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