Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria
ABSTRACT The mechanism of bone marrow failure (BMF) in paroxysmal nocturnal hemoglobinuria (PNH) is not yet known. Since in PNH the biosynthesis of the glycolipid molecule glycosylphosphatidylinositol (GPI) is disrupted in hematopoietic stem and progenitor cells by a somatic mutation in the PIG-A gene, BMF might result from an auto-immune attack, whereby T-cells target GPI in normal cells, whereas PIG-A mutant GPI-negative cells are spared. In a deliberate test of this hypothesis, we have demonstrated in PNH patients the presence of CD8+ T-cells reactive against antigen presenting cells (APC) loaded with GPI. These T cells were significantly more abundant in PNH patients than in healthy controls, their reactivity depended on CD1d expression and they increased upon co-culture with CD1d-expressing, GPI-positive APC. In GPI-specific T-cells captured by CD1d dimer technology, we identified, through global T-cell receptor alpha (TCRα) analysis, an invariant TCRVα21 sequence, which was then found at frequencies higher than background in the TCR repertoire of 6 out of 11 PNH patients. Thus, a novel, autoreactive, CD1d-restricted, GPI-specific T-cell population, enriched in an invariant TCRα chain, is expanded in PNH patients and may be responsible for BMF in PNH.
- Blood 08/2013; 122(7):1099-100. DOI:10.1182/blood-2013-06-508556 · 10.43 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired bone marrow disorder caused by expansion of a clone of hematopoietic cells lacking glycosylphosphatidylinositol (GPI)-anchored membrane proteins. Multiple lines of evidence suggest immune attack on normal hematopoietic stem cells provides a selective growth advantage to PNH clones. Recently, frequent loss of HLA alleles associated with copy number-neutral loss of heterozygosity in chromosome 6p (CN-6pLOH) in aplastic anemia (AA) patients was reported, suggesting that AA hematopoiesis “escaped” from immune attack by loss of HLA alleles. We report here the first case of CN-6pLOH in a Japanese PNH patient only in GPI-anchored protein positive (59%) granulocytes but not in GPI-anchored protein negative (41%) granulocytes. CN-6pLOH resulted in loss of the alleles A*02:06-DRB1*15:01-DQB1*06:02, which have been reported to be dominant in Japanese PNH patients. Our patient had maintained nearly normal blood count for several years. Our case supports the hypothesis that a hostile immune environment drives selection of resistant hematopoietic cell clones, and indicates that clonal evolution may occur also in normal phenotype (non-PNH) cells in some cases. This article is protected by copyright. All rights reserved.European Journal Of Haematology 12/2013; 92(5). DOI:10.1111/ejh.12253 · 2.41 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Introduction: The treatment of paroxysmal nocturnal hemoglobinuria (PNH) has been drastically changed by the introduction of the first therapeutic complement inhibitor eculizumab: 13 years of clinical experience have clearly proven that clinical complement inhibition is feasible, safe and potentially effective. At the same time, a number of observations have been collected showing that current anti-complement treatment is suitable for further improvements, especially for PNH, where extravascular hemolysis secondary to the activation of early complement has emerged as a novel unmet clinical need.Areas covered: Here we discuss publicly available information on second generation of complement therapeutics, which are currently in preclinical or clinical investigations. These agents are characterized by a broad target spectrum, since they inhibit the complement cascade at different levels: indeed, they include agents targeting component 5 as the key event of the terminal effector complement, as well as compounds designed to intercept the early steps of complement activation.Expert opinion: The field of therapeutic complement inhibition is growing rich with the development of several agents; the most promising approaches have already started their clinical development. It is conceivable that in the near future some of these strategies may offer improved therapeutic options for PNH and other complement-mediated human disorders.02/2014; 8(6):43-52. DOI:10.1517/21678707.2015.1041376