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A distinctive new indirect immunofluorescence pattern in liver tissue has been associated with anti-HMGCR autoantibodies. It is known as HALIP (HMGCR Associated Liver Immunofluorescence Pattern). In this study, we furthered the original studies to demonstrate the association of anti-HMGCR antibodies with the HALIP. Human anti-HMGCR antibodies from patients’ sera were purified and incubated with rat triple tissue (kidney/stomach/liver). A characteristic HALIP was observed. Additionally, a colocalization assay of human anti-HMGCR antibodies with rabbit polyclonal anti-HMGCR antibodies showed colocalization of both immunofluorescence patterns. This study confirms that the HALIP is due to human anti-HMGCR antibodies.

Background Guillain–Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain–Barré syndrome. Methods Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. Results None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. Conclusion Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS.

It is essential to find new biomarkers for severity stratification of patients with coronavirus disease (COVID-19). Growth differentiation factor 15 (GDF-15) is upregulated in pathological conditions that involve inflammation and/or oxidative stress. We determined circulating levels of GDF-15 and correlated them with clinical and laboratory parameters reflecting severity in 84 patients with COVID-19, finding that GDF-15 levels were higher in both patients than in 20 healthy controls and were higher in patients with poorer respiratory function. GDF-15 levels also correlated with interleukin-6, C-reactive protein, ferritin and D-dimer levels and with neutrophilia and lymphopenia. Of all the analysed biomarkers, GDF-15 showed the best area under the receiver operating characteristics curve in identifying patients with poor respiratory function. In conclusion, our data support GDF-15 as a biomarker associated with pulmonary impairment in COVID-19 and so can potentially be useful in stratifying COVID-19 cases by severity.

Background: The LRP1 (CR9) domain and, in particular, the sequence Gly1127-Cys1140 (P3) plays a critical role in the binding and internalization of aggregated LDL (agLDL). We aimed to evaluate whether immunization with P3 reduces high-fat diet (HFD)-induced atherosclerosis. Methods: Female New Zealand White (NZW) rabbits were immunized with a primary injection and four reminder doses (R1-R4) of IrP (irrelevant peptide) or P3 conjugated to the carrier. IrP and P3-immunized rabbits were randomly divided into a normal diet group and a HFD-fed group. Anti-P3 antibody levels were determined by ELISA. Lipoprotein profile, circulating and tissue lipids, and vascular pro-inflammatory mediators were determined using standardized methods while atherosclerosis was determined by confocal microscopy studies and non-invasive imaging (PET/CT and Doppler ultrasonography). Studies treating human macrophages (hMΦ) and coronary vascular smooth muscle cells (hcVSMC) with rabbit serums were performed to ascertain the potential impact of anti-P3 Abs on the functionality of these crucial cells. Results: P3 immunization specifically induced the production of anti-P3 antibodies (Abs) and did not alter the lipoprotein profile. HFD strongly induced cholesteryl ester (CE) accumulation in the aorta of both the control and IrP groups, and their serum dose-dependently raised the intracellular CE of hMΦ and hcVSMC, promoting TNFR1 and phospho-NF-kB (p65) overexpression. These HFD pro-inflammatory effects were dramatically decreased in the aorta of P3-immunized rabbits and in hMΦ and hcVSMC exposed to the P3 rabbit serums. Microscopy studies revealed that P3 immunization reduced the percentage of lipids, macrophages, and SMCs in the arterial intima, as well as the atherosclerotic extent and lesion area in the aorta. PET/CT and Doppler ultrasonography studies showed that the average standardized uptake value (SUVmean) of the aorta and the arterial resistance index (ARI) of the carotids were more upregulated by HFD in the control and IrP groups than the P3 group. Conclusions: P3 immunization counteracts HFD-induced fatty streak formation in rabbits. The specific blockade of the LRP1 (CR9) domain with Anti-P3 Abs dramatically reduces HFD-induced intracellular CE loading and harmful coupling to pro-inflammatory signaling in the vasculature., The main support to develop this project was received from Fundació MARATÓ TV3 Project 201521-10 (to VLl-C) and FIS PI18/01584 (to VLl-C), FIS16/00139 (to JCE-G) from the Instituto de Salud Carlos III (ISCIII) and co-financed with ERDFs. Support was received from Fundació Marató TV3 (Project 201521-10) for post-doctoral funding to OB and from Ministerio de Economía y Competitividad to DdG-C (IJCI-2016-29393). CIBER Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM; CB07/08/0016 to JCE-G) and CIBER Enfermedades Cardiovasculares (CIBERCV; CB16/1100403 to DdGC, VLl-C and CB16/11/00411 to LB and MB-P) are projects run by the Instituto de Salud Carlos III (ISCIII). We also acknowledge support from “Secretaria d’Universitats i Recerca del Departament d’Economia I Coneixement de la Generalitat de Catalunya” [2017SGR946 to VLl-C and 2017SGR1480 to LB]. DdG-C, VL-C and JCE-G are members of the Group of Vascular Biology of the Spanish Society of Atherosclerosis (SEA).

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Antibodies against myelin-associated glycoprotein (MAG) almost invariably appear in the context of an IgM monoclonal gammopathy associated neuropathy. Very few cases of anti-MAG neuropathy lacking IgM-monoclonal gammopathy have been reported. We investigated the presence of anti-MAG antibodies in 69 patients fulfilling diagnostic criteria for CIDP. Anti-MAG antibodies were tested by ELISA and confirmed by immunohistochemistry. We identified four (5.8%) anti-MAG positive patients without detectable IgM-monoclonal gammopathy. In two of them, IgM-monoclonal gammopathy was detected at 3 and 4-year follow-up coinciding with an increase in anti-MAG antibodies titers. In conclusion, anti-MAG antibody testing should be considered in chronic demyelinating neuropathies, even if IgM-monoclonal gammopathy is not detectable.

Altres ajuts: Cofinanced by Fondos FEDER (Fondo Europeo de Desarrollo Regional), "Una manera de hacer Europa", European Union, and CERCA Programme, Generalitat de Catalunya; Silvia Vidal was supported by Fondode Investigaciones Sanitarias (FIS) and is a participant in the Program for Stabilization of Investigators of the Direcció d'Estrategia i Coordinació del Departament de Salut, Generalitat de Catalunya. To assess the relationship between the presence of toll-like receptor 4 (TLR4) polymorphisms and bacterial infections in cirrhotic patients with ascites. We prospectively included consecutive patients with cirrhosis and ascites hospitalized during a 6-year period. Patients with human immunodeficiency virus (HIV) infection or any other immunodeficiency, patients with advanced hepatocellular carcinoma (beyond Milan's criteria) or any other condition determining poor short-term prognosis, and patients with a permanent urinary catheter were excluded. The presence of D299G and/or T399I TLR4 polymorphisms was determined by sequencing and related to the incidence and probability of bacterial infections, other complications of cirrhosis, hepatocellular carcinoma, and mortality during follow-up. A multivariate analysis to identify predictive variables of mortality in the whole series was performed. We included 258 patients: 28 (10.8%) were carriers of D299G and/or T399I TLR4 polymorphisms (polymorphism group) and 230 patients were not (wild-type group). The probability of developing any bacterial infection at one-year follow-up was 78% in the polymorphism group and 69% in the wild-type group (P = 0.54). The one-year probability of presenting infections caused by gram-negative bacilli (51% vs 44%, P = 0.68), infections caused by gram-positive cocci (49% vs 40%, P = 0.53), and spontaneous bacterial peritonitis (29% vs 34%, respectively, P = 0.99) did not differ between the two groups. The one-year probability of transplant-free survival was 55% in the polymorphism group and 66% in the wild-type group (P = 0.15). Multivariate analysis confirmed that age, Child-Pugh score, active alcohol intake, previous hepatic encephalopathy, hepatocellular carcinoma and serum creatinine were associated with a higher risk of death during follow-up. Genetic polymorphisms D299G and/or T399I of TLR4 do not seem to play a relevant role in the predisposition of cirrhotic patients with ascites to bacterial infections.

Citocines; Malalties del fetge Citocinas, Enfermedades del hígado Cytokines; Liver diseases Probiotics can prevent pathological bacterial translocation by modulating intestinal microbiota and improving the gut barrier. The aim was to evaluate the effect of a fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 on bacterial translocation in rats with carbon tetrachloride (CCl4)-induced cirrhosis. Sprague-Dawley rats treated with CCl4 were randomized into a probiotic group that received fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 in drinking water or a water group that received water only. Laparotomy was performed one week after ascites development. We evaluated bacterial translocation, intestinal microbiota, the intestinal barrier and cytokines in mesenteric lymph nodes and serum. Bacterial translocation decreased and gut dysbiosis improved in the probiotic group compared to the water group. The ileal β-defensin-1 concentration was higher and ileal malondialdehyde levels were lower in the probiotic group than in water group. There were no differences between groups in serum cytokines but TNF-α levels in mesenteric lymph nodes were lower in the probiotic group than in the water group. Fermented milk containing Lactobacillus paracasei subsp. paracasei CNCM I-1518 decreases bacterial translocation, gut dysbiosis and ileal oxidative damage and increases ileal β-defensin-1 expression in rats treated with CCl4, suggesting an improvement in the intestinal barrier integrity. This study was partially funded by Danone Research (Palaiseau, Cedex, France), and grants PI08/0262 and PI14/00680 from the Instituto de Salud Carlos III, Madrid, Spain, and cofinanced by Fondos FEDER (Fondo Europeo de Desarrollo Regional), “Una manera de hacer Europa”, European Union, and CERCA Programme, Generalitat de Catalunya. The investigational product was provided by Danone Research. Silvia Vidal was supported by Fondo de Investigaciones Sanitarias (FIS) and is a participant in the Program for Stabilization of Investigators of the Direcció d’Estrategia i Coordinació del Departament de Salut, Generalitat de Catalunya. Pau Sancho-Bru is funded by Instituto de Salud Carlos III, Miguel Servet (CP11/00071).

Background: Emerging data suggest that innate immunity may play a role in asthma, particularly the toll-like receptors (TLRs). Some studies pointed to an involvement of TLRs 2 and 4 in the pathogenesis of allergic asthma, and other studies related TLRs to IgE. However, there are not any studies that have comprehensively evaluated the expression of TLRs 2 and 4 in inflammatory cells, in peripheral blood and induced sputum specimens from asthmatic patients, according to their total serum IgE. Methods: We studied 44 asthmatic patients (15 with high total serum IgE and 29 with normal total serum IgE). On a single visit, all patients underwent: induced sputum, pulmonary function tests, determination of exhaled nitric oxide fraction, venipuncture for blood analysis and skin prick allergy tests. The induced sputum cellularity was analyzed by flow cytometry, where expression of TLRs 2 and 4 was studied using fluorochrome-conjugated monoclonal antibodies. Results: Asthmatic patients with high total serum IgE showed, a higher percentage of macrophages expressing TLR4 (42.99 % +/- 22.49) versus asthmatic patients with normal total serum IgE (28.84 % +/- 15.16) (P = 0.048). Furthermore, we observed a correlation (but weak) between the percentage of macrophages expressing TLR4 in induced sputum and the total serum IgE level (R = 0.314; P = 0.040). Conclusion: Asthmatic subjects with high total serum IgE show increased macrophage expression of TLR4 in induced sputum. This outcome may result from a link between innate immunity and IgE-mediated, adaptive immune responses in asthma, and point to TLR4 as a potential therapeutic target.