BackgroundC3 glomerulopathy (C3G) is a heterogeneous group of chronic renal diseases characterized predominantly by glomerular C3 deposition and complement dysregulation. Mutations in factor H–related (FHR) proteins resulting in duplicated dimerization domains are prototypical of C3G, although the underlying pathogenic mechanism is unclear.MethodsUsing in vitro and in vivo assays, we performed extensive characterization of an FHR-1 mutant with a duplicated dimerization domain. To assess the FHR-1 mutant’s association with disease susceptibility and renal prognosis, we also analyzed CFHR1 copy number variations and FHR-1 plasma levels in two Spanish C3G cohorts and in a control population.ResultsDuplication of the dimerization domain conferred FHR-1 with an increased capacity to interact with C3-opsonized surfaces, which resulted in an excessive activation of the alternative pathway. This activation does not involve C3b binding competition with factor H. These findings support a scenario in which mutant FHR-1 binds to C3-activated fragments and recruits native C3 and C3b; this leads to formation of alternative pathway C3 convertases, which increases deposition of C3b molecules, overcoming FH regulation. This suggests that a balanced FHR-1/FH ratio is crucial to control complement amplification on opsonized surfaces. Consistent with this conceptual framework, we show that the genetic deficiency of FHR-1 or decreased FHR-1 in plasma confers protection against developing C3G and associates with better renal outcome.ConclusionsOur findings explain how FHR-1 mutants with duplicated dimerization domains result in predisposition to C3G. They also provide a pathogenic mechanism that may be shared by other diseases, such as IgA nephropathy or age-related macular degeneration, and identify FHR-1 as a potential novel therapeutic target in C3G.
Immunohistochemical techniques localize basic fibroblast growth factor (FGF) in endothelial and smooth muscle cells of the common carotid artery. Thus, we studied the effect in rats of basic FGF infused for 14 days onto the adventitia or into the media in vivo. In untreated rats, the adventitial layer is uniform, and few vessels are observed in cross sections (mean +/- SEM is 0.351 +/- 0.16 capillaries/field at a magnification of x 480). Whereas saline infusion increases the mean number of vasa vasorum to 2.73 +/- 0.011 capillaries/field (p less than 0.01), basic FGF (1 ng/microliter/hr) increases the capillary number to 13.4 +/- 0.67 capillaries/field. The effects are local and restricted to the site of delivery; no cell proliferation is observed even 2 mm from the site of infusion. There is also no evidence of the infiltration of macrophages and monocytes. In an effort to determine the effect of basic FGF in the media, a small longitudinal (1-mm) incision was made in the adventitia, and saline or basic FGF (1 ng/microliter/hr) was infused for 14 days into the arterial wall. Under these conditions, basic FGF is a potent inducer of smooth muscle cell proliferation in the vascular wall as well as of new capillaries. In these instances, however, the capillaries formed are thick-walled. The results support the hypothesis that basic FGF may be contributing to the growth and maintenance of the vasa vasorum and of vascular smooth muscle cells.
Summary Both human leucocyte antigen (HLA)‐G and indoleamine 2,3 dioxygenase (IDO) are key molecules involved in immune tolerance. HLA‐G is a non‐classical HLA class I molecule that can be expressed in both membrane‐bound (HLA‐G1) and soluble (HLA‐G5) forms, both of which exhibit tolerogenic properties via interaction with inhibitory receptors present on natural killer (NK) cells, T cells and antigen‐presenting cells (APC). IDO is an enzyme that acts by depleting the surrounding microenvironment of the essential amino acid, tryptophan, thereby inhibiting T‐cell proliferation. Our present study was aimed at analysing the potential link that may exist between IDO and HLA‐G. Our results showed that during allogeneic reactions, soluble HLA‐G expression was not regulated by the addition of IDO substrate (i.e. tryptophan), metabolite (i.e. kynurenine) or inhibitor (i.e. 1‐methyl‐tryptophan), that IDO activity was not altered by HLA‐G5 treatment, and that HLA‐G5‐mediated inhibition of the T‐cell alloproliferative response was neither affected by the presence of tryptophan and kynurenine nor reversed after IDO activity blockage, demonstrating that HLA‐G5 can exert its function in the absence of functional IDO. Similarly, inhibition of the T‐cell alloresponse, induced by HLA‐G1‐expressing antigen‐presenting cells, was not altered by IDO metabolites or inhibitor. Taken together, these findings show that the function and expression of IDO and HLA‐G5 are not mutually influenced, but rather inhibit the T‐cell alloproliferative response through two independent pathways. IDO and HLA‐G are thus complementary for inducing and maintaining immune tolerance in physiological (pregnancy) and pathological (tumour and allograft) situations.
In elderly patients with HF, the determination of biomarkers may be helpful to establish those patients at higher risk.
Genitourinary schistosomiasis is an acquired cause of urinary tract diseases, especially hematuria. Schistosoma haematobium can infect travelers after a single exposure. Bladder is the most frequent organ involved within the urinary tract, although upper tract can also be affected. Case report of 34-year-old woman with left upper urinary tract obstruction due to schistosomiasis is presented, as well as its diagnosis and minimally invasive surgical management through a laparoscopic ureteral reimplantation. After 1-year follow-up, she remains asymptomatic and without upper tract obstruction demonstrated by CT.
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