1. In-vivo dominant immune responses in aplastic anaemia: molecular tracking of putatively pathogenetic T-cell clones by TCR Β-CDR3 sequencing.
- Author
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Risitano, Antonio M., Maciejewski, Jaroslaw P., Green, Spencer, Plasilova, Magdalena, Zeng, Weihua, and Young, Neal S.
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APLASTIC anemia , *BONE marrow , *BLOOD cells , *IMMUNOSUPPRESSION , *SUPPRESSOR cells , *IMMUNOLOGY , *IMMUNOREGULATION , *LYMPHOCYTES , *T cells , *BLOOD diseases , *DISEASE risk factors - Abstract
Background Aplastic anaemia is a bone-marrow-failure syndrome characterised by low blood-cell counts and fatty bone marrow. In most cases, no obvious aetiological factor can be identified. However, clinical responses to immunosuppression strongly suggest an immune pathophysiology. Methods To test the hypothesis that aplastic anaemia results from antigen-specific lymphocyte attack against haemopoietic tissue, we analysed effector immunity, seeking especially dominant specific T-cell responses. Blood samples from 54 patients with aplastic anaemia were subjected to flow cytometry to define T-cell-receptor V -chain usage and expansion of particular V subsets. We measured the size distribution of the complementarity determining region 3 (CDR3) for expanded V subsets, then cloned and sequenced skewed, oligoclonal, or monoclonal peaks. Findings Expanded V subsets were identified in almost all the patients. Over-represented V subsets from CD8-positive cells showed oligoclonal or monoclonal CDR3 size patterns. The CDR3 sequence repertoire in aplastic anaemia showed much redundancy compared with healthy donors. We identified patient-specific putative pathogenetic clonotypes that were not detectable in controls. In selected patients who were assessed longitudinally, these clonotypes were quantitatively related to disease activity. Selective killing of autologous haemopoietic progenitors by the V -specific lymphocyte population was shown in one patient. These apparently pathogenetic CDR3 sequences showed homology between individuals, suggesting a role for a "semi-public" immune response in the pathophysiology of aplastic anaemia. Interpretation In-vivo dominant clonal immune response can be identified in many patients with aplastic anaemia, which is evidence for an underlying antigen-driven immune process. [ABSTRACT FROM AUTHOR]
- Published
- 2004
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