The Major Histocmpatibility Complex

7/29/2019 The Major Histocmpatibility Complex

1/43

is a large genomic region or gene familyfound in mostvertebrates that encodesMHC molecules. MHC molecules play an important role in the immune

system and autoimmunity.
http://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Gene_familyhttp://en.wikipedia.org/wiki/Vertebratehttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Autoimmunityhttp://en.wikipedia.org/wiki/Autoimmunityhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Immune_systemhttp://en.wikipedia.org/wiki/Vertebratehttp://en.wikipedia.org/wiki/Gene_familyhttp://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Histocompatibilityhttp://en.wikipedia.org/wiki/Histocompatibility


2/43

Protein images comparing the MHC I (1hsa) and MHC II

(1dlh) molecules.
http://en.wikipedia.org/wiki/File:MHC_I_vs_MHC_II.png


3/43

Proteins are continually synthesized in the cell.These include normal proteins (self) andmicrobial invaders (nonself). A MHC moleculeinside the cell takes a fragment of those proteinsand displays it on the cell surface. (The proteinfragment is sometimes compared to a hot dog, and

the MHC protein to the bun.[1]) When the MHC-protein complex is displayed on the surface of thecell, it can be presented to a nearby immune cell,usually a T cell or natural killer (NK) cell.
http://en.wikipedia.org/wiki/Cell_(biology)http://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/NK_cellhttp://en.wikipedia.org/wiki/NK_cellhttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Cell_(biology)


4/43

. The MHC is the most gene-dense region of themammalian genome. MHC genes vary greatly fromindividual to individual

MHC alleles have polymorphisms (diversity). Thispolymorphism is adaptive in evolution because it increasesthe likelihood that at least some individuals of a population

will survive an epidemic
http://en.wikipedia.org/wiki/Genomehttp://en.wikipedia.org/wiki/Alleleshttp://en.wikipedia.org/wiki/Polymorphismshttp://en.wikipedia.org/wiki/Polymorphismshttp://en.wikipedia.org/wiki/Alleleshttp://en.wikipedia.org/wiki/Genome


5/43

MHC molecules: Class I and Class II . Class I MHC molecules are found on almost all cells

and present proteins to cytotoxic T cells. Class II MHCmolecules are found on certain immune cellsthemselves, chieflymacrophages and B cells, alsoknown as antigen-presenting cells (APCs). These APCsingest microbes, destroy them, and digest them intofragments. The Class II MHC molecules on the APCspresent the fragments to helper T cells, whichstimulate an immune reaction from other cells
http://en.wikipedia.org/wiki/Cytotoxic_T_cellshttp://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/B_cellshttp://en.wikipedia.org/wiki/B_cellshttp://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/Cytotoxic_T_cells


6/43

The MHC region is divided into three subgroups, class

I, class II, and class III.

Name Function Expression

MHC class I

Encodes non-identical pairs

(heterodimers) of peptide-binding

proteins, as well as antigen-

processing molecules such

as TAP and Tapasin.

All nucleated cells. MHC class I

proteins contain an chain & 2-

micro-globulin(not part of the MHC

encoded by chromosome 15). They

present antigen fragments to cytotoxic

T-cells via theCD8 receptor on

the cytotoxic T-cells and also bind

inhibitory receptors onNK cells.

MHC class II

Encodes heterodimeric peptide-

binding proteins and proteins that

modulate antigen loading onto MHC

class II proteins inthe lysosomal compartment such

as MHC II DM, MHC II DQ, MHC II

DR, and MHC II DP.

On most immune system cells,

specifically on antigen-presenting

cells. MHC class II proteins contain

& chains and they present antigenfragments to T-helper cells by binding

to the CD4receptor on the T-helper

cells.

MHC class IIIregion

Encodes for other immune

components, such

as complement components

(e.g., C2, C4, factor B) and some that

encode cytokines (e.g., TNF-) and

also hsp.

Variable (see below).
http://en.wikipedia.org/wiki/Heterodimershttp://en.wikipedia.org/wiki/Antigen_processinghttp://en.wikipedia.org/wiki/Antigen_processinghttp://en.wikipedia.org/wiki/Transporter_associated_with_antigen_processinghttp://en.wikipedia.org/wiki/Tapasinhttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/CD8http://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/NK_cellshttp://en.wikipedia.org/wiki/Lysosomalhttp://en.wikipedia.org/wiki/MHC_II_DMhttp://en.wikipedia.org/wiki/MHC_II_DQhttp://en.wikipedia.org/wiki/MHC_II_DRhttp://en.wikipedia.org/wiki/MHC_II_DRhttp://en.wikipedia.org/wiki/MHC_II_DPhttp://en.wikipedia.org/wiki/Antigen-presenting_cellshttp://en.wikipedia.org/wiki/Antigen-presenting_cellshttp://en.wikipedia.org/wiki/CD4http://en.wikipedia.org/wiki/T-helper_cellshttp://en.wikipedia.org/wiki/T-helper_cellshttp://en.wikipedia.org/wiki/Complement_systemhttp://en.wikipedia.org/wiki/Complement_component_2http://en.wikipedia.org/wiki/Complement_component_4http://en.wikipedia.org/wiki/Complement_factor_Bhttp://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/TNF-%CE%B1http://en.wikipedia.org/wiki/TNF-%CE%B1http://en.wikipedia.org/wiki/Heat_shock_proteinhttp://en.wikipedia.org/wiki/Heat_shock_proteinhttp://en.wikipedia.org/wiki/TNF-%CE%B1http://en.wikipedia.org/wiki/TNF-%CE%B1http://en.wikipedia.org/wiki/TNF-%CE%B1http://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/Complement_factor_Bhttp://en.wikipedia.org/wiki/Complement_component_4http://en.wikipedia.org/wiki/Complement_component_2http://en.wikipedia.org/wiki/Complement_systemhttp://en.wikipedia.org/wiki/T-helper_cellshttp://en.wikipedia.org/wiki/T-helper_cellshttp://en.wikipedia.org/wiki/T-helper_cellshttp://en.wikipedia.org/wiki/T-helper_cellshttp://en.wikipedia.org/wiki/CD4http://en.wikipedia.org/wiki/Antigen-presenting_cellshttp://en.wikipedia.org/wiki/Antigen-presenting_cellshttp://en.wikipedia.org/wiki/Antigen-presenting_cellshttp://en.wikipedia.org/wiki/Antigen-presenting_cellshttp://en.wikipedia.org/wiki/MHC_II_DPhttp://en.wikipedia.org/wiki/MHC_II_DRhttp://en.wikipedia.org/wiki/MHC_II_DRhttp://en.wikipedia.org/wiki/MHC_II_DQhttp://en.wikipedia.org/wiki/MHC_II_DMhttp://en.wikipedia.org/wiki/Lysosomalhttp://en.wikipedia.org/wiki/NK_cellshttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/CD8http://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/Cytotoxic_T-cellshttp://en.wikipedia.org/wiki/Tapasinhttp://en.wikipedia.org/wiki/Transporter_associated_with_antigen_processinghttp://en.wikipedia.org/wiki/Antigen_processinghttp://en.wikipedia.org/wiki/Antigen_processinghttp://en.wikipedia.org/wiki/Antigen_processinghttp://en.wikipedia.org/wiki/Heterodimers


7/43

Responses The MHC proteins act as "signposts" that serve to alert

the immune system if foreign material is presentinside a cell. They achieve this by displayingfragmented pieces ofantigens on the host cell'ssurface. These antigens may be selfor nonself. If theyare nonself, there are two ways by which the foreignprotein can be processed and recognized as being"nonself".
http://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Antigen


8/43

Phagocytic cells such as macrophages, neutrophils,and monocytes degrade foreign particles that areengulfed during a process known as phagocytosis.Degraded particles are then presented on MHC ClassII molecules
http://en.wikipedia.org/wiki/Macrophageshttp://en.wikipedia.org/wiki/Neutrophilshttp://en.wikipedia.org/wiki/Monocyteshttp://en.wikipedia.org/wiki/Phagocytosishttp://en.wikipedia.org/wiki/Phagocytosishttp://en.wikipedia.org/wiki/Monocyteshttp://en.wikipedia.org/wiki/Neutrophilshttp://en.wikipedia.org/wiki/Macrophages


9/43

On the other hand, if a host cell was infected bya bacterium orvirus, or was cancerous, it may havedisplayed the antigens on its surface with a Class IMHC molecule. cancerous cells and cells infected by avirus have a tendency to displayunusual, nonselfantigens on their surface. Thesenonself antigens, regardless of which type of MHCmolecule they are displayed on, will initiatethe specific immunityof the host's body
http://en.wikipedia.org/wiki/Bacteriahttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Canceroushttp://en.wikipedia.org/wiki/Specific_immunityhttp://en.wikipedia.org/wiki/Specific_immunityhttp://en.wikipedia.org/wiki/Canceroushttp://en.wikipedia.org/wiki/Virushttp://en.wikipedia.org/wiki/Bacteria


10/43

Cells constantly process endogenous proteins andpresent them within the context of MHC I. Immuneeffector cells are trained not to react to self peptideswithin MHC, and as such are able to recognize whenforeign peptides are being presented during aninfection/cancer


11/43

The best-known genes in the MHC region are the subset that

encodes antigen-presenting proteins on the cell surface as human

leukocyte antigen (HLA) genes

The most intensely studied HLA genes are the nine so-called classical MHC genes: HLA-A, HLA-B, HLA-C, HLA-DPA1, HLA-DPB1, HLA-DQA1, HLA-DQB1, HLA-DRA, and HLA-DRB1. In humans, the MHCis divided into three regions: Class I, II, and III. The A, B,C, E, F, and G genes belong to MHC class I, whereas thesix D genes belong to class II.
http://en.wikipedia.org/wiki/Human_leukocyte_antigenhttp://en.wikipedia.org/wiki/Human_leukocyte_antigenhttp://en.wikipedia.org/wiki/HLA-Ahttp://en.wikipedia.org/wiki/HLA-Bhttp://en.wikipedia.org/wiki/HLA-Chttp://en.wikipedia.org/wiki/HLA-Chttp://en.wikipedia.org/wiki/HLA-DPA1http://en.wikipedia.org/wiki/HLA-DPB1http://en.wikipedia.org/wiki/HLA-DQA1http://en.wikipedia.org/wiki/HLA-DQB1http://en.wikipedia.org/wiki/HLA-DQB1http://en.wikipedia.org/wiki/HLA-DRAhttp://en.wikipedia.org/wiki/HLA-DRB1http://en.wikipedia.org/wiki/HLA-DRB1http://en.wikipedia.org/wiki/HLA-DRB1http://en.wikipedia.org/wiki/HLA-DRB1http://en.wikipedia.org/wiki/HLA-DRAhttp://en.wikipedia.org/wiki/HLA-DRAhttp://en.wikipedia.org/wiki/HLA-DRAhttp://en.wikipedia.org/wiki/HLA-DQB1http://en.wikipedia.org/wiki/HLA-DQB1http://en.wikipedia.org/wiki/HLA-DQB1http://en.wikipedia.org/wiki/HLA-DQA1http://en.wikipedia.org/wiki/HLA-DQA1http://en.wikipedia.org/wiki/HLA-DQA1http://en.wikipedia.org/wiki/HLA-DPB1http://en.wikipedia.org/wiki/HLA-DPB1http://en.wikipedia.org/wiki/HLA-DPB1http://en.wikipedia.org/wiki/HLA-DPA1http://en.wikipedia.org/wiki/HLA-DPA1http://en.wikipedia.org/wiki/HLA-DPA1http://en.wikipedia.org/wiki/HLA-Chttp://en.wikipedia.org/wiki/HLA-Chttp://en.wikipedia.org/wiki/HLA-Chttp://en.wikipedia.org/wiki/HLA-Bhttp://en.wikipedia.org/wiki/HLA-Bhttp://en.wikipedia.org/wiki/HLA-Bhttp://en.wikipedia.org/wiki/HLA-Ahttp://en.wikipedia.org/wiki/HLA-Ahttp://en.wikipedia.org/wiki/HLA-Ahttp://en.wikipedia.org/wiki/Human_leukocyte_antigenhttp://en.wikipedia.org/wiki/Human_leukocyte_antigen


12/43

MHC genes are expressed in codominant fashion[6]. This means that

the alleles (variants) inherited from both progenitors are expressed in

equivalent way

As there are 3 Class-I genes, named in humans HLA-A,HLA-B and HLA-C, and as each person inherits a setof genes from each progenitor, that means that any cellin an individual can express 6 different types of MHC-Imolecules
http://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Allelehttp://en.wikipedia.org/wiki/Major_histocompatibility_complex


13/43

the Class-II locus person inherits a couple of genes HLA-DP (DPA1 and

DPA2, which encode and chains), a couple of genesHLA-DQ (DQA1 and DQA2, for and chains), onegene HLA-DR (DRA1) and one or two genes HLA-DR (DRB1 and DRB3, -4 o -5).

one heterozygous individual can inherit 6 or 8 Class-IIalleles, three or four from each progenitor
http://en.wikipedia.org/wiki/Locushttp://en.wikipedia.org/wiki/Heterozygoushttp://en.wikipedia.org/wiki/Heterozygoushttp://en.wikipedia.org/wiki/Locus


14/43

The set of alleles which is present in each chromosome

is called MHC haplotype

. In humans, each HLA allele is named with a number.For instance, for a given individual, his haplotypemight be HLA-A2, HLA-B5, HLA-DR3, etc... Eachheterozygous individual will have two MHChaplotypes, one in each chromosome (one of paternalorigin and the other of maternal origin).
http://en.wikipedia.org/wiki/Haplotypehttp://en.wikipedia.org/wiki/Haplotype


15/43

The MHC genes are highly polymorphic; This means that there are many different alleles in the

different individuals inside a population. Thepolymorphism is so high that in a mixed population(non-endogamic) there are not two individuals withexactly the same set of MHC genes and molecules,with the exception of the identical twins
http://en.wikipedia.org/wiki/Endogamyhttp://en.wikipedia.org/wiki/Twinhttp://en.wikipedia.org/wiki/Twinhttp://en.wikipedia.org/wiki/Endogamy


16/43

The polymorphic regions in each allele are located in

the region for peptide contact, which is going to be

displayed to the lymphocyte

, the contact region for each allele of MHC molecule is highly variable,as the polymorphic residues of the MHC will create specific clefts in

which only certain types of residues of the peptide can enter. Thisimposes a very specific link between the MHC molecule and thepeptide, and it implies that each MHC variant will be able to bindspecifically only those peptides which are able to properly enter in thecleft of the MHC molecule, which is variable for each allele. this way,the MHC molecules have a broad specificity, because they can bindmany, but not all types of possible peptides. essential characteristic ofMHC molecules: in a given individual, it is enough to have a fewdifferent molecules to be able to display a high variety of peptides.


17/43

inside a population, the presence of many different alleles ensures that it willalways be an individual with a specific MHC molecule able toload the correct peptide to recognize a specific microbe. The

evolution of the MHC polymorphism ensures that apopulation will not sucumb face to a new pathogen or amutated one, because at least some individuals will be able todevelop an adecuate immune response to win over the

pathogen. The variations in the MHC molecules(responsibles for the polymorphism) are the result of theinheritance of different MHC molecules, are not inducedbyrecombination, as it is the case for the antigen receptors
http://en.wikipedia.org/wiki/Recombinationhttp://en.wikipedia.org/wiki/Receptorhttp://en.wikipedia.org/wiki/Receptorhttp://en.wikipedia.org/wiki/Recombination


18/43

MHC molecules areanchored in the cellmembrane at the bottomof the illustration; they canthen bind to immune cells

at the top of theillustration. The MHCClass I molecule (left) onmost cells binds to the T-cell receptor (TCR) andCD8 receptor (top). The

MHC Class II molecule(right) on immune cellsbinds to the TCR and CD4receptor on other immunecells (top).


19/43

The classical MHC molecules (also referred to as HLA molecules in humans)

have a vital role

the complex immunological dialogue that must occurbetween T cells and other cells of the body. Atmaturity, MHC molecules are anchored in the cell

membrane, where they display short polypeptides to Tcells, via the T cell receptors (TCR). The polypeptidesmay be "self," that is, originating from a proteincreated by the organism itself, or they may be foreign("nonself"), originating from bacteria, viruses, pollen, .The overarching design of the MHC-TCR interaction isthat T cells should ignore self-peptides while reactingappropriately to the foreign peptides.
http://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/Polypeptidehttp://en.wikipedia.org/wiki/T_cell_receptorhttp://en.wikipedia.org/wiki/T_cell_receptorhttp://en.wikipedia.org/wiki/Polypeptidehttp://en.wikipedia.org/wiki/T_cell


20/43

method for identifying an antigen: B cells with their membrane-

boundantibodies, B cell receptors (BCR).

, whereas the BCRs of B cells can bind to antigens withoutmuch outside help, the TCRs require "presentation" of theantigen through the help of MHC. however, MHC are kept

busy presenting self-peptides, which T cells shouldappropriately ignore. A full-force immune response usuallyrequires the activation of B cells via BCRs andT cells via theMHC-TCR interaction. This duality creates a system of

"checks and balances" and underscores the immunesystem's potential for running amok and causing harm tothe body
http://en.wikipedia.org/wiki/B_cellhttp://en.wikipedia.org/wiki/Antibodyhttp://en.wikipedia.org/wiki/Antibodyhttp://en.wikipedia.org/wiki/B_cell


21/43

Structure of a molecule of MHC Class-I.

MHC molecules retrieve polypeptides from the interior of the cellthey are part of and display them on the cell's surface for

recognition byT cells. However, MHC class I and MHC classII differ significantly in the method of peptide presentation.
http://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/MHC_class_Ihttp://en.wikipedia.org/wiki/MHC_class_IIhttp://en.wikipedia.org/wiki/MHC_class_IIhttp://en.wikipedia.org/wiki/MHC_class_IIhttp://en.wikipedia.org/wiki/MHC_class_IIhttp://en.wikipedia.org/wiki/MHC_class_Ihttp://en.wikipedia.org/wiki/T_cellhttp://en.wikipedia.org/wiki/File:MHC_Class_1.svg


22/43

MHC Class-I genes (MHC-I) code glucoproteins,

with immunoglobulin structure: they present one heavy chain type , subdivided in three regions: 1,

2 y 3. are exposed to the extracellular space, and they are linked tothe cellular membrane through a transmembrane region. The chain isalways asociated to a molecule of2 microglobulin, which is coded byan independent region on chromosome 15. These molecules are presentin the surface ofall nucleated cells.[6]

The most important function of the gene products for the Class-I genesis the presentation ofintracellular antigenic peptides tothe cytotoxic T lymphocytes (CD8+). The antigenic peptide islocated in a cleft existing between the 1 and 2 regions in the heavychain.

different isotypes (different genes) for the Class-I molecules, which canbe grouped as:

"classic molecules", whose function consist in antigen presentation tothe T8 lymphocytes: inside this group we find HLA-A, HLA-B y HLA-C.
http://en.wikipedia.org/wiki/Immunoglobulinhttp://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Peptidehttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocyteshttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocyteshttp://en.wikipedia.org/wiki/Peptidehttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocyteshttp://en.wikipedia.org/wiki/Isotypehttp://en.wikipedia.org/wiki/HLAhttp://en.wikipedia.org/wiki/HLAhttp://en.wikipedia.org/wiki/HLAhttp://en.wikipedia.org/wiki/Isotypehttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocyteshttp://en.wikipedia.org/wiki/Peptidehttp://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Immunoglobulin


23/43

"non classic molecules" (named also MHC class IB),with specialized functions: they do not presentantigens to T lymphocytes, but they interact with

inhibitory receptors in NK cells; inside this group wefind HLA-E, HLA-F, HLA-G.

Structure of a
http://en.wikipedia.org/wiki/NK_cellhttp://en.wikipedia.org/wiki/NK_cell


24/43

Structure of a

molecule of MHC

MHC Class-II

genes code glucoproteins withimmunoglobulin structure, in thiscase the functional complex isformed bytwo chains, one andone (each one with twodomains: 1 and 2, 1 and 2).Each chain is linked to the cellular

membrane through atransmembrane region, and bothchains are confronted, withdomains 1 and 2 consecutives, inthe extracellular espace.[6]

These molecules are presentmostly in the membrane ofthe antigen presentingcells (dendritic and phagocyticcells), where they presentprocessed extracellular antigenicpeptides to the helper Tlymphocytes (CD4+). Theantigenic peptide is located in acleft formed by 1 and 1 peptides
http://en.wikipedia.org/wiki/Major_histocompatibility_complexhttp://en.wikipedia.org/wiki/Antigen_presenting_cellhttp://en.wikipedia.org/wiki/Antigen_presenting_cellhttp://en.wikipedia.org/wiki/Helper_T_cellshttp://en.wikipedia.org/wiki/Helper_T_cellshttp://en.wikipedia.org/wiki/File:MHC_Class_2.svghttp://en.wikipedia.org/wiki/Helper_T_cellshttp://en.wikipedia.org/wiki/Helper_T_cellshttp://en.wikipedia.org/wiki/Antigen_presenting_cellhttp://en.wikipedia.org/wiki/Antigen_presenting_cellhttp://en.wikipedia.org/wiki/Major_histocompatibility_complex


25/43

MHC-II molecules in humans present 5-6

isotypes, and can be grouped in "classic molecules", presenting peptides to T4

lymphocytes; inside this group we find HLA-DP, HLA-DQ,HLA-DR;

"non classic molecules", accesories, with intracellularfunctions (they are not exposed in the cellular membrane,but in internal membrares inlysosomes); normally, theyload the antigenic peptides on the classic MHC-IImolecules; in this group are included HLA-DM and HLA-DO.

On top of the MHC-II molecules, in the Class-II region arelocated genes coding for antigen processing molecules,such as TAP (transporter associated with antigen

processing) or Tapasin
http://en.wikipedia.org/wiki/Lysosomehttp://en.wikipedia.org/wiki/Lysosomehttp://en.wikipedia.org/wiki/TAPhttp://en.wikipedia.org/wiki/TAPhttp://en.wikipedia.org/wiki/Tapasinhttp://en.wikipedia.org/wiki/Tapasinhttp://en.wikipedia.org/wiki/Tapasinhttp://en.wikipedia.org/wiki/TAPhttp://en.wikipedia.org/wiki/Lysosome


26/43

MHC Class-III This class include genes coding several secreted

proteins with immune functions: components ofthe complement system (such as C2, C4 and B factor)

and molecules relatedwith inflammation (cytokines such as TNF-, LTA,LTB) or heat shock proteins (hsp).

Class-III molecules do not share the same function asclass- I and II molecules, but they are located betweenthem in the short arm of human chromosome 6, andfor this reason they are frequently described together.
http://en.wikipedia.org/wiki/Complement_systemhttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/TNF-alphahttp://en.wikipedia.org/wiki/TNF-alphahttp://en.wikipedia.org/wiki/Heat_shock_proteinhttp://en.wikipedia.org/wiki/Heat_shock_proteinhttp://en.wikipedia.org/wiki/TNF-alphahttp://en.wikipedia.org/wiki/TNF-alphahttp://en.wikipedia.org/wiki/TNF-alphahttp://en.wikipedia.org/wiki/Cytokinehttp://en.wikipedia.org/wiki/Inflammationhttp://en.wikipedia.org/wiki/Complement_system


27/43

Functions of MHC-I and II molecules Both types of molecules present antigenic peptides to

T lymphocytes, which are responsible for the specificimmune response to destroy the pathogen producing

those antigens. However, Class-I and II moleculescorrespond to two different pathways of antigenprocessing, and are associated to two different systemsof immune defense


28/43

Functions of MHC-I and II moleculesTable 2. Characteristics of the antigen processing pathways

Characteristic MHC-II pathway MHC-I pathway

Composition of the stable peptide-MHC complex Polymorphic chains and , peptide binds to bothPolymorphic chain and 2 microglobulin, peptide

bound to chain

Types ofantigen presenting cells (APC)

Dendritic cells, mononuclear phagocytes, B

lymphocytes, some endothelial cells, epithelium

ofthymus

All nucleated cells

T lymphocytes able to respond Helper T lymphocytes (CD4+) Cytotoxic T lymphocytes (CD8+)

Origin of antigenic proteinsProteins present in endosomes or lysosomes (mostly

internalized from extracellular medium)

cytosolic proteins (mostly synthetized by the cell; may

also enter from the extracellular medium

via phagosomes)
http://en.wikipedia.org/wiki/Antigen_presenting_cellhttp://en.wikipedia.org/wiki/Dendritic_cellhttp://en.wikipedia.org/wiki/B_lymphocyteshttp://en.wikipedia.org/wiki/B_lymphocyteshttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/Helper_T_cellshttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocyteshttp://en.wikipedia.org/wiki/Endosomehttp://en.wikipedia.org/wiki/Lysosomehttp://en.wikipedia.org/wiki/Cytosolhttp://en.wikipedia.org/wiki/Phagosomehttp://en.wikipedia.org/wiki/Phagosomehttp://en.wikipedia.org/wiki/Cytosolhttp://en.wikipedia.org/wiki/Lysosomehttp://en.wikipedia.org/wiki/Endosomehttp://en.wikipedia.org/wiki/Cytotoxic_T_lymphocyteshttp://en.wikipedia.org/wiki/Helper_T_cellshttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/B_lymphocyteshttp://en.wikipedia.org/wiki/B_lymphocyteshttp://en.wikipedia.org/wiki/Dendritic_cellhttp://en.wikipedia.org/wiki/Antigen_presenting_cell


29/43

MHC II MHC I

Enzymes responsible for peptide generation Proteases from endosomes and lysosomes

(for instance,cathepsin)Cytosolic proteasome

Location of loading the peptide on the MHC

moleculeSpecialized vesicular compartment Endoplasmic reticulum

Molecules implicated in transporting the

peptides and loading them on the MHC

molecules

DM, invariant chainTAP (transporter associated with antigen

processing)
http://en.wikipedia.org/wiki/Proteasehttp://en.wikipedia.org/wiki/Cathepsinhttp://en.wikipedia.org/wiki/TAPhttp://en.wikipedia.org/wiki/TAPhttp://en.wikipedia.org/wiki/Cathepsinhttp://en.wikipedia.org/wiki/Protease


30/43

T lymphocytes belonging to one specific individual presenta property called MHC restriction (see below): they onlycan detect an antigen if it is displayed by an MHC molecule

from the same individual. This is due to the fact that each Tlymphocyte has a dual specificity: the T cell receptor (TCR)recognizes at the same time some residues from thepeptide and some residues from the displaying MHCmolecule. This property is of great importance in organ

transplantation, and during their development, Tlymphocytes must "learn" to recognize the MHC moleculesbelonging to the individual (the "self" recognition), duringthe complex process ofmaturation and selection havingplace in the thymus
http://en.wikipedia.org/wiki/Organ_transplantationhttp://en.wikipedia.org/wiki/Organ_transplantationhttp://en.wikipedia.org/wiki/T_lymphocytehttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/T_lymphocytehttp://en.wikipedia.org/wiki/Organ_transplantationhttp://en.wikipedia.org/wiki/Organ_transplantation


31/43

MHC molecules can only displaypeptides. For this reason,as T lymphocytes can only recognize an antigen if it isdisplayed by an MHC molecule, they only can react to

antigens of proteic origin (coming from microbes) and notto other types of chemical compounds (neither lipids,nor nucleic acids, nor sugars). Each MHC molecule candisplayonly one peptideeach time, because the cleft in

the molecule has space only to load one peptide. However,one given MHC molecule has a broad specificity, becauseit can display many different peptides (although not all).
http://en.wikipedia.org/wiki/Lipidhttp://en.wikipedia.org/wiki/Nucleic_acidshttp://en.wikipedia.org/wiki/Sugarhttp://en.wikipedia.org/wiki/Sugarhttp://en.wikipedia.org/wiki/Nucleic_acidshttp://en.wikipedia.org/wiki/Lipid


32/43

Peptide processing for peptides associated to MHC-I molecules: proteins present in the cytosol are degraded by

the proteasome, and the resulting peptides are internalized by the TAP channel in theendoplasmic reticulum, where they

become associated with MHC-I molecules freshly synthesized. The MHC-I/peptide complexes enter in the Golgi apparatus,

where they are glycosylated, and from there they enter in secreting vesicles, which fuse with the cell membrane. In this

way, the complexes become exposed to the outside of the cell, allowing the contact with circulating T lymphocytes.
http://en.wikipedia.org/wiki/Cytosolhttp://en.wikipedia.org/wiki/Proteasomehttp://en.wikipedia.org/wiki/Endoplasmic_reticulumhttp://en.wikipedia.org/wiki/Golgi_apparatushttp://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/File:MHC_Class_I_processing.svghttp://en.wikipedia.org/wiki/Cell_membranehttp://en.wikipedia.org/wiki/Golgi_apparatushttp://en.wikipedia.org/wiki/Endoplasmic_reticulumhttp://en.wikipedia.org/wiki/Endoplasmic_reticulumhttp://en.wikipedia.org/wiki/Endoplasmic_reticulumhttp://en.wikipedia.org/wiki/Proteasomehttp://en.wikipedia.org/wiki/Cytosol


33/43

MHC molecules obtain the peptide that they display to theoutside of the cell during their own biosynthesis, inside thecell. That means that those peptides come from microbes

that are inside the cell. This is the reason why Tlymphocytes, which only can recognize a peptide if it isdisplayed by an MHC molecule, are only able to detectmicrobes associated to cells, developing only an immune

response against intracellular microbes.


34/43

It is important to notice that MHC-I molecules acquirepeptides coming from cytosolic proteins, whereas MHC-IImolecules acquire peptides from proteins contained in

intracellular vesicles. For this reason, MHC-I moleculesdisplay "self" peptides, viral peptides (synthesized by theown cell) or peptides coming from ingested microbes inphagosomes. MHC-II molecules, however, display peptidescoming from microbes ingested in vesicles (MHC-II

molecules are present only in cells with phagocyticcapacity). MHC molecules are stable on the cell membraneonly if they display a loaded peptide: the peptide stabilizesthe structure of the MHC molecules, whereas "empty"molecules are degraded inside the cell.


35/43

In each individual, MHC molecules can display bothforeign peptides (coming from pathogens) as well aspeptides coming from the self proteins of this individual.

For this reason, in a given moment, only a small fraction ofthe MHC molecules in one cell will display a foreignpeptide: most of the displayed peptides will be selfpeptides, because these are much more abundant.

However, T lymphocytes are able to detect a peptidedisplayed by only 0.1%-1% of the MHC molecules to initiatean immune response


36/43

On the other hand, the self peptides cannot initiate animmune response (except in the caseofautoimmune diseases), because the specific T

lymphocytes for the self peptides are destroyed orinactivated in the thymus. However, the presence of selfpeptides displayed by MHC molecules is essential for thesupervising function of the T lymphocytes: these cells are

constantly patrolling the organism, verifying the presenceof self peptides associated to MHC molecules. In the rarecases in which they detect a foreign peptide, they willinitiate an immune response
http://en.wikipedia.org/wiki/Autoimmunehttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/Thymushttp://en.wikipedia.org/wiki/Autoimmune


37/43

Role of MHC molecules in transplants

rejection As previously described, each human cell express 6 MHC

class-I alleles (one HLA-A, -B and -C allele from eachprogenitor) and 6-8 MHC class-2 alleles (one HLA-DP and

-DQ, and one or two HLA-DR from each progenitor, andsome combinations of these). The MHC polymorphism is

very high: it is estimated that in the population there are atleast 350 alleles for HLA-A genes, 620 alleles for HLA-B,

400 alleles for DR and 90 alleles for DQ.


38/43

As these alleles can be inherited and expressed in manydifferent combinations, each individual in the population

will most likely express some molecules which will be

different from the molecules in another individual, exceptin the case of identical twins. All MHC molecules can betargets for transplant rejection, but HLA-C and HLA-DPmolecules show low polymorphism, and most likely they

are less important in rejection


39/43

In a tranplant (an organ transplantation or stemcells transplantation), MHC molecules work as antigens:they can initiate an immune response in the receptor, thus

provoking the transplant rejection. MHC moleculesrecognition in cells from another individual is one of themost intense immune responses currently known. Thereason why an individual reacts against the MHC

molecules from another individual is pretty wellunderstood.
http://en.wikipedia.org/wiki/Stem_cellhttp://en.wikipedia.org/wiki/Stem_cellhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Antigenhttp://en.wikipedia.org/wiki/Stem_cellhttp://en.wikipedia.org/wiki/Stem_cell


40/43

During T lymphocytes maturation in the thymus, thesecells are selected according to their TCR capacity to weaklyrecognize complexes "self peptide:self MHC". For this

reason, in principle T lymphocytes should not react againsta complex "foreign peptide:foreign MHC", which is whatcan be found in transplanted cells. However, what seems tohappen is a kind of cross-reaction: T lymphocytes from the

receptor individual can be mistaken, because the MHCmolecule of the donor is similar to self MHC molecule inthe binding region to the TCR (the MHC variable region isin the binding motif for the peptide they display).
http://en.wikipedia.org/wiki/T_lymphocytehttp://en.wikipedia.org/wiki/T_lymphocyte


41/43

hyperacute rejection: it happens when the receptorindividual has preformed anti-HLA antibodies, generatedbefore the trasplantation; this can be due to previous blood

transfusions (because this includes donor lymphocytes,expressing HLA molecules), to the generation of anti-HLAduring pregnancy (against the HLA molecules from thefather present in the fetus) and due to a previous

trasplantation;


42/43

acute humoral rejection and chronic disfunction ofthe transplanted organ: due to the formation of anti-HLAantibodies in the receptor individual, against the HLA

molecules present in the endothelial cells of thetransplanted tissue.

In both cases, there is an immune reaction against thetransplanted organ, which can produce lesions in the

organ, eventually producing lost of function, immediatelyin the first case, and progressive in the second one.


43/43

For this reason, it is crucial to realize a cross-reactiontest between donor cells and receptor serum, to detect thepotential presence of preformed anti-HLA antibodies in

the receptor against donor HLA molecules, in order toavoid the hyperacute rejection . Normally, what ischecked is the compatibility between HLA-A, -B and -DRmolecules: the higher the number of incompatibilities, thelower the 5 years survival of the transplant

Documents

The Major Histocmpatibility Complex