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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
Autoimune
diabet 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
HLA-DO

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HLA-DO

  • 1. Subject : HLA-DO In the name of God Alireza Kazemi
  • 2. 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
  • 3. Antigen Processing In MHC-II Pathway
  • 4. 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.
  • 5.
  • 6. Structure : Heterodimer (Alpha and Beta) Gene Locus : HLA-DOA and HLA-DOB in MHC class II region of the MHC gene complex
  • 7.  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
  • 8.
  • 9. 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
  • 10.  HLA-DO is not induced by the class II transactivator (CIITA)  In mice: H2-O
  • 11. Forms a tight complex with DM and inhibit it Might play a role in tolerance induction
  • 12. 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
  • 13.  Overall : HLA DR-DM-DO Ag peptide not expressed at the cell surface HLA DR-DM Ag peptide expressed at the cell surface
  • 14.
  • 15.  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
  • 16.
  • 17.  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 :
  • 18.  Transport of over-expressed HLA-DO genes to NOD mice CD11c+ DCs Formation of NOD-DO transgenic mice Autoimune diabet 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