Dendritic cells in patients with type I Gaucher disease are decreased in number but functionally normal.

Gaucher disease is a lysosomal storage disorder, in which undigested glucosylceramide is deposited in the cytoplasm of mature macrophages, which accumulate in the bone marrow and the reticuloendothelial system. Dendritic cells are bone marrow-derived cells, specialized for the uptake, processing, transport and presentation of antigens to T-lymphocytes. We investigated peripheral blood dendritic cell-precursors, as well as the potential of peripheral blood monocytes and bone marrow-derived progenitor cells, to differentiate into mature dendritic cells in 12 patients with type I Gaucher disease. Results of the 10 adult patients were compared with those of 10 healthy volunteers, matched for age and sex. Six patients were anemic and 9 were thrombocytopenic, but none had severe bone disease. Both myeloid and plasmacytoid dendritic cells of patients with Gaucher disease, as well as the yield of the monocyte-derived dendritic cells, obtained after GM-CSF and IL-4 stimulation, were found significantly decreased, when compared to controls (myeloid dendritic cells: 0.19 +/- 0.07% vs. 0.34 +/- 0.10%, P = 0.009, plasmacytoid dendritic cells: 0.17 +/- 0.12% vs. 0.39 +/- 0.13%, P = 0.004, monocyte-derived dendritic cells: 4.8 +/- 3.5% vs. 8.3 +/- 3.2%, P = 0.036). However, the immunophenotypic profile of dendritic cells, estimated by CD1a, CD40, CD54, CD80, CD83 and HLA-DR expression, the endocytic and allo-stimulatory capacity of the immature, as well as of the TNF-alpha- or lipopolysaccharite-stimulated mature monocyte-derived dendritic cells, was similar to those obtained by healthy controls. In addition, bone marrow-derived CD34+ cells differentiated in the presence of GM-CSF, SCF, TNF-alpha and IL-4 into mature dendritic cells that did not differ in number, phenotype and allo-stimulatory activity from those of controls. Our findings suggest that patients with Gaucher disease exhibit mainly quantitative defects of their dendritic cells' system, demonstrated by decreased circulating dendritic cell precursors of both myeloid and plasmacytoid type. This finding may contribute to the poor immune response against infectious agents and an impaired immune surveillance, associated with an increased risk of developing a neoplastic disease.

Transient abnormal myelopoiesis of infancy associated with trisomy 21.

PURPOSE: A unique myelodysplastic syndrome referred to as transient abnormal myelopoiesis (TAM) has been reported to occur primarily in infants with Down's syndrome (DS) or other abnormalities of chromosome 21. This disorder raises basic questions regarding the pathogenesis of leukemia, yet its natural history is poorly documented and derives from small series and isolated case reports. PATIENTS AND METHODS: To better characterize TAM, we accumulated data on 35 cases identified through a questionnaire mailed to pediatric oncologists in the United States. These cases, pooled with two that we recently encountered, and 58 comparable cases reported in the literature comprise a series of 95 cases of TAM in DS. RESULTS: The patients in this series were notable for the high morbidity and mortality of this reportedly benign condition. Eleven percent of the patients died during the initial event, and the overall mortality for the entire series was 27%. Twenty-eight of the 85 patients (33%) who survived the initial event developed a subsequent hematologic disorder, most often acute nonlymphocytic leukemia, at a median age of 16 months. CONCLUSIONS: No initial clinical or hematologic features predicted the development of a subsequent hematologic disorder. However, those patients initially mosaic for the presence of trisomy 21 did not develop subsequent abnormalities. This series reviews questions regarding leukemogenesis in DS and underscores the importance of conducting future prospective studies of this unique hematologic disorder.

Progressive morphological abnormalities observed in rat spinal motor neurons at extended intervals after axonal regeneration.

It is generally accepted that mammalian spinal motor neurons return to normal after axotomy if their regenerated axons successfully reinnervate appropriate peripheral targets. However, morphological abnormalities, recently observed in spinal motor neurons examined 1 year after nerve crush injury, raise the possibility that delayed perikaryal changes occur after regeneration is complete. In order to distinguish between chronic and progressive alterations in neurons with long-term regenerated axons, rat spinal motor neurons and dorsal root ganglion cells were examined at 5 and 10 months following unilateral sciatic nerve crush. Neurons with regenerated axons were identified by retrograde labelling with horseradish peroxidase. The structural properties of neurons ipsilateral to nerve injury were compared to those of neurons from the spinal cord and dorsal root ganglia on the contralateral side and from age-matched control rats. At 5 months postcrush, the morphology of motor and sensory neurons ipsilateral to injury was comparable to that of control cells. However, several features of the motor neurons with regenerated axons distinguished them from control motor neurons at 10 months postcrush. Mean perikaryal area of ipsilateral spinal motor neurons was larger than the means for control motor neurons (p less than .001). Ipsilateral spinal motor neurons also appeared clustered within the spinal cord and had thicker dendrites. Dorsal root ganglion cells with regenerated axons were slightly larger than control cells at 10 months postcrush but they exhibited no other morphological changes. The present findings indicate that spinal motor neurons are progressively altered after their regenerated axons have reestablished functional synapses with their peripheral targets.