Weight: 35,31 Paper Topics: steroid purpose study demonstrate efficacy of suggest regimen for oral treatment csu patients refractory high dosage antihistamines conducted retrospective chart review patients diagnosed urticaria feburary 1 2012 december 31 2014 total 98 patients csu included these 16 patients 163% antihistamineresistant prescribed 2-week course steroid thirteen patients 812% successfully controlled antihistamines stopping course second course steroid induced remission additionally patients 125% adverse events complications associated oral steroid observed study period study demonstrated excellence 2-week course oral corticosteroid antihistamine-resistant csu propose standardized corticosteroid treatment regimenthe altered distribution follicular helper cells predict pronounced clinical course primary sjogren's syndrome margit zeher division
Weight: 11,14 Paper Topics: hybridoma monoclonal antibodies mabs produced cells specifically target antigens technique introduced kohler milstein 1975 1 possible obtain pure mabs large amounts greatly enhancing basic research potential clinical use scientific technological advances enabled successful translation mabs clinic world 570 therapeutic mabs studied clinical trials commercial companies 2 79 therapeutic mabs approved united states food drug administration us fda currently market 3 including 30 mabs treatment cancer table the increasing importance therapeutic mabs apparent fig 1 mabs predominant treatment modality various diseases past 25 years time major technological advances discovery development mab therapies quicker efficient
Weight: 7,18 Paper Topics: classes cells influenza major acute respiratory infection causes mortality morbidity worldwide conventional antivirals m2 ion channel blockers neuraminidase inhibitors mainstays managing influenza disease lessen symptoms minimizing hospitalization death patients severe influenza however development viral resistance drug classes major public health concern vaccines prophylaxis mainstays limited efficacy difficulty matching predicted dominant viral strains circulating strains such potential interventions explored viruses rely host cellular functions replicate recent therapeutic developments focus targeting host factors involved virus replication controlling virus replication potential targets drug development include controlling virus-induced host immune responses recently suggested involvement innate lymphoid nadph oxidases influenza virus pathogenesis immune cell metabolism
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IL-6 and IL-27Despite the apparent protective role of IL-6, high levels of IL-6 in serum or cerebrospinal fluid have been reported in severe neurologically complicated IAV cases, with IL-6 used as a marker for prognosis (199-201, 209, 210) . The role of IL-6 in regulation of BBB permeability was reported (211) , with potentially detrimental neurological complications. As such, the suppression of hyper-induced IL-6 as a form of therapy in severe IAV infection should be considered. One such option is the anti-IL6 antibodybased drug tocilizumab, which is currently administered clinically for the treatment of rheumatoid arthritis. However, study on the usage of this drug to treat hyper upregulation of IL-6 due to severe IAV infection has yet to be conducted. On the other hand, in a case of H1N1 virus-induced ARDS, the use of an extracorporeal cytokine hemoadsorption device to remove cytokines including TNF and IL-6 from the bloodstream (212) has showed beneficial to the patient (213) . More research is required to confirm whether the removal or neutralization of IL-6 could be a potential therapy for severe IAV infections.
Weight: 1,90 Paper Topics: tnf tnf blockade maintains il-10 phenotype human effector cd4 cd8 cells ceri a roberts cd4 cd8 effector cell subpopulations display regulatory potential characterized expression prototypically anti-inflammatory cytokine il-10 however underlying cellular mechanisms regulate expression il-10 different cell subpopulations yet fully elucidated recently showed inhibitors tnfi promote il-10 expression human cd4 cells including il-17 cd4 cells here characterized regulation il-10 expression blockade tnf signaling cytokine/co-stimulatory pathways human cell subpopulations addition tnfi drug adalimumab anti-cd3-stimulated human cd4 cell/monocyte cocultures led increased percentages il-10 cells pro-inflammatory
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resUlTsBlockade of TnFα, But not il-17, iFnγ, il-6r, or cD80/cD86-Mediated costimulation, regulates il-10 in human cD4 + T cells Our previous work demonstrated that in addition to adalimumab, other TNFα inhibitors (etanercept, infliximab, or certolizumab) as well as TNFR1/2 blocking mAbs were capable of increasing frequencies of IL-10-expressing IL-17 + CD4 + T cells (20) . We investigated whether blockade of additional pro-inflammatory pathways could promote IL-10 expression in CD4 + T cells. Blockade of IL-17A did not enhance the frequencies of IL-10 + cells in any of the CD4 + T cell populations tested (Figure 4A) . Blockade of IFNγ did not affect the percentage of IL-10 + cells within total CD4 + T cells, or within IFNγ or TNFα + subpopulations, but led to modestly increased frequencies of IL-10 + expressing cells within the IL-17 + population, although this effect was much weaker than the effect of TNF blockade in parallel cultures ( Figure 4A) . Addition of tocilizumab (IL-6R blockade) or abatacept (CTLA4-Ig, which blocks CD80/CD86-mediated co-stimulation), both of which are biologic drugs routinely used in the clinic to treat rheumatoid arthritis, did not increase IL-10 + frequencies in CD4 + T cells, IL-17 + , IFNγ + , or TNFα + CD4 + T cell subpopulations (Figure 4B) . To determine whether blockade of these pathways might regulate IL-10 expression with different kinetics to TNF blockade, IL-10 + frequencies were analyzed within both CD4 + and CD8 + T cells at different time points in anti-CD3-stimulated PBMC cultures exposed to these antibodies or drugs. IL-10 + CD4 + and IL-10 + CD8 + T cell frequencies were not regulated at any time point by blockade of IL-17, IFNγ, IL-6R, or CD80/CD86-mediated co-stimulation ( Figure S5 in Supplementary Material). Blockade of IL-1R1 in CD4 + T cell/monocyte cocultures resulted in a significantly increased proportion of IL-10 + cells within total CD4 + T cells and within IL-17 + , IFNγ + , or TNFα + subpopulations ( Figure 4B) . However, this effect was not replicated in either CD4 + or CD8 + T cells in whole PBMC cultures ( Figure S5 in Supplementary Material), indicating that the capacity of IL-1 blockade to regulate IL-10 expression may be dependent on the in vitro culture conditions. Together these data indicate that IL-10 expression in CD4 + T cells and CD8 + T cells can be regulated by blocking TNFα signaling, but not by blocking IFNγ, IL-17, IL-6R, or CD80/CD86-mediated co-stimulation, at least in vitro.
Weight: 1,65 Paper Topics: problems volume publications role endothelium health disease increased exponentially decades thoroughly considered plethora excellent reviews subject newcomers referred reliable sources detailed information presented paper 1 2 3 4 endothelium monolayer endothelial cells ecs lines interior surface blood vessels lymphatic vessels heart chambers natural blood container large surface 6000 humans 5 ecs form diffuse tissue weighing 720 adults large proportion over 600 g covering surface capillaries 6 microvessels brain represent 3-4% brain compartment constitute significant length ca 400 miles surface exchange ca 20 blood parenchyma brain 7 early stages gastrulation vertebrate embryos
Weight: 1,50 Paper Topics: complications 3 particularly acute respiratory infections ari prevalent worldwide infections influenza virus responsible morbidity mortality children groups considered high risk viral infections 1 2 there published studies prevalence viral respiratory infections juvenile idiopathic arthritis jia patients known patients higher risk severe influenza infections compared healthy children studies suggested ari trigger jia 4 available evidence suggests influenza vaccination safe immunogenic children jia however known influenza vaccination actually protective influenza-like illness ili 5 6 7 8 9 10 11 12 the objectives study evaluate frequency ari ili jia patients affect disease activity assess immunogenicity safety efficacy influenza vaccine jia patients treated
Weight: 0,66 Paper Topics: including nerve neuromyelitis optica nmo rare inflammatory disease primarily affecting optic spinal cord relatively sparing brain white matter 1 nmo exhibits relapsing-remitting course reminiscent multiple sclerosis ms previously thought variant ms however nmo considered unique pathogenesis characterized elevation autoantibodies aquaporin aqp4 2 3 nmo accompanied elevation serum autoantibodies anti-nuclear anti-ssa anti-ssb antibodies ms notably relapses nmo prevented triggered disease-modifying agents prescribed ms including interferon-beta 4 5 recent studies indicated primary autoimmune targets nmo astrocytes abundantly express aqp4 end foot processes 6 7 8 consistently inflammatory lesions nmo surrounded deposits antibodies complement associated necrotic astrocytes aqp4
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DiscussionWe further proved that IgG-producing PBs in the CSF during relapse share identical CDR sequences with those from PBs in the peripheral blood ( Table 2 ). The IgG sequences were highly mutated ( Figure S4 and S5) , indicating that helper T-cells guided the PBs toward germinal centers. Although we did not separate CD138 − and CD138 + PBs in this analysis, the number of mutations in the H-chain variable regions showed a singlepeak distribution (Figure S4) . These results suggest that both CD138 − and CD138 + PBs are affinity-maturated B-cells, although CD138 expression levels could inversely correlate with the tissue-migrating ability  . There remained a possibility that mB might give rise to PBs within the CSF. However, further affinity maturation in PBs was not observed in CSF compared with peripheral blood, indicating that clonal expansion and differentiation of mB in the CSF is not a major pathway. This assumption is also supported by the rare occurrence of CSF oligoclonal bands and raised IgG index in NMO, which indicates that the intrathecal IgG synthesis was low, transient, and restricted to acute relapse in NMO patients [6, 31] . Taken together, it is likely that CXCR3-expressing PBs are expanded in the periphery and recruited to the CNS in the pathogenesis of NMO. In the CNS, B-cell stimulatory cytokines such as IL-6 would support the PB survival and AQP4-Ab production, leading to the destruction of astrocytes and the glia limitans. We and another group have shown that PBs from peripheral blood and CSF produce anti-AQP4 IgG antibody in NMO [10, 12] . We therefore postulated that the common IgGs shared by PBs from the PBMC and CSF (Table 2 ) could bind to AQP4. Despite substantial efforts, however, we have not succeeded in this attempt so far. Though we speculate that peripherally expanded PBs producing anti-AQP4 should be able to cross BBB like other PBs, irrespective of the antigen specificity, more efforts will be needed to formally prove our postulate. We previously demonstrated the role of IL-6-dependent PBs in the production of AQP4-Ab  . In the present report, we indicate that PBs may play a more critical role in the CNS by locally producing AQP4-Ab. The relevance of this model can be verified in clinical trials of drugs targeting appropriate cells or molecules. In fact, we have recently shown that humanized anti-IL-6 receptor antibody (Tocilizumab) was efficacious in a patient with NMO in reducing the number of PBs in the peripheral blood as well as stabilizing the clinical conditions  . In another report, Tocilizumab successfully controlled three NMO patients who were resistant to the anti-CD20 antibody Rituximab  . These results indicate that PBs, rather than CD20 + mB, play a pivotal role in NMO. Therefore, it will be intriguing to test the effect of drugs altering the migration of PBs toward the CNS  . Figure S1 . Flow cytometric analysis of PB. Flow cytometric scheme of B-cell subpopulation analysis. The partitioned cells are CD19 + CD27 + cells within peripheral blood mononuclear cells (PBMC; left panel). The CD19 + CD27 + cells were further analyzed to investigate the expression of CD38 and CD180 (middle panel). CD38 high CD180 -cells (partitioned in the middle panel), corresponding to plasmablast (PB) cells, were analyzed again to investigate the expression of CD19 and CD27 (right panel). This result assured that the encircled population in Figure 1A represented CD19 int CD27 high CD38 high CD180 -PB cells.
Weight: 0,58 Paper Topics: receptors treg correct balance immune effector regulatory responses depends number molecular interactions antigen-presenting cell apc t-cell key interaction immunological tolerance programmed death-ligand pd-l1 programmed death-1 pd-1 apc expression pd-l1 leads binding molecule pd-1 t-cells resulting activation tyrosine phosphatase shp-2 dephosphorylation critical kinases involved t-cell receptor tcr signalling blockade interaction diminishes frequencies enhances th1 th17 effector cell frequencies increases cytokine production vitro vivo pd-l1:pd-1 interaction targeted immunological situations feature restricted antigen presentation t-cell anergy immune tolerance detrimental characteristicsnamely chronic infectious diseases malignancies scenario clinical trials demonstrated remarkable efficacy drugs developed target receptors 87% clinical response
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