Delta-2-Ivermectin B1a

Innate-like CD5+B1a cells localized in serous cavities are activated by innate stimuli, such as lipopolysaccharide (LPS), leading to T cell-independent antibody responses. Although ion channels play crucial roles in the homeostasis and activation of immune cells, the electrophysiological properties of B1a cells have not been investigated to date. Previously, in the mouse B cell lymphoma cells, we found that the voltage-independent two-pore-domain potassium (K2P) channels generate a negative membrane potential and drive Ca2+influx. Here, we newly compared the expression and activities of K2P channels in mouse splenic follicular B (FoB), marginal zone B (MZB), and peritoneal B1a cells. Next-generation sequencing analysis showed higher levels of transcripts for TREK-2 and TWIK-2 in B1a cells than those in FoB or MZB cells. Electrophysiological analysis, using patch clamp technique, revealed higher activity of TREK-2 with the characteristic large unitary conductance (~ 250 pS) in B1a than that in FoB or MZB cells. TREK-2 activity was further increased by LPS treatment (>2 h), which was more prominent in B1a than that in MZB or FoB cells. The cytosolic Ca2+concentration of B cells was decreased by high-K+-induced depolarization (ΔRKCl(%)), suggesting the basal Ca2+influx to be driven by negative membrane potential. The LPS treatment significantly increased the ΔRKCl(%) in B1a, though not in FoB and MZB cells. Our study was the first to compare the K2P channels in mouse primary B cell subsets, elucidating the functional upregulation of TREK-2 and augmentation of Ca2+influx by the stimulation of Toll-like receptor 4 in B1a cells.

Background:Sepsis morbidity and mortality are aggravated by acute lung injury (ALI) or acute respiratory distress syndrome (ARDS). Mouse B-1a cells are a phenotypically and functionally unique sub-population of B cells, providing immediate protection against infection by releasing natural antibodies and immunomodulatory molecules. We hypothesize that B-1a cells ameliorate sepsis-induced ALI.Methods:Sepsis was induced in C57BL/6 mice by cecal ligation and puncture (CLP). PBS or B-1a cells were adoptively transferred into the septic mice intraperitoneally. After 20 h of CLP, lungs were harvested and assessed by PCR and ELISA for pro-inflammatory cytokines (IL-6, IL-1β) and chemokine (MIP-2) expression, by histology for injury, by TUNEL and cleaved caspase-3 for apoptosis, and by myeloperoxidase (MPO) assay for neutrophil infiltration.Results:We found that septic mice adoptively transferred with B-1a cells significantly decreased the mRNA and protein levels of IL-6, IL-1β and MIP-2 in the lungs compared to PBS-treated mice. Mice treated with B-1a cells showed dramatic improvement in lung injury compared to PBS-treated mice after sepsis. We found apoptosis in the lungs was significantly inhibited in B-1a cell injected mice compared to PBS-treated mice after sepsis. B-1a cell treatment significantly down-regulated MPO levels in the lungs compared to PBS-treated mice in sepsis. The protective outcomes of B-1a cells in ALI was further confirmed by using B-1a cell deficient CD19-/-mice, which showed significant increase in the lung injury scores following sepsis as compared to WT mice.Conclusions:Our results demonstrate a novel therapeutic potential of B-1a cells to treat sepsis-induced ALI.

Multiple sclerosis (MS) is a chronic, immune-mediated disease of the central nervous system comprising of inflammation, demyelinisation and neurodegeneration. The natural history of MS is heterogenous. Owing to the vast range and severity of the symptoms MS can cause the effect of the disease on one's cognitive and physical status is unpredictable. According to the new, phenotype based classification two subgroups can be distinguished; relapsing-remitting (RR) and progressive MS. Relapsing-remitting MS can be further divided into active and inactive disease. The activity of the disease can be proven either clinically and/or by radiological means. A patient's disease is considered inactive, if it fulfills the criteriae set in the "no evidence of disease activity-3" (NEDA-3) concept, meaning that no progression can be seen on the MRI scans, the patient is relapse free and there is no worsening on any disability scale. Nowadays a paradigm shift can be seen in the treatment of MS. The aim of this shift is to provide each and every patient with the most potent medication best suiting his/her illness as soon as possible. Alemtuzumab offers a great option as either a first line treatment or as escalation therapy for patients with a highly active disease. The efficacy of alemtuzumab was proven in two phase III trials (CARE-MS I, II), where it was compared to subcutaneous interferon b-1a, administered three times weekly. In both studies alemtuzumab was superior to subcutaneous interferon b-1a in terms of relapse rate reduction, in all scouted MRI parameters. In the CARE-MS II trial it was found superior in terms of progression slowing. In the studies' first 2 years 32% and 39% of the alemtuzumab treated patients managed to achieve the NEDA-3 state (data from CARE-MS II and I respectively). At the end of the 4 year extension of both studies these numbers have increased to 60% and 55% respectively. The aim of our synopsis is to suggest neurologists an evidence based guideline, a therapeutic algorithm to be used when they give their MS patients the very best, personalised treatment, and also to appoint the recently introduced alemtuzumab to its proper place in the algorithm.