Dendritic cell (DC) maturation and migration are events critical for the initiation of immune responses. After encountering pathogens, DCs upregulate the expression of costimulatory molecules and subsequently migrate to secondary lymphoid organs. Calcium (Ca2+) entry governs the functions of many hematopoietic cell types, but the role of Ca2+ entry in DC biology remains unclear. Here we report that the Ca2+-activated nonselective cation channel TRPM4 was expressed in and controlled the Ca2+ homeostasis of mouse DCs. The absence of TRPM4, which elicited Ca2+ overload, did not influence DC maturation but did considerably impair chemokine-dependent DC migration. Our results establish TRPM4-regulated Ca2+ homeostasis as crucial for DC mobility but not maturation and emphasize that DC maturation and migration are independently regulated.

Transferrin receptor (TfR) has been identified as a candidate IgA1 receptor expressed on human mesangial cells (HMC). TfR binds IgA1 but not IgA2, co-localizes with mesangial IgA1 deposits, and is overexpressed in patients with IgA nephropathy (IgAN). Here, structural requirements of IgA1 for its interaction with mesangial TfR were analyzed. Polymeric but not monomeric IgA1 interacted with TfR on cultured HMC and mediates internalization. IgA1 binding was significantly inhibited (>50%) by soluble forms of both TfR1 and TfR2, confirming that TfR serves as mesangial IgA1 receptor. Hypogalactosylated serum IgA1 from patients with IgAN bound TfR more efficiently than IgA1 from healthy individuals. Serum IgA immune complexes from patients with IgAN containing aberrantly glycosylated IgA1 bound more avidly to TfR than those from normal individuals. This binding was significantly inhibited by soluble TfR, highlighting the role of TfR in mesangial IgA1 deposition. For addressing the potential role of glycosylation sites in IgA1-TfR interaction, a variety of recombinant dimeric IgA1 molecules were used in binding studies on TfR with Daudi cells that express only TfR as IgA receptor. Deletion of either N- or O-linked glycosylation sites abrogated IgA1 binding to TfR, suggesting that sugars are essential for IgA1 binding. However, sialidase and beta-galactosidase treatment of IgA1 significantly enhanced IgA1/TfR interaction. These results indicate that aberrant glycosylation of IgA1 as well as immune complex formation constitute essential factors favoring mesangial TfR-IgA1 interaction as initial steps in IgAN pathogenesis.

No abstract

This study shows that CV remodelling and ECF excess occurred at a very early stage of CKD. The independent association between ECF excess and cardiac and vascular remodelling and hypertrophy may be instrumental in the increased cardiovascular risk in CKD patients. Early therapeutic control of ECF may reduce CV events in CKD patients.

Inhibitory signaling is an emerging function of ITAM-bearing immunoreceptors in the maintenance of homeostasis. Monovalent targeting of the IgA Fc receptor (FcαRI or CD89) by anti-FcαRI Fab triggers potent inhibitory ITAM (ITAMi) signaling through the associated FcRγ chain (FcαRI-FcRγ ITAMi) that prevents IgG phagocytosis and IgE-mediated asthma. It is not known whether FcαRI-FcRγ ITAMi signaling controls receptors that do not function through an ITAM and whether this inhibition requires Src homology protein 1 phosphatase. We show in this study that FcαRI-Fcγ ITAMi signals depend on Src homology protein 1 phosphatase to target multiple non-ITAM-bearing receptors such as chemotactic receptors, cytokine receptors, and TLRs. We found that anti-FcαRI Fab treatment in vivo reduced kidney inflammation in models of immune-mediated glomerulonephritis and nonimmune obstructive nephropathy by a mechanism that involved decreased inflammatory cell infiltration and fibrosis development. This treatment also prevented ex vivo LPS activation of monocytes from patients with lupus nephritis or vasculitis, as well as receptor activation through serum IgA complexes from IgA nephropathy patients. These findings point to a crucial role of FcαRI-FcRγ ITAMi signaling in the control of multiple heterologous or autologous inflammatory responses. They also identify anti-FcαRI Fab as a new potential therapeutic tool for preventing progression of renal inflammatory diseases.

Objective. Infective endocarditis (IE) mimics primary systemic vasculitis, and there are sporadic reports of positivity for antineutrophil cytoplasmic antibodies (ANCAs) among patients with IE. Because the frequency of ANCAs in IE is unknown, this study was undertaken to assess the seroprevalence of ANCAs in a large number of patients with IE.Methods. The study was conducted in the framework of a single-center prospective cohort study of incident IE cases. Demographic, clinical, laboratory, and microbiologic data were collected, and magnetic resonance imaging of the brain was performed at diagnosis. For those patients whose serum had been stored at diagnosis, ANCAs were assessed by indirect immunofluorescence assay in ethanol-, formalin-, and methanol-fixed neutrophils. In addition, ANCA specificity for proteinase 3 (PR3) and myeloperoxidase (MPO) was assessed by enzyme-linked immunosorbent assay. Rheumatoid factor (RF), antinuclear antibodies (ANAs), anticardiolipin antibodies (aCL), and serum Ig levels were also measured. Comparisons between groups were made using Wilcoxon's rank sum and chi-square or Fisher's exact tests.Results. Among 109 patients with IE, 18% had cytoplasmic ANCAs (cANCA) and/or perinuclear ANCAs (pANCA) and 8% had PR3-ANCAs or MPOANCAs, some with very high titers. Positivity for both cANCA or pANCA and PR3-ANCAs or MPO-ANCAs was found in 6% of patients, and RF, ANAs, and aCL were detected in 35%, 16%, and 23% of samples, respectively. No consistent clinical pattern of IE was observed in the anti-PR3/anti-MPO-positive IE patients, whereas positivity for cANCA/pANCA was associated with younger age (P ‫؍‬ 0.022), more frequent occurrence of echocardiographic vegetations (P ‫؍‬ 0.043), and abovenormal serum IgG levels (P ‫؍‬ 0.017).Conclusion. ANCAs, including PR3-and MPOANCAs, occur in a substantial proportion of patients with IE. The link between cANCA/pANCA and specific features of IE requires further study.Antineutrophil cytoplasmic antibodies (ANCAs) target various constituents of human neutrophils. Indirect immunofluorescence assays can distinguish ANCAs with cytoplasmic (cANCA) or perinuclear (pANCA) staining patterns; the specific self-reactivities can be further characterized by enzyme-linked immunosorbent assay (ELISA). ANCAs are a major biomarker of ANCA-associated vasculitides (1), with up to 95% of patients showing positive serology results depending on the vasculitis type (2). Specifically, ANCAs directed against proteinase 3 (PR3) and myeloperoxidase (MPO) are highly predictive of ANCA-associated vasculitis, although MPO-ANCAs are also found in other autoimmune diseases and have been associated with infection or drug exposure (2-4). Sporadic case reports have described PR3-or MPO-ANCAs in patients with infective endocarditis (IE) (2,3,5-7). The production of non-organ-specific autoantibodies in IE is well established with regard to rheumatoid factor (RF), and findings in a single case series have suggested a similar relationship between IE and antinuclear antibodies (ANAs), anti...

Background and objectivesVolume overload is frequent in prevalent patients on kidney replacement therapies and is associated with outcome. This study was devised to follow-up volume status of an incident population on peritoneal dialysis (PD) and to relate this to patient-relevant outcomes.Design, setting, participants, & measurementsThis prospective cohort study was implemented in 135 study centers from 28 countries. Incident participants on PD were enrolled just before the actual PD treatment was started. Volume status was measured using bioimpedance spectroscopy before start of PD and thereafter in 3-month intervals, together with clinical and laboratory parameters, and PD prescription. The association of volume overload with time to death was tested using a competing risk Cox model.ResultsIn this population of 1054 participants incident on PD, volume overload before start of PD amounted to 1.9±2.3 L, and decreased to 1.2±1.8 L during the first year. At all time points, men and participants with diabetes were at higher risk to be volume overloaded. Dropout from PD during 3 years of observation by transfer to hemodialysis or transplantation (23% and 22%) was more prevalent than death (13%). Relative volume overload >17.3% was independently associated with higher risk of death (adjusted hazard ratio, 1.59; 95% confidence interval, 1.08 to 2.33) compared with relative volume overload ≤17.3%. Different practice patterns were observed between regions with respect to proportion of patients on PD versus hemodialysis, selection of PD modality, and prescription of hypertonic solutions.ConclusionsIn this large cohort of incident participants on PD, with different treatment practices across centers and regions, we found substantial volume overload already at start of dialysis. Volume overload improved over time, and was associated with survival.

The CKD-EPI creatinine equation does not offer a better GFR prediction in renal transplant patients compared with the MDRD Study equation, even in the earlier CKD stages.