Positive Selection of B Cells Expressing Low Densities of Self-reactive BCRs

B cell tolerance or autoimmunity is determined by selective events. Negative selection of self-reactive B cells is well documented and proven. In contrast, positive selection of conventional B cells is yet to be firmly established. Here, we demonstrate that developing self-reactive B cells are not always highly sensitive to the deletion mechanisms imposed by membrane-bound self-antigens. At low amounts, membrane-bound antigens allow survival of B cells bearing a single high affinity self-reactive B cell receptor (BCR). More importantly, we show that forced allelic inclusion modifies B cell fate; low quantities of self-antigen induce the selection and accumulation of increased numbers of self-reactive B cells with decreased expression of antigen-specific BCRs. By directly measuring antigen binding by intact B cells, we show that the low amounts of self-antigen select self-reactive B cells with a lower association constant. A fraction of these B cells is activated and secretes autoantibodies that form circulating immune complexes with self-antigen. These findings demonstrate that conventional B cells can undergo positive selection and that the fate of a self-reactive B cell depends on the quantity of self-antigen, the number of BCRs engaged, and on its overall antigen-binding avidity, rather than on the affinity of individual BCRs

Genetic and Functional Characterization of an MCR-3-Like Enzyme-Producing Escherichia coli Isolate Recovered from Swine in Brazil

A collection of 126 pigs was screened for carriage of colistin-resistant Enterobacteriaceae in a farm in Minas Gerais, Brazil. Out of this collection, eight colistin-resistant Escherichia coli isolates were recovered, including one from Minas Gerais State producing a new MCR-3 variant (MCR-3.12). Analysis of the lipopolysaccharide revealed that MCR-3.12 had a function similar to that of MCR-1 and MCR-2 as a result of the addition of a phosphoethanolamine group to the lipid A moiety. Genetic analysis showed that the mcr-3.12 gene was carried by an IncA/C2 plasmid and was embedded in an original genetic environment. This study reports the occurrence of the MCR-3-like determinant in South America and is the first to demonstrate the functionality of this group of enzymes as a phosphoethanolamine transferase

International multicentre observational study to assess the efficacy and safety of a 0·5 mg kg−1 per day starting dose of oral corticosteroids to treat bullous pemphigoid

BackgroundEuropean guidelines propose a 0 center dot 5 mg kg(-1) per day dose of oral prednisone as initial treatment for bullous pemphigoid (BP). We assessed the safety and efficacy of this regimen depending on BP extent and general condition of the patients.MethodsIn a prospective international study, we consecutively included all patients diagnosed with BP. Patients received a 0 center dot 5 mg kg(-1) per day dose of prednisone, which was then gradually tapered 15 days after disease control, with the aim of stopping prednisone or maintaining minimal treatment (0 center dot 1 mg kg(-1) per day) within 6 months after the start of treatment. The two coprimary endpoints were control of disease activity at day 21 and 1-year overall survival. Disease severity was assessed according to the Bullous Pemphigoid Disease Area Index (BPDAI) score.ResultsIn total, 198 patients were included between 2015 and 2017. The final analysis comprised 190 patients with a mean age of 80 center dot 9 (SD 9 center dot 1) years. Control of disease activity was achieved at day 21 in 119 patients [62 center dot 6%, 95% confidence interval (CI) 55 center dot 3-69.5]; 18 of 24 patients (75%, 95% CI 53 center dot 3-90 center dot 2), 75 of 110 patients (68 center dot 8%, 95% CI 59 center dot 2-77 center dot 3) and 26 of 56 patients (46.4%, 95% CI 33 center dot 0-60 center dot 3) had mild, moderate and severe BP, respectively (P = 0 center dot 0218). A total of 30 patients died during the study. The overall Kaplan-Meier 1-year survival was 82 center dot 6% (95% CI 76 center dot 3-87 center dot 4) corresponding to 90 center dot 9%, 83 center dot 0% and 80 center dot 0% rates in patients with mild, moderate and severe BP, respectively (P = 0 center dot 5). Thresholds of 49 points for BPDAI score and 70 points for Karnofsky score yielded maximal Youden index values with respect to disease control at day 21 and 1-year survival, respectively.ConclusionsA 0 center dot 5 mg kg(-1) per day dose of prednisone is a valuable therapeutic option in patients with mild or moderate BP whose general condition allows them to be autonomous.</p

Interactions et effets des lipopolysaccharides bactériens dans l'alvéole pulmonaire

Résumé français (1000 caractères maxi)Résumé anglais (idem)ORSAY-PARIS 11-BU Sciences (914712101) / SudocSudocFranceF

Lipopolysaccharide from Salmonella enterica Activates NF-κB through both Classical and Alternative Pathways in Primary B Lymphocytes▿

Lipopolysaccharides (LPS) are potent polyclonal B-lymphocyte activators. Recently, we have shown that LPS inhibits both spontaneous and drug-induced apoptosis in mature B lymphocytes, through cytosolic retention of Bax, a proapoptotic protein of the Bcl-2 family, by preventing its translocation to mitochondria. Research within the last few years has revealed that members of the NF-κB transcription factor regulate cell viability by activating genes involved in mitochondrion-dependent apoptosis. In this report, we examined the effect of sustained LPS stimulation on cytosolic and nuclear proteins of the IκB/NF-κB family to determine which NF-κB pathway, canonical (classical) or noncanonical (alternative), is activated by this agent in mature B cells. Immunoblotting analyses showed that LPS induced a time-dependent degradation of the NF-κB inhibitors IκBβ and IκBɛ (preferentially to isoform IκBα), via IκB kinase β. In addition, we observed that LPS triggered the processing of NF-κB p105 to p50 and that of NF-κB p100 to p52 in parallel with nuclear translocation of active p50 and p52, as NF-κBp50/RelA and NF-κBp52/RelB heterodimers, respectively. These results suggest that sustained stimulation with LPS can activate NF-κB through both classical and alternative pathways

Priming and activation of mouse macrophages by trehalose 6,6'-dicorynomycolate vesicles from Corynebacterium glutamicum

Vesicles consisting of pure trehalose dicorynomycolate (TDCM), the corynebacterial analog of the most studied mycobacterial glycolipid 'cord factor', were isolated from Corynebacterium glutamicum cells by mild detergent treatment; these induced in vivo a macrophage priming similar to that obtained with mycobacterial-derived trehalose dimycolate. In vitro, both TDCM and bacterial lipopolysaccharide (LPS) induced in macrophages the production of nitric oxide (NO) and tumor necrosis factor-alpha (TNF-alpha), endotoxin tolerance, and were primed for an enhanced secondary NO response to LPS. Interferon-gamma pretreatment did not influence the LPS-induced TNF-alpha response, but considerably increased the TDCM-induced response