1. Human Leukocyte Antigen (HLA)
Lec.7
Major Histocompatibility Complex (MHC)
Human Leukocyte Antigen (HLA)

2. MHC: It is a group of tissue antigens, controlled by chromosomal region,it is essential for the acquired immune system to recognize foreign molecules in vertebrates and have relevance to transplantation rejection reaction which in turn determines histocompatibility.

3. In human, the genes coding for this system (HLA) are locating on short arms of chromosome Number 6.
MHC system is highly polymorphic with multiple different alleles within each locus.
A number of different diseases have been associated with particular MHC alleles such as HLA- DR4 with rheumatoid arthritis,HLA-B27 with ankylosing spondylitus and HLA-DR3 with diabetes mellitus type1 and SLE .

4. Human HLA gene complex encode 3 classes of antigens:
1- Class I genes include 3 main loci: A, B, C
-They are glycoproteins expressed on the surface of all nucleated cells.
- major function to present processed Ags to T-cytotoxic (CD8+) cell.
- bind with endogenous Ag.
2- Class II genes include 3 main loci: DP, DQ ,DR
-They are glycoproteins expressed on the surface of antigen presenting cells such as macrophages, B-cells,dendritic cells and activated T- cells.
- major function to present processed Ags to T-helper (CD4+) cell.
-Bind with exogenous Ag.

6. 3- Class III genes named as complement region located between classI & class II regions.
Class III genes generally encode various secreted proteins that have immune functions, including components of the complement system(C2,C4,BF) and inflammatory molecules.

7. Structure Of MHC molecules:
Structure of MHC class I:
-Class I Ags are glycoprotein in nature. They consist of α- heavy chain and β-2 microglobulin light chain
Class I heavy chain consists of:
1-three extra cellular domains, designated – α1, α2 & α3.
2- trasmembranous region
3- cytoplasmic tail
Heavy chain α1 & α2 domains form the antigen binding groove of classI MHC mol while β2-microglobulin is required for expression of class I molecules on cell membrane.

9. Structure of MHC class II:
Are glycoprotein in nature consist of two chains, one α- heavy chain and one β - light chain, each chain consists of:
1- two extra celluar domains heavy chain (α1 , α 2) & light chain (β1 , β2)
2- a trasmembranous region
3- a cytoplasmic tail
Heavy chain α 1 domain & light chain β 1 domain form the antigen binding groove of class II MHC molecules

10. Function of HLA Ags:
Both class I & class II MHC molecules are important in controlling immunological responses by a process
known as MHC restriction.
-MHC restriction:
Cytotoxic T-cells ( CD8+ ) are only activated when they recognize antigen on infected cell in association with MHC I molecules,
while T- Helper cells (CD4+) recognize antigens on antigen-presenting cells only when the antigens are presented on the surface of cells in association with MHC II.

12. Assembly of edogenous peptides with MHC-I (cytosolic pathway):
Peptides presented by MHC class I molecule are generated from cytosolic proteins (endogenous Ags).
Endogenous Ags proteins are processed & degraded by proteolytic activity of proteasomes in the cytoplasm,
then these peptides are of are transported by TAP(Transporter Protein) into endoplasmic reticulum (ER).
Inside ER, peptide loading involves other protein named calnexin which promote the assembly of stable MHC class I with peptide.
These fully assembled molecules are transported to golgi apparatus then to the cell surface.

14. Assembly of exogenous peptides with MHC-II (endocytic pathway):
Exogenous Ag enter the cell by phagocytosis or endocytosis.
The endocytic pathway appears to involve three increasingly acidic compartments: early endosomes late endosomes, or endolysosomes; and lysosomes.
Internalized antigen moves from early to late endosomes and finally to lysosomes,
within the compartments of the endocytic pathway,Ag is degraded into small peptides of
which bind to MHC II molecules.
Then the fully assembled MHC II-peptide complex is transported to the cell surface.