Shared and individual specificities of immunodominant cytotoxic T-cell clones in paroxysmal nocturnal hemoglobinuria as determined by molecular analysis

Similar immune mechanisms have been suggested to operate in aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH), and the presence of PNH clones in AA may indicate that an immune reaction directed against hematopoietic stem cells may be responsible for the immune selection pressure lea...

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Bibliographic Details
Published in:Experimental hematology 2004-03, Vol.32 (3), p.261-269
Main Authors: Plasilova, Magdalena, Risitano, Antonio M, O'Keefe, Christine L, Rodriguez, Alexander, Wlodarski, Marcin, Young, Neal S, Maciejewski, Jaroslaw
Format: Article
Language:English
Subjects:
Adult
Aged
Anemia, Aplastic - complications
Anemia, Aplastic - immunology
Autoimmune Diseases - immunology
Clone Cells - immunology
Complementarity Determining Regions - genetics
Disease Progression
DNA, Complementary - genetics
Female
Gene Rearrangement, beta-Chain T-Cell Antigen Receptor
Glycosylphosphatidylinositols - deficiency
Hemoglobinuria, Paroxysmal - complications
Hemoglobinuria, Paroxysmal - genetics
Hemoglobinuria, Paroxysmal - immunology
Humans
Immunodominant Epitopes - immunology
Male
Membrane Proteins - genetics
Middle Aged
Polymerase Chain Reaction
Receptors, Antigen, T-Cell, alpha-beta - genetics
T-Lymphocytes, Cytotoxic - immunology
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Summary:Similar immune mechanisms have been suggested to operate in aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH), and the presence of PNH clones in AA may indicate that an immune reaction directed against hematopoietic stem cells may be responsible for the immune selection pressure leading to PNH evolution. We previously described expansions of selective cytotoxic T-lymphocyte (CTL) clones in AA patients. We applied a molecular analysis of the T-cell receptor repertoire to study the characteristics of CTL response in patients with various forms of PNH. Immunodominant T-cell clones were detected using combined flow cytometric and molecular analysis of the variable beta (VB) chain and CDR3 representation, followed by determination of the frequency of individual CDR3 clonotypes. Clonotypic polymerase chain reaction (PCR) was performed to establish clonotypic utilization pattern. In patients with a past history of AA, and when subgrouped by current blood counts as “hypoproliferative” PNH patients (in contrast to purely hemolytic form of PNH), more pronounced skewing of VB family utilization was found, consistent with T-cell responses involving several immunodominant CTL clones. Sequences of the PNH-derived clonotypes were used to design PCR-based assays for the utilization analysis of individual clones in PNH patients. The clonotypic distribution pattern established by this PCR method indicated that immunodominant T-cell specificities were shared between some patients but also may be found at low frequencies in controls. Analysis of the CDR3 sequence pattern as a marker for expanded immunodominant clonotypes may have an application in the study of T-cell responses in PNH.
ISSN:0301-472X
1873-2399
DOI:10.1016/j.exphem.2003.11.011