Potential link between MHC-self-peptide presentation and hematopoiesis; the analysis of HLA-DR expression in CD34-positive cells and self-peptide presentation repertoires of MHC molecules associated with paroxysmal nocturnal hemoglobinuria.
The mechanisms of MHC allele associations with paroxysmal nocturnal hemoglobinuria (PNH) and its aplastic anemia subtype (AA/PNH) remain unclear. It might be dependent on MHC molecule functional properties, such as a scope and frequency of antigen sampling and presentation. For documented PNH-associated MHC alleles we analyzed current reference databases on MHC molecule-eluted peptide presentation repertoires and searched for a range of presented peptides. MHC class II expression was measured on CD34+ cells and appeared to be increased in PNH patients. Two class I alleles (HLA-A*24:02 and B*18:01) have been previously confirmed to associate with protection and increased risk of AA/PNH, respectively. Their product molecules presented immunodominant epitopes derived from proapoptotic (serine/threonine-protein phosphatase) and antiapoptotic (phospholipase D), respectively, intracellular enzymes dependent on phosphoinositide (PI) content. For total PNH and non-aplastic PNH (n/PNH) subtype-associated DRB1*15:01 and DRB1*04:01 class II molecules presentation of exceptionally broad arrays of their own peptide fragments has been found. We conclude that self antigen peptides presented with high frequency in the context of MHC molecules of increased expression may be involved in the immune recognition and the regulation of HSC in the periphery. The block in the normal plasma membrane PI production due to the PIG-A mutation can help explain the differences in the activation of intracellular regulatory pathways observed between PNH and normal HSC. This is evident in the variation in MHC association patterns and peptide presentation repertoires between these two groups of patients.
Department of Immunogenetics Institute of Hematology and Transfusion Medicine, 14 Indira Gandhi Street, 02-776, Warsaw, Poland. szpik@ihit.waw.pl
Jacek
J
Nowak
Jolanta
J
Wozniak
Ewa
E
Mendek-Czajkowska
Agnieszka
A
Dlugokecka
Renata
R
Mika-Witkowska
Marta
M
Rogatko-Koros
Elzbieta
E
Graczyk-Pol
Anna
A
Marosz-Rudnicka
Joanna
J
Dziopa
Agnieszka
A
Golec
Joanna
J
Kopec-Szlezak
Krzysztof
K
Warzocha
D000328:Adult; D000368:Aged; D000483:Alleles; D000595:Amino Acid Sequence; D000741:Anemia, Aplastic / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D018952:Antigens, CD34 / Q000378:metabolism; D005260:Female; D059871:HLA-A24 Antigen / Q000235:genetics / Q000378:metabolism; D015235:HLA-B Antigens / Q000235:genetics / Q000378:metabolism; D059811:HLA-DRB1 Chains / Q000235:genetics* / Q000378:metabolism; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism; D006457:Hemoglobinuria, Paroxysmal / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*
D018952:Antigens, CD34; C438506:HLA-A*24:02 antigen; D059871:HLA-A24 Antigen; D015235:HLA-B Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; C489631:HLA-DRB1*15:01 antigen; D000949:Histocompatibility Antigens Class II; D010455:Peptides