Major Histocompatibility Complex

Expression of MHC Molecules: -Since there are ______ for MHC class I molecules and each individual inherits one set of genes from Mom and one from Dad, any nucleated cell will express ________ class I molecules -MHC class II molecules are comprised of 2 chains (alpha and beta) and there are _____________ for each (DR, DP, DQ). When you do the mixing and matching with genes from Mom and Dad, each APC can express _______________ class II molecules

3 genes; 6 distinct; 3 major genes; at least 12 different

Antigen Association with MHC Class I and Class II: -The antigen-loaded MHC class I molecule is then transported through the _____________, moves through the cytoplasm in a transport vesicle and is expressed on the surface of the cell -MHC class I molecules that are not loaded with antigen ________ and are ______________________

Golgi apparatus; dissociate; degraded intracellularly

MHC Molecules: -In terms of immune responsiveness, there are 2 major types of MHC molecules: ~MHC class I - the genes for this molecule are in the _____________ regions of the complex. The molecules produced by these genes are found on essentially _______________. Immunologically, their primary function is to __________________. The CD8 receptor recognizes the MHC class I molecule ~Other class I genes (HLA-E, -F, -G and -H) code for minor class I molecules, a few of which have been defined with specific functions (NK recognition)

HLA-A; HLA-B; and HLA-C; all nucleated cells; present antigen to CD8+T cells (CTLs)

MHC Class II Molecules: -These are products of the______ region genes. -The molecule is composed of 2 chains: ~an ______ chain ~a _______ chain -Each chain has 2 ________ domains: ~alpha chain: alpha1 and alpha2 ~Beta chain - beta1and beta2 -Both the alpha chain and beta chain have a transmembrane domain and a ____________

HLA-D; alpha; beta; external; cytoplasmic tail

MHC Molecules: -MHC class II - genes in the ____ region code for the production of this molecule. The main genes are _________. The class II molecule is normally found on _________________ (B cells, MACs, dendritic cells). Presents antigen to ______________. The MHC class II molecule is recognized by the CD4 receptor -Other class II-region genes code for proteins involved in antigen presentation that are not expressed on the cell surface

HLA-D; DR; DQ; DP; antigen-presenting cells; CD4+T helper cells

Does MHC differentiate between self & non-self?

NO!!

MHC Class I Molecules: -The HLA A, B, and C genes code for an ________ which contains _______________ external to the cell membrane, a transmembrane segment and a cytoplasmic tail -Beta2 microglobulin is a small globular peptide non-covalently ________________ of the alpha chain. Beta2 microglobulin is not produced by MHC genes. Comes from _______________

alpha chain; 3 globular domains; linked to the alpha3 domain; chromosome 15

Antigen Recognition: -Once the antigen-loaded MHC molecule (class I or II) is expressed on the cell surface, it can present antigen to _________ ________________ -In the case of the immune system, this cell is a _____(CD4+ TH cell or a CD8+ CTL) and the ____________ recognizes the combination of processed Ag and MHC -The TCR also has _____. The CDR 1 and 2 regions recognize and bind the __________ of the MHC while CDR 3 binds the ________

any cell with the appropriate receptor; T cell; T cell receptor (TCR); CDRs; alpha helices; processes antigen

MHC Class II Molecules: -The antigen-binding groove is ______________________ -Variability in the amino acid sequence of the alpha1 and beta1 domains accounts for ________________ -When first assembled intracellularly, there is a ________ ___________ chain that occupies the antigen-binding site and prevents __________ from binding

between alpha1 & beta1; binding specificity; gamma or invariant; self antigens

MHC Class I Molecules: -The alpha1 and alpha2 domains form a _______________________. It is in the alpha1 and alpha2 domains that the __________ ________________ occurs. This variability is in _______________ in the a helices and the beta pleated sheet -This is very similar to the variability in the antigen-binding sites formed by the variable regions of the heavy and light chains of antibodies

binding groove for binding antigen; major structural variability; amino acid residues

Peptide-MHC Interactions: -While MHC molecules display specificity, this is a much _______ specificity than that displayed by antibodies and TCRs. -Class I molecules bind peptides that are ______________ while class II molecules bind _________ _______ peptides although the optimal length is _______________ -MHC molecules bind ___________________. It is the ____ that discriminates between self and non-self via the specificity of the _______

broader; 8-11 amino acids long; 10-30 amino acid length; 12-16 amino acids; both foreign & self peptides; Tcell; TCR

MHC Molecules: -There is also an area called MHC class III that contains genes that code for ___________________ and _______________________. -These genes have _____________________ but just happen to be located between class I and class II genes

complement components; tumor necrosis factor (TNF); nothing to do with the MHC

Antigen Association with MHC Class I and Class II: -MHC class I presents _________________ -Endogenous antigens are those that are synthesized by the _______ that is producing the MHC class I molecule -These antigens are generally ___________ although neo- or tumor antigens would also be in this class

endogenous antigens; same cell; viral antigens

Antigen Association with MHC Class I and Class II: -MHC class II molecules present antigen that is of __________ origin (outside the cell). Antigen- presenting cells endocytose and process exogenous Ag -MHC class II are synthesized in the RER and transported through the Golgi apparatus in a transport vesicle where they fuse with a ___________________ containing processed antigen -The __________ is hydrolyzed off the Ag-binding grove, Ag is associated, and the Ag-loaded molecule is transported in a vesicle to the cell surface where it is expressed

exogenous; phagolysosome; gamma chain

T Cell Epitopes: -Due to the requirement that antigens must be processed for recognition by the TCR, many of the epitopes recognized by T cells are processed peptide fragments from the ______ or other areas of the ____________ and are often not accessible for recognition in the intact protein -These epitopes are often __________ or _________ peptide fragments

interior; intact antigen; hydrophobic; aromatic

Expression of MHC Molecules: -Expression of MHC molecules is, therefore, _________ and each molecule must be able to bind and present multiple peptides. However, not all peptides produced in antigen processing will be bound and presented -It is this property of selective binding and presentation of peptides (______________________) that determines which peptides will be presented and, therefore, which epitopes will induce an immune response (_________________________)

limited; determinant selection model; immunodominant epitopes

What is the size of the binding cleft for MHC Class II molecules?

peptides of 10-30 residues or more

What is the size of the binding cleft for MHC Class I molecules?

peptides of 8-11 residues

MHC Genes: -These genes code for the expression of cell surface proteins that function, among other things, to _______________ -The genes are found on ________________ in humans and ________________ in mice ~in humans, the MHC is termed ____ ~in mice, the MHC is termed ____

present antigen; chromosome 6; chromosome 17; HLA; H-2

Antigen Association with MHC Class I and Class II: -____________: proteinase complexes in the cytoplasm, process endogenous antigens into peptides _____ amino acid residues in length -These processed endogenous peptides are transported to the rough endoplasmic reticulum where they are loaded into the antigen-binding groves of newly synthesized MHC class I molecules

proteosomes; 8-11

MHC Proteins: -The MHC proteins were originally defined in relationship to ______________. MHC molecules are structurally ______ to each individual. MHC molecules on tissue cells will be recognized as _________ by a recipient's immune system in a tissue transplant. For this reason, they are often called _____________

tissue rejection; unique; foreign; MHC antigens