HSC-independent definitive hematopoiesis persists into adult life.

It is widely believed that hematopoiesis after birth is established by hematopoietic stem cells (HSCs) in the bone marrow and that HSC-independent hematopoiesis is limited only to primitive erythro-myeloid cells and tissue-resident innate immune cells arising in the embryo. Here, surprisingly, we find that significant percentages of lymphocytes are not derived from HSCs, even in 1-year-old mice. Instead, multiple waves of hematopoiesis occur from embryonic day 7.5 (E7.5) to E11.5 endothelial cells, which simultaneously produce HSCs and lymphoid progenitors that constitute many layers of adaptive T and B lymphocytes in adult mice. Additionally, HSC lineage tracing reveals that the contribution of fetal liver HSCs to peritoneal B-1a cells is minimal and that the majority of B-1a cells are HSC independent. Our discovery of extensive HSC-independent lymphocytes in adult mice attests to the complex blood developmental dynamics spanning the embryo-to-adult transition and challenges the paradigm of HSCs exclusively underpinning the postnatal immune system.

Mast Cell Repopulating Ability Is Lost During the Transition From Pre-HSC to FL HSC.

Recent advances in developmental immunology have revealed a hematopoietic stem cell (HSC)-independent origin for various innate immune lineages, including mast cells (MCs). It is now established that adult bone marrow (BM) long-term HSCs do not regenerate MCs but, instead, the physiological production of MCs starts before the emergence of HSCs in the aorta-gonad-mesonephros (AGM) region and is mostly completed before birth. However, while the AGM region represents a major site of MC generation during ontogeny, whether the first emerging HSCs in the AGM or fetal liver (FL) possess the potential to regenerate MCs is unknown. Here, we combined three fate-mapping mouse models with detailed HSC transplantation assays to determine the potential of AGM and FL HSCs to produce MCs. We show that HSCs from E11.5 AGM and E12.5 FL efficiently repopulated MCs in recipients. In stark contrast, HSCs from ≥E14.5 FL failed to reconstitute MCs. An Endothelial (EC) fate-mapping study confirmed the EC origin of the majority of MCs. Additionally, our HSC-labeling showed that HSCs do not produce MCs in a physiological setting. Hence, although most MCs are generated and maintained via an HSC-independent pathway, the earliest HSCs to emerge in the AGM and seed the early FL can produce MCs, but only during a minimal time window. Our results challenge the stem cell theory in hematology and EC-derived mast cells may contribute to the pathogenesis of postnatal mast cell disorders.

Correlation of serum levels of complement C4a desArg with pathologically estimated severity of glomerular lesions and mesangial hypercellularity scores in patients with IgA nephropathy.

The aim of the present study was to explore serum biomarkers for the pathology of IgA nephropathy using serum proteomics. The subjects were 57 patients with IgA nephropathy who were divided into two groups (group 1, n=25; group 2, n=32) and 14 healthy controls. Serum protein profiles were analyzed using the ProteinChip surface-enhanced laser desorption ionization (SELDI) system. Associations between signal intensities of proteins and histological findings in patients with IgA nephropathy were studied in group 1. Serum levels of a candidate biomarker protein (complement component C4a desArg) for IgA nephropathy were determined by enzyme linked-immunosorbent assay (ELISA) in group 2 and the relationships of these levels with histological findings were evaluated. There were significant differences in 93 protein signals between patients in group 1 and controls. Among these signals, 3 proteins at 8592, 8757 and 8806 m/z were significantly correlated with the severity of glomerular lesions. The protein at 8592 m/z was identified as C4a desArg and the signal intensity of 8592 m/z was strongly correlated with serum C4a levels, including C4a desArg, determined by ELISA. In addition, the serum levels of C4a (mainly C4a desArg) were significantly higher in patients in group 2 compared to controls and were correlated with the severity of glomerular lesions and with mesangial hypercellularity scores. In conclusion, the serum levels of complement C4a desArg are significantly higher in patients with IgA nephropathy compared to healthy controls and are significantly correlated with the severity of glomerular lesions and mesangial hypercellularity scores. Thus, serum C4a desArg is a potential biomarker for the severity of histological findings in patients with IgA nephropathy.

High serum thioredoxin levels are reduced after tonsillectomy in patients with IgA nephropathy.

OBJECTIVE: The role of oxidative stress in IgA nephropathy (IgAN), the most common type of primary glomerulonephritis, is unknown. We evaluated the clinical significance of serum levels of oxidative stress markers, thioredoxin (TRX) and manganese superoxide dismutase (MnSOD), in patients with IgAN. METHODS: Forty-eight patients with histologically confirmed IgAN and 14 healthy subjects were enrolled in this study. Serum samples from 14 IgAN patients were obtained after tonsillectomy, a procedure hypothesized to be an effective treatment for IgAN. RESULTS: Serum TRX levels were significantly higher in patients with IgAN than in healthy subjects (mean [ng/mL]; 49.5 vs.14.4, p<0.001). Serum TRX levels are positively correlated with blood urea nitrogen, serum uric acid and proteinuria, and negatively with estimated glomerular filtration rate (eGFR). In addition, serum TRX levels gradually increased as the severity of renal histology increased. High levels of serum TRX were significantly decreased after tonsillectomy in patients with IgAN (mean [ng/mL]; 55.5 to 41.1, p=0.02). In contrast, serum MnSOD levels did not differ between IgAN patients and healthy subjects, and these levels did not change after tonsillectomy in IgAN patients. CONCLUSION: Serum TRX is associated with IgAN, and tonsillectomy may decrease oxidative stress in IgAN patients, leading to clinical improvement.

Insulin-like growth factor binding protein-1 levels are increased in patients with IgA nephropathy.

The mechanisms underlying the pathogenesis of immunoglobulin A (IgA) nephropathy (IgAN) are not well understood. In this study, we examined gene expression profiles in kidneys obtained from mice with high serum IgA levels (HIGA mice), which exhibit features of human IgAN. Female inbred HIGA, established from the ddY line, were used in these experiments. Serum IgA levels, renal IgA deposition, mesangial proliferation, and glomerulosclerosis were increased in 32-week-old HIGA mice in comparison to ddY animals. By microarray analysis, five genes were observed to be increased by more than 2.5-fold in 32-week-old HIGA in comparison to 16-week-old HIGA; these same five genes were decreased more than 2.5-fold in 32-week-old ddY in comparison to 16-week-old ddY mice. Of these five genes, insulin-like growth factor (IGF) binding protein (IGFBP)-1 exhibited differential expression between these mouse lines, as confirmed by quantitative RT-PCR. In addition, serum IGFBP-1 levels were significantly higher in patients with IgAN than in healthy controls. In patients with IgAN, these levels correlated with measures of renal function, such as estimated glomerular filtration rate (eGFR), but not with sex, age, serum IgA, C3 levels, or IGF-1 levels. Pathologically, serum IGFBP-1 levels were significantly associated with the severity of renal injury, as assessed by mesangial cell proliferation and interstitial fibrosis. These results suggest that increased IGFBP-1 levels are associated with the severity of renal pathology in patients with IgAN.

Clinical significance of alanine aminotransferase levels and the effect of ursodeoxycholic acid in hemodialysis patients with chronic hepatitis C.

BACKGROUND: The natural history of hepatitis C virus (HCV) carriers and the effect of ursodeoxycholic acid (UDCA) have not been fully elucidated among hemodialysis (HD) patients. METHODS: Eighty-four anti-HCV antibody- and HCV RNA-positive and 154 anti-HCV antibody-negative HD patients who were retrospectively observed for at least 3 years were analyzed. We investigated the factors associated with thrombocytopenia (< 1.3 x 10(5)/microL) and decreased platelet count (PLT) (more than 20% decrease during the follow-up period), which were considered to be indicators of hepatic fibrosis. In addition, another 16 HD patients with HCV who received 300 mg/day UDCA orally for at least 6 months were investigated. Changes in alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transpeptidase (GGT) and PLT were assessed. RESULTS: After the 60.3-months mean follow-up period, HCV infection was independently associated with both thrombocytopenia [odds ratio (OR) 2.589] and decreased PLT (OR 2.339) in 238 HD patients. In 84 HD patients with HCV, the average ALT levels (> or = 15 IU/L) during the follow-up period was associated with thrombocytopenia (OR 3.882) and decreased PLT (OR 4.470). In addition, ALT, AST and GGT significantly decreased at 6 months after starting UDCA, but PLT did not change in 16 HD patients with HCV. CONCLUSIONS: These results indicate that HCV infection is a risk for thrombocytopenia which should be associated with hepatic fibrosis in HD patients. In addition, the clinical course of ALT levels predicts the progression of thrombocytopenia, and UDCA may effectively lower ALT levels in HD patients with HCV.

[Case of multiple nodular lesions of bilateral kidneys with IgG4-related systemic disease].

A 59-year-old woman was admitted to our hospital because of a pancreatic mass lesion. Serum gamma-globulin and IgG4 levels were elevated to 2.2 g/dL and 1,310 mg/dL, respectively. Computed tomography examination revealed multiple low-density areas without enhancement by contrast in the pancreatic body and bilateral kidneys. Endoscopic retrograde cholangiopancreatography images demonstrated diffuse narrowing of the main pancreatic duct with an irregular wall from the body to the tail of the pancreas. Positron emission tomography examination revealed intense 18F-fluorodeoxyglucose uptake by the pancreas and kidneys. Accordingly, the patient was diagnosed as having IgG4-related autoimmune pancreatitis. In addition, the findings of a renal tissue specimen obtained by biopsy demonstrated IgG4-positive plasma cell infiltration in both abnormal mass lesions and normal regions by imaging, leading to the final diagnosis of IgG4-related sclerotic disease. The patient was treated with prednisolone (30 mg/day), and the size of the pancreatic and renal lesions markedly decreased four weeks later. We report here a rare case of IgG4-related autoimmune pancreatitis with multiple renal lesions, which were confirmed by renal biopsy.