Although no single, indisputable feature can reliably differentiate PFM from LAFM and a considerable overlapping among the two groups exists, the use of multiple clinical, histological and immunopathological criteria associated with gene rearrangement analysis can be useful in evaluation of those patients.

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Deficiency of glycosylphosphatidylinositol (GPI)-anchored molecules on blood cells accounts for most features of paroxysmal nocturnal hemoglobinuria (PNH) but not for the expansion of PNH (GPI ؊ ) clone(s).A plausible model is that PNH clones expand by escaping negative selection exerted by autoreactive T cells against normal (GPI ؉ ) hematopoiesis. By a systematic analysis of T-cell receptor beta (TCR-␤) clonotypes of the CD8 ؉ CD57 ؉ T-cell population, frequently deranged in PNH, we show recurrent clonotypes in PNH patients but not in healthy controls: 11 of 16 patients shared at least 1 of 5 clonotypes, and a set of closely related clonotypes was present in 9 patients. The presence of T-cell clones bearing a set of highly homologous TCR-␤ molecules in most patients with hemolytic PNH is consistent with an immune process driven by the same (or similar) antigen(s)-probably a nonpeptide antigen, because patients sharing clonotypes do not all share identical HLA alleles. These data confirm that CD8 ؉ CD57 ؉ T cells play a role in PNH pathogenesis and provide strong new support to the hypothesis that the expansion of the GPI ؊ blood cell population in PNH is due to selective damage to normal hematopoiesis mediated by an autoimmune attack against a nonpeptide antigen(s) that could be the GPI anchor itself. IntroductionParoxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder of the hematopoietic stem cell (HSC) 1 characterized by 3 clinical hallmarks: intravascular hemolysis, tendency to venous thrombosis, and variable degrees of bone marrow failure. [2][3][4] The primary molecular lesion responsible for PNH is a somatic mutation of the X-linked PIGA gene in HSCs, 5,6 resulting in either complete or partial deficiency of all glycosylphosphatidylinositol (GPI)-linked proteins from the cell membrane of the progeny of the mutated HSC (GPI Ϫ ). 7,8 The deficiency of the GPI-linked proteins (including the complement-regulating proteins CD59 and CD55) from the surface of blood cells explains the intravascular hemolysis 9 and probably underlies the increased tendency to venous thrombosis. 10 However, a PIGA gene mutation per se does not explain the bone marrow failure and the expansion of the GPI Ϫ clone. In fact, very rare GPI Ϫ blood cells are present in healthy subjects, 11 but only in PNH patients do the GPI Ϫ cells expand and contribute to hematopoiesis to various degrees, side by side with normal (GPI ϩ ) hematopoiesis. 12,13 Clinical observations, 14,15 in vitro hematopoietic colony studies, 16,17 and data from PNH mouse models [18][19][20] indicate that GPI Ϫ HSCs do not have an absolute growth advantage. The close relationship of PNH to idiopathic aplastic anemia (IAA) has suggested that autoreactive T cells against HSCs believed to be responsible for IAA may be at work also in PNH. Specifically, it has been hypothesized that in PNH autoreactive T cells destroy selectively GPI ϩ (normal) HSCs, whereas GPI Ϫ (PNH)HSCs can escape T-cell-mediated damage, thus being able to survive and expand. 21 In r...

Although the progression of chronic lymphocytic leukemia (CLL) requires the cooperation of the microenvironment, the exact cellular and molecular mechanisms involved are still unclear. We investigated the interleukin (IL)-23 receptor (IL-23R)/IL-23 axis and found that circulating cells from early-stage CLL patients with shorter time-to-treatment, but not of those with a more benign course, expressed a defective form of the IL-23R complex lacking the IL-12Rβ1 chain. However, cells from both patient groups expressed the complete IL-23R complex in tissue infiltrates and could be induced to express the IL-12Rβ1 chain when cocultured with activated T cells or CD40L cells. CLL cells activated in vitro in this context produced IL-23, a finding that, together with the presence of IL-23 in CLL lymphoid tissues, suggests the existence of an autocrine/paracrine loop inducing CLL cell proliferation. Interference with the IL-23R/IL-23 axis using an anti-IL-23p19 antibody proved effective in controlling disease onset and expansion in xenografted mice, suggesting potential therapeutic strategies.

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