Pathologic differentiation between lupus and nonlupus membranous glomerulopathy

Pathologic differentiation between lupus and nonlupus membranous glomerulopathy. The following clinical and pathologic features were evaluated in 170 patients with electron microscopically documented membranous glomerulopathy: age, sex, race, American Rheumatism Association lupus criteria, serum ANA, serum complement, glomerular hypercellularity, stage of subepithelial dense deposits, endothelial tubuloreticular inclusions, tubular basement membrane deposits, tissue ANA, glomerular deposition of IgG, IgM, IgA, C3, C4, and C1q. At the time of biopsy 148 patients had no clinical evidence for lupus, and 22 had a clinical diagnosis of lupus. Six additional patients eventually developed overt lupus after an average of 12 months. Incidences of serologic and pathologic features in lupus as compared with nonlupus membranous glomerulopathy were determined. These data were used to calculate sensitivity, specificity, positive and negative predictive values, and overall efficiency of each parameter in differentiating between lupus and nonlupus membranous glomerulopathy. In general, serologic, morphologic and immunohistopathologic features are more accurate at ruling out lupus than making the diagnosis of lupus. However, a number of features are significantly more frequent in lupus membranous glomerulopathy. Therefore, identification of these features, especially more than one, warrants a high suspicion of lupus rather than nonlupus membranous glomerulopathy even in patients without clinically overt systemic lupus erythematosus. The positive/negative predictive values of some of the pathologic features studied are as follows: mesangial dense deposits 63/99, subendothelial dense deposits 77/93, tubuloreticular inclusions 61/96, intense C1q deposition 47/95, tubular basement membrane deposits 100/87, and glomerular hypercellularity 26/86.Différentiation pathologique entre glomérulopathie extra-membraneuse lupique et non lupique. Les caractéristiques cliniques et pathologiques suivantes ont été évaluées chez 170 malades atteints de glomérulopathie extra-membraneuse documentée par microscopie électronique: l'âge, le sexe, la race, les critères de lupus de l'American Rheumatism Association, les ANA sériques, le complément sérique, l'hypercellularité glomérulaire, le stade des dépôts denses sous-épithéliaux, les inclusions endothéliales tubuloréticulaires, les dépôts dans la membrane basale tubulaire, les ANA tissulaires, les dépôts glomérulaires d'IgG, IgM, IgA, C3, C4, et C1q. Au moment de la biopsie, 148 malades n'avaient pas d'argument clinique pour un lupus, et 22 avaient un diagnostic clinique de lupus. Six malades supplémentaires ont développé un lupus patent après une moyenne de 12 mois. L'incidence des caractéristiques sérologiques et pathologiques dans la glomérulopathie extra-membraneuse lupique ou non lupique a été déterminée. Ces données ont été utilisées pour calculer la sensibilité, la spécificité, les valeurs prédictives positives et négatives, et l'efficacité globale de chaque paramètre pour différencier entre glomérulopathie extra-membraneuse lupique ou non lupique. D'une façon générale, les caractéristiques sérologiques, morphologiques et immunohistopathologiques sont plus puissantes pour éliminer le lupus que pour faire le diagnostic de lupus. Cependant, un certain nombre de caractéristiques sont significativement plus fréquentes dans la glomérulopathie extra-membraneuse lupique. C'est pourquoi la mise en évidence de ces caractéristiques, surtout s'il y en a plus d'une, apporte une forte suspicion de glomérulopathie extra-membraneuse plus lupique que non lupique, même chez des malades sans lupus erythémateux disséminé cliniquement patent. Les valeurs prédictives positives/négatives de certaines des caractéristiques pathologiques étudiées sont les suivantes: dépôts denses mésangiaux 63/99, dépôts denses sous-endothéliaux 77/93, inclusions tubuloréticulaires 61/96, dépôts intenses de C1q 47/95, dépôts dans la membrane basale tubulaire 100/87, et hypercellularité glomérulaire 26/86

Immune complex glomerulonephritis is induced in rats immunized with heterologous myeloperoxidase

Anti-neutrophil cytoplasmic antibodies (ANCA), including anti-myeloperoxidase (MPO) antibodies, are associated with pauci-immune necrotizing small vessel vasculitis or glomerulonephritis, 1n order to substantiate a pathogenic role for ANCA, an animal model of pauci-immune ANCA-induced glomerulonephritis or vasculitis is required. Brouwer reported pauci-immune glomerulonephritis in rats immunized with human MPO followed by perfusion of kidneys with lysosomal enzyme extract combined with HO, and suggested that this could serve as a model of ANCA-induced disease. We repeated these studies in spontaneously hypertensive rats (SHR) and Brown Norway rats (BNR). We immunized rats with human MPO, When circulating anti-MPO antibodies were detectable by indirect immunofluorescence microscopy and ELISA, blood pressure was measured, then perfusion of the left kidney of each rat was done via the renal artery in a closed, blood-free circuit with either MPO + HO, MPO, HO alone or MPO + HO neutral protease. Rats were killed on day 4 or day 10 after perfusion, and specimens were examined by light and immunofluorescence microscopy. Pathological lesions and deposits of IgG. C3, and MPO were found in immunized rats perfused with MPO + HO with or without neutral protease, or MPO alone, in both rat strains and on both day 4 and day 10, The degree of histologic injury was proportional in intensity to the amount of IgG immune deposits. Spontaneously hypertensive rats sustained more damage and higher blood pressure than Brown Norway rats. No lesion was observed in immunized rats perfused with HO or in the non-perfused right kidneys. Some of the non-immunized rats perfused with MPO + HO developed pathological lesions. In conclusion, these rat models are examples of immune complex-mediated glomerulonephritis, and therefore are not similar to human ANCA-associated disease

Immunopathogenesis of environmentally induced lupus in mice.

Systemic lupus erythematosus (SLE) is a systemic autoimmune syndrome defined by clinical and serologic features, including arthritis, glomerulonephritis, and certain autoantibodies such as anti-nuclear ribonucleoprotein (nRNP)/Smith antigen (Sm), DNA, and ribosomal P. Although lupus is considered primarily a genetic disorder, we recently demonstrated the induction of a syndrome strikingly similar to spontaneous lupus in many nonautoimmune strains of mice exposed to the isoprenoid alkane pristane (2,6,10,14-tetramethylpentadecane), a component of mineral oil. Intraperitoneal injection of pristane leads to the formation of lipogranulomas consisting of phagocytic cells that have engulfed the oil and collections of lymphocytes. Subsequently, pristane-treated BALB/c and SJL mice develop autoantibodies characteristic of SLE, including anti-nRNP/Sm, antiribosomal P, anti-Su, antichromatin, anti-single-stranded DNA, and anti-double-stranded DNA. This is accompanied by a severe glomerulonephritis with immune complex deposition, mesangial or mesangiocapillary proliferation, and proteinuria. All inbred mice examined appear to be susceptible to this novel form of chemically induced lupus. Pristane-induced lupus is the only inducible model of autoimmunity associated with the clinical syndrome as well as with the characteristic serologic abnormalities of SLE. Defining the immunopathogenesis of pristane-induced lupus in mice may provide insight into the causes of spontaneous (idiopathic) lupus and also may lead to information concerning possible risks associated with the ingestion or inhalation of mineral oil and exposure to hydrocarbons in the environment

Next-generation of BBQ analogues that selectively target breast cancer

We previously reported on the interaction of 10-chloro-7H-benzo[de]benzo[4,5]imidazo[2,1-a]isoquinolin-7-one (10-Cl-BBQ) with the Aryl hydrocarbon Receptor (AhR) and selective growth inhibition in breast cancer cell lines. We now report on a library of BBQ analogues with substituents on the phenyl and naphthyl rings for biological screening. Herein, we show that absence of the phenyl Cl of 10-Cl-BBQ to produce the simple BBQ molecule substantially enhanced the growth inhibitory effect with GI50 values of 0.001–2.1 μM in select breast cancer cell lines MCF-7, T47D, ZR-75-1, SKBR3, MDA-MB-468, BT20, BT474 cells, while having modest effects of 2.1–7 μM in other cell lines including HT29, U87, SJ-G2, A2780, DU145, BE2-C, MIA, MDA-MB-231 or normal breast cells, MCF10A (3.2 μM). The most potent growth inhibitory effect of BBQ was observed in the triple negative cell line, MDA-MB-468 with a GI50 value of 0.001 μM, presenting a 3,200-fold greater response than in the normal MCF10A breast cells. Additions of Cl, CH3, CN to the phenyl ring and ring expansion from benzoimidazole to dihydroquinazoline hindered the growth inhibitory potency of the BBQ analogues by blocking potential sites of CYP1 oxidative metabolism, while addition of Cl or NO2 to the naphthyl rings restored potency. In a cell-based reporter assay all analogues induced 1.2 to 10-fold AhR transcription activation. Gene expression analysis confirmed the induction of CYP1 oxygenases by BBQ. The CYP1 inhibitor α-naphthoflavone, and the SULT1A1 inhibitor quercetin significantly reduced the growth inhibitory effect of BBQ, confirming the importance of both phase I and II metabolic activation for growth inhibition. Conventional molecular modelling/docking revealed no significant differences between the binding poses of the most and least active analogues. More detailed DFT analysis at the DSD-PBEP86/Def-TZVPP level of theory could not identify significant geometric or electronic changes which would account for this varied AhR activation. Generation of Fukui functions at the same level of theory showed that CYP1 metabolism will primarily occur at the phenyl head group of the analogues, and substituents within this ring lead to lower cytotoxicity

Childhood Overweight is Associated with Increased Monocyte Concentration and Altered Subset Distribution

Childhood obesity rates have nearly tripled in the last 30 years. Obesity increases risk for chronic disease. While monocytes, cells of the innate immune system that are altered with obesity, are purported to play an integral role in the development of these chronic diseases, no research has focused on early phenotypic changes in monocytes of overweight children. Two monocytes subsets exist, classic and pro-inflammatory; alterations in number and distribution may be implicated in disease development in obesity. The purpose of this study was to examine the concentration and relative distribution of monocytes among “normal weight” (N=66) and “at risk for being overweight/overweight” (N=56) Mexican American children. Blood samples were collected and analyzed for total monocyte concentration and monocyte subset concentration via flow cytometry. Total monocyte concentration, as well as the concentration of both classic and pro-inflammatory monocyte subsets was significantly greater in the “at risk for overweight/overweight” children (P\u3e0.05). Understanding early alterations in monocyte populations will be the first step in the development of early diagnosis and treatment techniques

Elevated MCP-1, TNF-α, Monocyte Concentration, and Dyslipidemia in Obese Mexican-American Children

Background: Obesity is an independent risk factor for chronic disease. The prevalence of obesity is especially high among Mexican-American children. Peripheral blood monocytes contribute to systemic inflammation and may mediate the relationship between obesity and chronic disease. Obesity affects monocytes and the circulating levels of cytokines/chemokines that influence monocyte behavior. Purpose: investigate alterations in blood monocytes and plasma cytokines/chemokine levels among healthy weight (zBMI ≤ 85th percentile; N=66), overweight (zBMI=85th-95th percentile; N=23), and obese (zBMI ≥ 95th percentile; N=39) Mexican-American children. Methods: Blood samples were analyzed for total monocyte concentration, pro-inflammatory monocyte concentration, and classic monocyte concentration via flow cytometry. Serum MCP-1, Fractalkine, IL-8, and TNF-α were measured using a Milliplex MagPix assay. Serum cholesterol, HDL, triglycerides, and glucose were measured using an enzymatic reagent kit. Results: Total monocyte concentration (P=0.012), classic monocyte concentration (P=0.045), MCP-1 (P=0.015), and TNF- α (P=0.002) were significantly greater in obese children compared to heathly weight children. Also, overweight and obese children had elevated triglycerides (P=0.001) and reduced HDL (P=0.033) compared to healthy weight children. Conclusion: Elevations in circulating monocytes, MCP-1, and TNF-α have been implicated in the development of obesity-related chronic disease in adults. Childhood obesity alters monocytes and circulating chemokines, putting children at a greater risk of developing obesity-related chronic diseases in adulthood. Further characterization of early immune alterations in childhood obesity may provide additional clinical insight into the assessment of obesity-related disease risk

High Elmo1 expression aggravates and low Elmo1 expression prevents diabetic nephropathy

About one-third of patients with type 1 diabetes mellitus develop nephropathy, which often progresses to end-stage renal diseases. The present study demonstrates that below-normal Elmo1 expression in mice ameliorates the albuminuria and glomerular histological changes resulting from long-standing type 1 diabetes, whereas above-normal Elmo1 expression makes both worse. Increasing Elmo1 expression leads to aggravation of oxidative stress markers and enhances the expression of fibrogenic genes. Suppressing Elmo1 action in human patients could be a promising option for treating/preventing the progressive deterioration of renal function in diabetes