Subject : HLA-DO
In the name of God
Alireza Kazemi
Non-classical Play accessory roles in the antigen loading
process . Examples: HLA-DM , HLA-DO
Low Polymorphism
Classical
High Polymorphism
Bind to peptide antigens and present them to
T cells . Examples: HLA-DP , DQ , DR
Antigen Processing In MHC-II
Pathway
Has a well-understood function in catalyzing peptide
exchange on MHCII proteins
After CLIP release DM stabilizes the intermediate
empty MHC class II molecules
In Mice : H2M (H2DM)
HLA-DM Deficiency The ability of APCs to present
either protein or peptide antigen is severely
compromised.
Structure : Heterodimer (Alpha and Beta)
Gene Locus : HLA-DOA and HLA-DOB in MHC
class II region of the MHC gene complex
Not expressed at the cell surface
Has a high degree of similarity to classical class II
MHC
In RER:HLA-DO,DM and DR synthesis Transport to
Golgi and MIIC (MHC Class II Compartment)
DO and DM molecules always bind in a side-by-side
arrangement
HLA-DO has a limited tissue distribution :
B Lymphocytes
Thymic Medullary Epithelial Cells
Trophoblasts
Subpopulations of dendritic cells(especially BCDA3+
plasmacytoid DCs)
Human dendritic cells cultured with GM-CSF have
been reported to express HLA-DO
HLA-DO is not induced by the class II transactivator (CIITA)
In mice: H2-O
Forms a tight complex with DM and inhibit it
Might play a role in tolerance induction
DO functions as a substrate mimic, by binding tightly
to DM and preventing MHCII access,In result :
kinetic studies show that DO acts as competitive
inhibitor of DM
HLA-DO expresion power of inhibitory
Overall :
HLA DR-DM-DO Ag peptide not expressed
at the cell surface
HLA DR-DM Ag peptide expressed
at the cell surface
In B cells and dendritic cells DO expression is
developmentally regulated :
In Bcells :Initiation of production High expresion
B cells in germinal center Down-regulated
expression
In DCs : DC + Ag = Mature DC Down regulated
expresion
This expression pattern has suggested a role for DO in
promoting tolerance to self-antigens
The observations show that HLA-DO is selectively expressed
in B cells and thymic medullary epithelial cells raises the
interesting possibility that this molecule might play a role in
tolerance induction
This idea supported by suppression of autoimmune diabetes
in H-2O transgenic non-obsese diabetic (NOD) mice :
Transport of over-expressed HLA-DO genes to NOD
mice CD11c+ DCs Formation of NOD-DO
transgenic mice
Autoimunediabet Not developed
Then : NOD-DO Tcells were transferred into NOD-SCID hosts
(lacking T and B cells) Autoimune diabet
developed
CONCLUSION : Overexpressed DO in DCs did not prevent diabetogenic Tcells from forming but
prevented their pathogenic effects
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