In systemic lupus erythematosus (SLE), autoantibody production can lead to kidney damage and failure, known as lupus nephritis. Basophils amplify the synthesis of autoantibodies by accumulating in secondary lymphoid organs. Here, we show a role for prostaglandin D2 (PGD2) in the pathophysiology of SLE. Patients with SLE have increased expression of PGD2 receptors (PTGDR) on blood basophils and increased concentration of PGD2 metabolites in plasma. Through an autocrine mechanism dependent on both PTGDRs, PGD2 induces the externalization of CXCR4 on basophils, both in humans and mice, driving accumulation in secondary lymphoid organs. Although PGD2 can accelerate basophil-dependent disease, antagonizing PTGDRs in mice reduces lupus-like disease in spontaneous and induced mouse models. Our study identifies the PGD2/PTGDR axis as a ready-to-use therapeutic modality in SLE.

Lupus nephritis (LN), one of the most severe outcomes of systemic lupus erythematosus (SLE), is initiated by glomerular deposition of immune-complexes leading to an inflammatory response and kidney failure. Autoantibodies to nuclear antigens and autoreactive B and T cells are central in SLE pathogenesis. Immune mechanisms amplifying this autoantibody production drive flares of the disease. We previously showed that basophils were contributing to LN development in a spontaneous lupus-like mouse model (constitutive Lyn −/− mice) and in SLE subjects through their activation and migration to secondary lymphoid organs (SLOs) where they amplify autoantibody production. In order to study the basophil-specific mechanisms by which these cells contribute to LN development, we needed to validate their involvement in a genetically independent SLE-like mouse model. Pristane, when injected to non-lupus-prone mouse strains, induces a LN-like disease. In this inducible model, basophils were activated and accumulated in SLOs to promote autoantibody production. Basophil depletion by two distinct approaches dampened LN-like disease, demonstrating their contribution to the pristane-induced LN model. These results enable further studies to decipher molecular mechanisms by which basophils contribute to lupus progression.

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The mechanisms of intracellular transport of bile acids from the sinusoidal pole to the canalicular pole of the hepatocyte are poorly understood. There is physiological and autoradiographic evidence for a vesicular pathway. The purpose of this study was to determine the localization of natural bile acids in the liver using antibodies against cholic acid conjugates and ursodeoxycholic acid. An indirect immunoperoxidase technique was used on rat liver sections fixed either with paraformaldehyde (PF) and saponin, a membrane-permeabilizing agent that allows penetration of antibodies into the cell, or with PF alone. Retention of taurocholate in the liver after tissue processing was 26±SD 15% of the bile acid initially present. When sections fixed with PF and saponin were incubated with the antibody against cholic acid conjugates, a granular cytoplasmic staining was observed by light microscopy in all hepatocytes. By electron microscopy, strong electron-dense deposits were observed mostly on vesicles of the Golgi apparatus (GA) and, sometimes, in the smooth endoplasmic reticulum (SER). After taurocholate infusion, the intensity of the reaction increased. When the liver was fixed with PF alone, almost no reaction was visible on light microscopy, but on electron microscopy the label was localized on the hepatocyte plasma membrane, mainly on the bile canalicular domain and to a lesser extent on the sinusoidal domain. With the antibody against ursodeoxycholic acid, no staining was observed in three of four livers, and a slight staining was observed in one. However, after infusion of ursodeoxycholic acid, staining of GA and SER vesicles was observed when the liver was fixed with PF and saponin. With PF alone, the reaction was intense on the canalicular membrane. These results support the view that, within the limits of the method, vesicles from the GA and possibly vesicles of the SER are involved in the intracellular transport of bile acids before canalicular secretion.

Although a zonal distribution of hepatocytes expressing various metabolic functions in liver lobule has been described (1), it is still debated whether functional heterogeneity in the lobule also occurs with respect to plasma protein synthesis, an important function ofhepatocytes . Acute-phase reactants are a group of secretory proteins with dramatically altered rates of synthesis during the acute-phase response of the liver (2). In this article we analyze the hepatic cellular distribution of the mRNA and protein products of three acute-phase genes, «2-macroglobulin (a2M), alinhibitor 3 (a1I3), and al-antitrypsin (ooPI). a2M is a major acute-phase reactant in rats with drastically increased hepatic mRNA concentrations after turpentine injection (3). Concomitantly, the steady-state levels of atl3 mRNA are decreased (4) . a1PI is only a moderately reacting acute-phase protein in the rat (5). Here we investigate specifically whether hepatocytes expressing these three genes show a specialized location in normal rat livers and whether their topographic distribution is altered during the acute inflammatory reaction (AIR) .Animals. Adult male Sprague-Dawley rats (180-230 g) (Charles River Breeding Laboratories, St. Aubin-les-Elbeuf, France) were used. An AIR was induced by a subcutaneous injection of turpentine (0.5 ml per 100 g body weight) (Prolabo, Paris, France) . The animals were killed at 0, 4, 8, 12, 18, 24, 48, and 72 h after induction of the AIR . Three rats per time point were used for in situ hybridization (ISH) and immunoperoxidase experiments .Molecular Probes . The a2M (pRLA2M/29J) cDNA probe and the a,I3 (pRLA12/23J) cDNA probe were prepared as described (3, 4). The ca,PI (pliv 3) cDNA probe (6) was provided by Dr. M. Weiss (Institut Pasteur, Paris, France) .In Situ Hybridization . Liver fixation and preparation of paraffin sections were made as previously detailed (7) . The sections were fixed in 4% paraformaldehyde and hybridized as previously reported (7) . The probes were labeled by nick translation to a specific activity of 1-2 x 108 cpm/p,g DNA. Each section was hybridized with 105-106 cpm ofthe radioactive

Objective Cardiovascular disease (CVD) is the leading cause of death in systemic lupus erythematosus (SLE). B cells play a key role in the pathogenesis of lupus, and anti‐BAFF therapy has been approved for use in SLE. Since mature B cells also promote atherosclerosis, we undertook this study to evaluate, in a mouse model and in SLE patients, whether BAFF neutralization has an atheroprotective effect in SLE. Methods The effect of BAFF on atherosclerosis associated with lupus was investigated in the atherosclerosis/lupus‐prone apolipoprotein E–knockout D227K mouse model and in a cohort of SLE patients. Mice were treated with a blocking anti‐BAFF monoclonal antibody (mAb), while fed a standard chow diet. Carotid plaque and carotid intima‐media thickness were assessed by ultrasound at baseline and during follow‐up in SLE patients who were asymptomatic for CVD. Results Anti‐BAFF mAb in ApoE−/− D227K mice induced B cell depletion, efficiently treated lupus, and improved atherosclerosis lesions (21% decrease; P = 0.007) in mice with low plasma cholesterol levels but worsened the lesions (17% increase; P = 0.06) in mice with high cholesterol levels. The atheroprotective effect of the BAFF–BAFF receptor signaling inhibition on B cells was counterbalanced by the proatherogenic effect of the BAFF–TACI signaling inhibition on macrophages. In SLE patients, blood BAFF levels were associated with subclinical atherosclerosis (r = 0.26, P = 0.03). Anti‐BAFF mAb treatment had a differential effect on the intima‐media thickness progression in SLE patients depending on body mass index. Conclusion Depending on the balance between lipid‐induced and B cell–induced proatherogenic conditions, anti‐BAFF could be detrimental or beneficial, respectively, to atherosclerosis development in SLE.

Systemic lupus erythematosus (SLE) is a multifactorial chronic autoimmune disease, marked by the presence of autoantibodies to nuclear antigens belonging to different isotype classes. For several years, IgE antibodies have been incriminated in the development of allergic diseases and parasitic infections and different anti-IgE therapies have been developed to encounter the pathogenic role of IgE in these pathologies. Recently, multiple studies showed the presence of elevated total IgE levels and demonstrated a pathogenic role of autoreactive IgE in SLE. This review aims to summarize the findings incriminating IgE and autoreactive IgE in the pathophysiology of SLE, to describe their functional outcomes on their targeted cells as well as to discuss different IgE-related therapeutic modalities that emerged and that may be beneficial for SLE patient care.

Liver RNA and protein breakdown rates were measured simultaneously in fed and in 24 h-fasted rats during a short-term cyclic perfusion, 1 h after an intraperitoneal injection of glucagon or of saline. RNA was labelled in vivo by an intraperitoneal injection of [6-14C]orotic acid, 60 h before the start of the perfusion. The accumulation of radioactive cytidine and valine in the perfusion medium for 15 min was used to determine RNA breakdown and proteolysis respectively. The portal glucagon/insulin ratio was significantly higher in the fasted glucagon-treated rats than in their fed counterparts. Although glucagon administration significantly increased RNA and protein degradation rates in the fasted and in the fed groups, the effect was greater after 24 h of starvation. The relationship between these biochemical changes and the alterations of the hepatocyte lysosomal system was investigated by determining the fractional cytoplasmic volume of lysosomal structures (autophagic vacuoles and dense bodies) by morphometry in the fasted glucagon-treated rats and in their controls. Hyperlucagonaemia significantly enhanced the relative volume of autophagic vacuoles without affecting that of dense bodies. The results showed that hyperglucagonaemia induced in vivo stimulated both liver RNA and protein breakdown and that this effect was modulated by the nutritional status of the rats.