IgA nephropathy (IgAN) is characterized by deposits of IgA in the renal mesangium. It is thought that deposits of IgA mainly involve high molecular weight (HMW) IgA1. However, there is limited ...information on the exact composition of HMW IgA in these deposits. In this study, we investigated the presence of secretory IgA (SIgA) in human serum and in the glomerular deposits of a patient with IgAN. Furthermore, we analyzed the interaction of SIgA with mesangial cells. With enzyme-linked immunosorbent assay, SIgA concentrations in the serum of IgAN patients and healthy controls were measured. Both patients and controls had circulating SIgA that was restricted to the HMW fractions. Patients tended to have higher levels of SIgA, but this difference was not significant. However, in patients with IgAN, high serum SIgA concentrations were associated with hematuria. Binding of size-fractionated purified serum IgA and SIgA to mesangial cells was investigated with flow cytometry. These studies showed stronger binding of SIgA to primary mesangial cells compared to binding of serum IgA. Importantly, after isolation and elution of glomeruli from a nephrectomized transplanted kidney from a patient with recurrent IgAN, we demonstrated a 120-fold accumulation of SIgA compared to IgA1 in the eluate. In conclusion, we have demonstrated that SIgA strongly binds to human mesangial cells, and is present in significant amounts in serum. Furthermore, we showed that SIgA is accumulated in the glomeruli of an IgAN patient. These data suggest an important role for SIgA in the pathogenesis of IgAN.
Early pancreas graft loss is usually attributed to technical failure while the possibility of antibody‐mediated rejection (AMR) is generally overlooked. To investigate the role of AMR in early ...pancreas graft loss, we retrospectively assessed 256 patients with simultaneous pancreas–kidney transplantation (SPK) between 1985 and 2010 at our institute. We included 33 SPK patients who lost their pancreas graft <1 year after transplantation. AMR was diagnosed based on donor‐specific antibodies, C4d and histology in 7 cases, 8 cases were suspicious for AMR and 18 pancreas graft losses were not due to AMR. Acute AMR occurred >1 month after transplantation in 6/7 cases, whereas all other causes typically led to loss <1 month after transplantation. Thrombotic lesions occurred equally among the 33 cases. In 12/18 concurrent kidney specimens, the diagnostic results paralleled those of the pancreas graft. All patients with acute AMR of the pancreas graft lost their renal grafts <1 year after transplantation. In the setting of a thrombotic event, histopathological analysis of early pancreas graft loss is advisable to rule out the possibility of AMR, particularly because a diagnosis of acute AMR has important consequences for renal graft outcomes.
This study evaluating simultaneous pancreas‒kidney transplant outcomes shows that antibody‐mediated rejection is an important contributor to pancreas graft loss within 1 year posttransplantation, but this condition can be obscured by thrombosis.
C4d+ antibody‐mediated rejection following pancreas transplantation has not been well characterized. Therefore, we assessed the outcomes of 27 pancreas transplantation patients (28 biopsies), with ...both C4d staining and donor‐specific antibodies (DSA) determined, from a cohort of 257 patients. The median follow‐up was 50 (interquartile range IQR 8–118) months. Patients were categorized into 3 groups: group 1, patients with minimal or no C4d staining and no DSA (n = 13); group 2, patients with either DSA present but no C4d, diffuse C4d+ and no DSA or focal C4d+ and DSA (n = 6); group 3, patients with diffuse C4d+ staining and DSA (n = 9). Active septal inflammation, acinar inflammation and acinar cell injury/necrosis were significantly more abundant in group 3 than in group 2 (respective p‐values: 0.009; 0.033; 0.025) and in group 1 (respective p‐values: 0.034; 0.009; 0.002). The overall uncensored pancreas graft survival rate for groups 1, 2 and 3 were 53.3%, 66.7% and 34.6%, respectively (p = 0.044). In conclusion, recipients of pancreas transplants with no C4d or DSA had excellent long‐term graft survival in comparison with patients with both C4d+ and DSA present. Hence, C4d should be used as an additional marker in combination with DSA in the evaluation of pancreas transplant biopsies.
This is the first pancreas transplant biopsy study in which antibody‐mediated rejection as defined by positive C4d staining and donor specific antibodies was shown to correlate with worse long term graft survival, and with the pathological features of active septal and acinar inflammation and acinar cell injury/necrosis. See editorial by Colvin on page 1509.
Aims/hypothesis Simultaneous kidney-pancreas transplantation is an established treatment for patients with type 1 diabetes and end-stage renal failure, even though restored beta cell function may ...become affected by recurrent islet autoimmunity or graft rejection. We characterised infiltrating lymphocytes isolated from a pancreatic graft with normal endocrine function in a kidney-pancreas recipient with type 1 diabetes. Methods The pancreas graft was removed due to recurrent graft pancreatitis of unknown cause. Pancreas-infiltrating lymphocytes and peripheral blood mononuclear cells (PBMC) were isolated and characterised phenotypically and functionally. Results Compared with PBMC, pancreas-infiltrating lymphocytes exhibited a distinct activation/memory phenotype and T cell receptor profile that were indicative of selective infiltration of the pancreas. Islet autoreactive CD8⁺ T cells could be detected in the pancreas and were increased in frequency compared with PBMC. Additionally, an augmentation of CD8⁺ CD28⁻ regulatory T cells was observed in the pancreas; these induced expression of the inhibitory receptor immunoglobulin-like transcript-3 on antigen-presenting cells in a donor HLA class I-specific manner. Conclusions/interpretation These data demonstrate the simultaneous presence of regulatory and effector T cells in the pancreas allograft of a recipient with type 1 diabetes. They also indicate that circulating islet autoreactive T cells may reflect immunological processes in pancreatic tissue, even though their frequency in the periphery may lead to underestimation of their presence in the pancreas. Additional specificities were also present in the pancreas that were undetectable in the circulation.
Moldoveanu et al. present a diagnostic test for IgA nephropathy based on the presence of undergalactosylated IgA in serum. This underglycosylated IgA appears to be overrepresented in serum of IgA ...nephropathy patients and is most likely related to mesangial IgA deposition. Further studies on the nature, production, regulation, and cellular and molecular interactions of this undergalactosylated IgA may facilitate disease diagnosis and provide further insight into the pathogenesis of this important disease.
Generation of Memory B Cells and Plasma Cells in Vitro Arpin, Christophe; Déchanet, Julie; Van Kooten, Cees ...
Science (American Association for the Advancement of Science),
05/1995, Letnik:
268, Številka:
5211
Journal Article
Recenzirano
After germinal center B cells undergo somatic mutation and antigen selection, they become either memory B cells or plasma cells, but the signal requirements that control entry into either pathway ...have been unclear. When purified human germinal center cells were cultured with interleukin-2, interleukin-10, and cells expressing CD40 ligand, cells with characteristics of memory B cells were generated. Removal of CD40 ligand from the system resulted in terminal differentiation of germinal center B cells into cells with the characteristics of plasma cells. These results indicate that CD40 ligand directs the differentiation of germinal center B cells toward memory B cells rather than toward plasma cells.
Abnormally O-glycosylated IgA1 is likely to be involved in the pathogenesis of IgA nephropathy (IgAN). Buck et al. show that the enzyme activity and gene expression of specific glycosyltransferases, ...in purified B cells isolated from peripheral blood and bone marrow, is not reduced in IgAN patients. As only a small fraction of IgA in IgAN patients is abnormally glycosylated, it is probable that a more detailed molecular analysis at the single cell level is required to unravel the cause of this abnormality.
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