Association of HLA Haplotypes with Paroxysmal Nocturnal Hemoglobinuria

Nowak, Jacek; Witkowska, Agnieszka; Mendek-Czajkowska, Ewa; Rogatko-Koroś, Marta; Graczyk‐Pol, Elżbieta; Pyl, Hanna; Klimczak, A.; Wójcik, Małgorzata; Nowak, Emilia; Długokęcka, Agnieszka; Prochorec, Monika; Zupańska, B

doi:10.1016/j.transproceed.2010.07.030

Cited by 10 publications

(9 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Our previous analysis of HLA haplotypes in PNH suggested independent roles of class I and II molecules in PNH pathogenesis (Nowak et al 2010) and justified the assumptions on different mechanisms of HLA class I and II association with PNH subtypes. It has been shown the B*18:01 allele to be specific restrictive element for immunodominating octapeptide GEDGRVYV, a fragment 753-760 of phosphatidylinositol-activated phospholipase D (PLD) (Papadopoulos et al 1996; Protein Information Resource Georgetown University Medical Center 2010).…”

Section: Other Possible Explanationssupporting

confidence: 70%

The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

Nowak

Mika‐Witkowska

Mendek-Czajkowska

et al. 2011

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

The deficiency of glycosyl-phosphatidylinositol (GPI)-anchored proteins in plasma membranes of PIG-A gene mutated hematopoietic stem cells (HSCs) is so far insufficient to explain the domination of paroxysmal nocturnal hemoglobinuria (PNH) clone over the normal HSC. We attempted to elucidate possible link between MHC and initial severe aplastic anemia (ISAA/PNH) type and non-aplastic (n/PNH) outcome of PNH. In 50 PNH patients assigned as ISAA/PNH (n = 13), n/PNH (n = 33) or nonassigned (n = 4) and 200 ethnically matched controls we analyzed MHC associations. Our data confirmed strong associations of DRB1*15:01 (RR = 3.51, p = 0.0011) and DQB1*06:02 (RR = 7.09, p = 0.000026) alleles, especially with n/PNH subtype. B*18:01 allele was associated with increased risk of ISAA/PNH subtype (RR = 5.25, p = 0.0028). We conclude that both class II and class I MHC alleles are associated with different subsets of PNH. Clonal selection of PIG-A mutated cells with cognate metabolic block is associated with MHC class II alleles DRB1*15:01 and DQB1*06:02 independent from initial severe AA clone selection. MHC class I molecule B*18:01 can additionally influence the domination of PNH clone in PNH subjects with initial severe aplastic anemia.

show abstract

Section: Other Possible Explanationssupporting

confidence: 70%

The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

Nowak

Mika‐Witkowska

Mendek-Czajkowska

et al. 2011

Arch. Immunol. Ther. Exp.

View full text Add to dashboard Cite

show abstract

“…Our previous results indicated the association of MHC class I A*24:02 (protection) and B*18:01 (susceptibility) alleles with AA/PNH subtype and the strong association of MHC class II DRB1*15:01 and DRB1*04:01 alleles and DRB1*15:01 - DQB1*06:02 haplotype with both total PNH and non-aplastic PNH (n/PNH) subtype [24, 25]. …”

Section: Methodsmentioning

confidence: 99%

“…In Italian PNH patients an increased frequency of the B*14:02 - Cw*08:02 haplotype has been additionally suggested [22], indicating the role for MHC class I genes, at least in certain PNH subtypes. In our center, for the more uniform aplastic anemia PNH (AA/PNH) subtype the association with MHC class I B*18:01 allele has been recently revealed and for A*24:02 allele the protective role has been documented [24, 25]. …”

Section: Introductionmentioning

confidence: 99%

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

Nowak¹,

Woźniak

Mendek-Czajkowska

et al. 2012

Cell Biochem Biophys

View full text Add to dashboard Cite

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.Electronic supplementary materialThe online version of this article (doi:10.1007/s12013-012-9435-1) contains supplementary material, which is available to authorized users.

show abstract

“…In the case of the latter, GPI-AP deficiency itself may be important in helping the cell evade pro-apotoptic signals in certain circumstances whereas normal cells may not, allowing the mutant PIGA clone to expand (29,30). 10 clear that those patients who develop the largest population of type III erythrocytes will have more clinically significant disease (23).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome

Wong

Kavanagh

2015

Translational Research

View full text Add to dashboard Cite

The complement inhibitor eculizumab is a humanized monoclonal antibody against C5. It was developed to specifically target cleavage of C5 thus preventing release of C5a and activation of the terminal pathway. Paroxysmal nocturnal hemoglobinuria (PNH) and atypical hemolytic uremic syndrome (aHUS) are 2 diseases with distinctly different underlying molecular mechanisms. In PNH, progeny of hematopoietic stem cells that harbor somatic mutations lead to a population of peripheral blood cells that are deficient in complement regulators resulting in hemolysis and thrombosis. In aHUS, germline mutations in complement proteins or their regulators fail to protect the glomerular endothelium from complement activation resulting in thrombotic microangiopathy and renal failure. Critical to the development of either disease is activation of the terminal complement pathway. Understanding this step has led to the study of eculizumab as a treatment for these diseases. In clinical trials, eculizumab is proven to be effective and safe in PNH and aHUS.

show abstract

Association of HLA Haplotypes with Paroxysmal Nocturnal Hemoglobinuria

Cited by 10 publications

References 27 publications

The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

The Patterns of MHC Association in Aplastic and Non-aplastic Paroxysmal Nocturnal Hemoglobinuria

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

Anticomplement C5 therapy with eculizumab for the treatment of paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome

Contact Info

Product

Resources

About