Membranöse Glomerulopathie - eine Autoimmunerkrankung.

Membranous nephropathy is one of the most common glomerular diseases and leading causes of nephrotic syndrome in Caucasian adults. Known as a clinico-pathologic entity for over 50 years, it is defined by thickening of the glomerular capillary membrane with subepithelial immuncomplexes. Secondary forms (e. g. hepatitis B, autoimmune disease or medication-induced) are distinguished from idiopathic forms. Despite spontaneous remissions in about 30 % of cases, one third of idiopathic forms progress to end-stage renal disease after 10 years. Seminal research progress of the last decade has allowed the identification of autoantibodies directed against podocytary elements leading to secondary damage to the filtration barrier. The so-called idiopathic membranous nephropathy has thus become a prototype of autoimmune disease. The autoantibodies detectable in 70 - 80 % of cases of idiopathic membranous nephropathy are directed against the M-type phospholipase A2-receptor on the podocyte membrane and correlate with disease activity. These epochal findings influence on diagnostic and therapeutic strategies establishing a rationale for the use of B cell-directed therapy on top of optimal supportive therapy.

Hematopoietic and endothelial progenitor cell trafficking in patients with myeloproliferative diseases.

BACKGROUND AND OBJECTIVES: The presence of circulating hematopoietic progenitor cells in patients with myeloproliferative diseases (MPD) has been described. However, the exact nature of such progenitor cells has not been specified until now. The aim of this work was to investigate the presence of endothelial precursor cells in the blood of patients with MPD and to assess the role of the endothelial cell lineage in the pathophysiology of this disease. DESIGN AND METHODS: Endothelial progenitor cell marker expression (CD34, prominin (CD133), kinase insert domain receptor (KDR) or vascular endothelial growth factor receptor 2 (VEGFR2), and von Willebrand factor) was assessed in the blood of 53 patients with MPD by quantitative polymerase chain reaction. Clonogenic stem cell assays were performed with progenitor cells and monocytes to assess differentiation towards the endothelial cell lineage. The patients' were divided according to whether they had essential thrombocythemia (ET, n=17), polycythemia vera (PV, n=21) or chronic idiopathic myelofibrosis (CIMF, n=15) and their data compared with data from normal controls (n=16) and patients with secondary thrombo- or erythrocytosis (n=17). RESULTS: Trafficking of CD34-positive cells was increased above the physiological level in 4/17 patients with ET, 5/21 patients with PV and 13/15 patients with CIMF. A subset of patients with CIMF co-expressed the markers CD34, prominin (CD133) and KDR, suggesting the presence of endothelial precursors among the circulating progenitor cells. Clonogenic stem cell assays confirmed differentiation towards both the hematopoietic and the endothelial cell lineage in 5/10 patients with CIMF. Furthermore, the molecular markers trisomy 8 and JAK2 V617F were found in the grown endothelial cells of patients positive for trisomy 8 or JAK2 V617F in the peripheral blood, confirming the common clonal origin of both hematopoietic and endothelial cell lineages. INTERPRETATION AND CONCLUSIONS: Endothelial precursor cells are increased in the blood of a subset of patients with CIMF, and peripheral endothelial cells bear the same molecular markers as hematopoietic cells, suggesting a primary role of pathological endothelial cells in this disease.

Progenitor cell trafficking in physiologic conditions and in myeloproliferative diseases: quantification of CD34+ cells by polymerase chain reaction.

BACKGROUND AND OBJECTIVES: Previous studies using flow cytometry have shown that CD34+ cell trafficking is increased in patients with chronic idiopathic myelofibrosis. Few data exist on physiologic CD34 + cell trafficking and the quantification of very low cell ranges requires reliable and sensitive measurement techniques. The aim of this study was to establish a quantitative polymerase chain reaction (PCR) technique for studying CD34+ cell trafficking in physiologic conditions, and in patients with myeloproliferative diseases. DESIGN AND METHODS: CD34+ cell trafficking was measured in 56 controls [(healthy controls (n=21), patients with ischemic cardiopathy (n=21), patients with secondary thrombocytosis or erythrocytosis (n=14)], and in 37 untreated patients with myeloproliferative diseases diagnosed according to the WHO-criteria [(essential thrombocythemia (n=10), polycythemia vera (n=14) and chronic idiopathic myelofibrosis (n=13)]. Quantitative PCR was used to determine CD34 mRNA expression in peripheral blood samples. RESULTS: Physiologic CD34 mRNA expression ranges were determined in the healthy control group. Mean CD34 mRNA expression was within the physiologic range in patients with ischemic cardiopathy, secondary thrombocytosis or erythrocytosis, essential thrombocythemia and polycythemia vera (p=0.146), but was significantly increased in patients with chronic idiopathic myelofibrosis (p<0.001). When analyzed individually, 12/13 patients with chronic idiopathic myelofibrosis and 3/14 patients with polycythemia vera showed CD34 mRNA expression above the physiologic range. INTERPRETATION AND CONCLUSIONS: This is a first report about CD34+ cell trafficking measured by quantitative PCR. Quantitative PCR is a reliable method suitable for the quantification of very low cell populations. Our study confirms the significant increase of CD34+ cell trafficking in patients with chronic idiopathic myelofibrosis, and in a subset of patients with polycythemia vera. Prospective studies are underway to characterize these circulating CD34+ cells and to investigate their role in the pathophysiology of myeloproliferative diseases.