Friday, 2 January 2015

MAJOR HISTOCOMPATIBILTY COMPLEX (MHC): Gene arrangement, Haplotype, MHC types, Antigen presentation.

MHC are the unique class of protein which play a significant role in immune system regulation. Proteins for MHC is located on the P arm of the 6th chromosome and is termed as MHC locus.
MHC locus is further classified into three regions, namely, MCH 1, MHC 3 & MHC 2.


Both Class I and Class II genes are tightly linked, with a crossover rate of about 0.5%.  This means that any one individual tends to pass on the collection of 3 class I and II MHC from Mom as a unit and the collection of 3 class I and II MHC genes from Dad as a unit. This unit or block is called a HAPLOTYPE.

1. Class 1 MHC:
    a. Codes for a three-domain protein.
    b. The main peptide (α ) associates with a second (β ), which is coded for on an entirely         different  chromosome (#15).
    c. Displays antigen (small peptide) to Tc (cytotoxic) cells.
    d. Everyone has a block of 3 of these genes from Mom and 3 from Dad (A, B & C)..
    e. The genes are wildly polymorphic: each one of these 6 could be any one of as many as 100 different alleles.
    f. Expressed by almost all nucleated cells, but not found on red blood cells, sperm or nerve cells.

2. Class 2 MHC:
     a.  Each gene codes for 2 separate peptides (α and β ) which  function together.
     b. present antigen small peptide at the end between α and β to TH (helper) cells
     c. Everyone has 3 of these genes from Mom and 3 from Dad.
     d. block of genes on the centromere end (DP, DQ and DR).
     e. wildly polymorphic: each one of these 6 could be any one of as many as 100 different alleles.
     f. expressed by antigen presenting cells (macrophages, dendritic cells, B cells).

3. Class 3 MHC:
    a. Completely different - generally not membrane components.
    b. code for secreted proteins involved in the innate responses: complement proteins, cytokines, and heat shock proteins.
   c. included because the genes just happen to lie between I and II genes.




 A. Class I MHC
          1. chain α
                  a. 3 major domains, α1, α2, α3 (amino to carboxyl)
                  b. peptide binding site between α1 and α2
                  c. α3 connected to
                  d. transmembrane segment with cytoplasmic tail
          2. β microglobulin chain
                  a. gene actually located on a different chromosome, #15
                  b. peptide associates with α1 by weak linkages.
                  c. necessary for membrane expression of whole molecule.
                  d. This does not have a membrane-spanning region, but rather attached by weak bonds to the domain of the class I MHC immediately exterior to the membrane.
          3. Homologies
                  a. α3 domain and the β chain resemble each other.
                  b. Both resemble the constant domains of immunoglobulins.
                  c. Note the “bread and butter” sandwich structure.
                  d. Gene transcript requires processing (no alternative splicing forms), but the DNA is not changed.
         4. Interactions
                  a. α1 and α2 form a platform structure with 8 antiparallel β strands connecting two helical regions.
                 b. The space between the helices forms a deep groove, the peptide-binding cleft
                 c. Long enough to hold a peptide of 8 to 10 amino acids
                 d. The platform region also interacts with the β microglobulin, which kind of supports one side of the structure.
                 e. The β peptide is necessary for the proper folding of the α peptide and its placement into the cell membrane.

B. Class II MHC
         1. α chain
             a. two major external domains (α1 and α2)
             b. transmembrane domain with cytoplasmic tail
         2. β chain
             a. two major external domains (β1 and β2)
             b. transmembrane domain with cytoplasmic tail.
         3. Homologies
             a. α2 and β2 resemble the class I MHC α3 domain and  β chain and immunoglobulin constant regions
            b. α1 and β1 resemble the class I MHC α2 domain and α1domains respectively.
            c. MHCs are also in the immunoglobulin superfamily.
            d. Gene transcript requires processing (no alternative splicing forms), but the DNA is not changed.
        4. Interaction
            a. The α and β dimers are joined by weak interactions.
            b. The antigen binding cleft is formed by the α1 and β1 interaction.



Class I MHC
1. Sides of the cleft defined by αx helices
2. Bottom of the cleft define by β sheets
3. Ends of the cleft also defined.
4. Peptides bind best with 9 amino acids.
    a. 8 or 10 can fit, because of bending.
    b. Peptide bows outward slightly,
    c. Bowing helps display middle of the peptide from out of the groove of the cleft
5. Peptides held on the ends by their anchor residues, which interact with specific side chains of the amino acids of the class I MHC.
    a. Carboxy (COOH) terminal anchor (amino acid #9 of the peptide) is typically hydrophobic.
    b. Amino acid #8 and even #7 may be involved in anchoring.
    c. Amino terminal anchor is #2
    d. Middle amino acids may vary, although exactly what they are will be important to the T cell receptor they will ultimately interact with.

Class II MHC 
1. Sides of the cleft defined by α helices
2. Bottom of the cleft defined by β sheets
3. Ends of the cleft are undefined: the peptide can stick out like a long hotdog in a short bun
4. Peptides bound have 13 to 18 residues, but only 13 of them fit the cleft
5. Peptides do not bow outward, but rather lie flat in the cleft.
6. Peptides therefore interact with the class II MHC molecule at a series of  places in the cleft region.  7. Different MHCs will have different binding specificities based on these interactions.
8. The MHC amino acids involved in the interaction show the most of the polymorphism of the molecule.



MHC molecules are well known for antigen presentation. Cells which present the antigens to a T cell is referred to as "antigen presenting cell". There are three main APCs,
1. B cells
2. Macrophages
3. Folicular dendritic cells

On the basis of the pathway for antigen presentation, it is classified into 2 types.
1. Endogenous pathway.
2. Exogenous pathway.


Cytosolic Pathway: Class I Processing and Presentation

Proteasomes: these are huge protein complexes helps to cleave the larger peptide molecules into shorter fragments.


Following changes are seen as soon as an antigen enters the ER.

Antigen is loaded on to the MHC molecule and is pushed towards the TAP ( a protein). Then it is transferred to golgi for processing. In golgi, processing of antigen takes place ( which may include glycosylation process).

 Since the cytoplasmic proteins are loaded on to the MHC molecule this pathway is referred to as "endogenous"; this pathway is very significant because this is the key pathway to present SELF antigen against which the immune response is nil.
Meanwhile, foreign antigens are also loaded.

Exogenous pathway: class 2 processing and presentation

Foreign antigen enters the only by phagocytosis. The antigen is loaded on the MHC molecule in golgi vesicle but not in ER. processing of the antigen takes place in golgi vesicle itself.

Following schemes explains the process of antigen loading on to the MHC molecule.

NOTE: Invariant chain and clip are the two major proteins which are very much essential to maintain the stability of the MHC molecule.



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