells.
• MHC and HLA are the same.

Promiscuous Binding

• Binding between antigen and MHC molecules is often referred to as promiscuous because of the polymorphism of MHC molecules.
• Hundreds of allelic variants of MHC class one and two have been identified in humans.
• A single individual expresses up to six different class one molecules and up to 12 different class two molecules.
• MHC molecules can bind several different peptides as long as they fit within its binding groove.
• The binding groove of the MHC molecule is flexible enough to accommodate a variety of peptide sequences.
• MHC class one molecules bind peptides that typically range between eight and 10 amino acids.
• Class one binding requires that the antigen contains specific amino acids residuals near the N and C termini.
• Class two molecules exhibit an open class resulting in binding of peptides of 13 to 18 amino acids.
• There is no requirement for specific amino acid residuals near termini for class two antigen binding.

MHC Genes

• Class one genes are colored red, MHC two genes are colored blue, and MHC three are colored green.
• In humans, class 1c region is 2000 KB long and contains approximately 20 genes.
• Class one and two contain non-classical genes that are labeled in black, but the concept of classical and non-classical does not apply to class three.
• Class three contains genes that code for complement components and TNF proteins.
• MHC molecules are also called human leukocyte antigens, and these proteins are encoded for by MHC genes, which are found on chromosome six.
• One group of genes encodes the MHC class one molecule which is found by the CD eight molecule on the surface of cytotoxic T cells.
• Another group of genes encodes the MHC class two molecules, which is bound by the CD four molecule on the surface of helper T cells.
• MHC class one genes encode the proteins HLA-A, HLA-B and HLA-C.
• MHC class two genes encode the proteins HLA-DP, HLA-DQ and HLA-DR.

Classical vs Non-Classical MHC Molecules

• "Classical" refers to the primary, highly polymorphic MHC molecules that are directly involved in antigen presentation to T cells and play a central role in adaptive immunity.
• Classical MHC molecules are the ones most commonly associated with their respective classes (I or II) and their primary immune functions.

Classical MHC I

• HLA-A, HLA-B, HLA-C in humans.
• They present endogenous peptides to CD8+ cytotoxic T cells.
• They are highly polymorphic.

Classical MHC II

• HLA-DP, HLA-DQ, HLA-DR in humans.
• They present exogenous peptides to CD4+ helper T cells.
• They are also highly polymorphic.
• Non-classical MHC molecules are typically less polymorphic and have specialized or regulatory roles rather than directly presenting antigens to T cells.

Non-Classical examples MHC-I

• HLA-E, HLA-F, HLA-G (involved in immune regulation and tolerance, particularly in pregnancy or natural killer (NK) cell function).

Non-Classical examples MHC-II

• HLA-DM and HLA-DO (regulate peptide loading onto classical MHC class II molecules).
• Classical MHC class I molecules (HLA-A, -B, -C) and MHC Class II classical molecules (HLA-DP, -DQ, -DR) are the primary antigen-presenting molecules.
• They differ from nonclassical MHC molecules, which have auxiliary or regulatory roles rather than directly activating T cells.

HLA-DM and HLA-DO vs Classical MHC Class II

• Classical MHC class II molecules (HLA-DR, -DP, -DQ in humans) are primarily involved in presenting antigenic peptides to CD4+ T cells.
• They bind and present peptides to activate T-cell responses.
• HLA-DM and HLA-DO do not present antigens directly to T cells.
• HLA-DM facilitates the loading of peptides onto MHC class II molecules.
• HLA-DO regulates this process (HLA-DM) by inhibiting the binding of peptides to MHC class II.

HLA-DM vs HLA-DO

• HLA-DM assists in peptide exchange and loading onto MHC class II molecules, enhancing the presentation of high-affinity peptides.
• HLA-DO acts as a chaperone molecule that limits the peptide binding to MHC class II, modulating the peptide repertoire available for presentation.
• HLA-DM facilitates peptide loading onto MHC class II.
• HLA-DO controls the peptide binding process by MHC class II molecules.
• Both are important for shaping the antigen presentation and adaptive immune response.

MHC is a gene collection on chromosome six, encoding three molecule classes in humans and organizing intracellular recognition of self and non-self. It participates in the initial development of humoral and cell-mediated immune responses. The three classes have distinct characteristics and roles in the immune system.