Ig Production Research Articles

Inversion of PM2.5 atmospheric refractivity profile based on AlexNet model from the perspective of electromagnetic wave propagation

Human civilization has reached an unprecedented height, but the industrialization of economic development also brings global warming, ozone depletion, acid rain, fresh water resources crisis, energy shortage, and environmental problems. In autumn and winter, haze becomes the usual state in the modern society, and PM2.5 has been becoming an important form of air pollution. The research found that PM2.5 brings great influence to the human body or daily life. To some extent, the PM2.5 also affects the propagation of electromagnetic waves near the ground, reducing the transmission performance of electromagnetic wave. Based on Mie scattering theory, this paper qualitatively analyzed the scattering effects of PM2.5 particles on every frequency band of electromagnetic wave in daily use. Then the paper takes the satellite navigation signals as a research example, selecting university of Wyoming Davis stations in Antarctica sounding data by measuring the tropospheric atmospheric meteorological parameters (including the atmosphere pressure, geopotential height of different layers, dew point temperature, relative humidity and specific humidity, wind direction, wind speed, and temperature). The paper inversed the refractive index distribution of the troposphere based on AlexNet model and described the error quantitatively. The simulation results show that the estimated error is less than 5.1455%, proving the high accuracy of the AlexNet model. To test the influence of PM2.5, the paper takes Jiuquan, a city with serious pollution, as an example. Comparison between the inversion results and IGS products shows that high concentration of PM2.5 pollution has little influence on the inversion of refractive index profile.

P086 Identification of constitutive modifications in plasma cells and B lymphocytes in patients with inflammatory bowel disease

Abstract Background Plasma cells (PCs) and B lymphocytes (BLs) are a source of immunoglobulins (Ig), being IgA essential for intestinal homeostasis. An unbalanced intestinal Ig production has been described in inflammatory bowel disease (IBD). Nevertheless little is known about the role of mucosal Ig-producing BL and PC in IBD, reason why we decided to study them. Methods We included 12 healthy controls -HC-, 10 patients with ulcerative colitis (three active -aUC- and seven quiescent -qUC) and 10 patients with Crohn’s disease (three active -aCD- and seven quiescent -qCD). Disease was located in the distal colon in all patients, although the quiescent ones had no inflammation (endoscopic Mayo = 0; SES-CD = 0–1). Distal colon biopsies were collected together with peripheral blood. Mucus layer and epithelial barrier was removed from the biopsies and lamina propria mononuclear cells were harvested using the ‘walk-out’ protocol. Peripheral blood mononuclear cells were obtained after ficoll centrifugation. In both cases, cells were stained with specific antibodies, acquired in a FACSCanto II cytometer, and analysed with FlowJo. Median percentage of PC and BL (and their subsets) relative to each tissue was calculated and compared using non-parametric statistics, considering statistically significant p < 0.05. Results The proportion of plasmablasts, blood-precursors of PC, was higher in the blood of active IBD patients (HC: 0.8%; aUC: 5.3%; aCD: 3.4%). Even though there were no differences in the colonic proportion of PC between the study groups, there was a constitutive lower proportion of IgA-producing PC in IBD, irrespective of its type (UC or CD) or presence of inflammation (HC: 88%; qUC: 55%; aUC: 38%; qCD: 70%; aCD: 44%). Moreover, aCD patients also showed a significantly higher proportion of IgM-producing PC (HC: 6% vs. aCD: 10%), and a higher proportion PC expressing CD19 compared both with HC and qCD (HC: 43%; qCD: 52%; aCD: 74%). The proportion of BL and their subsets did not show differences between the study groups, neither in blood nor in colon. However, in UC patients, some circulating subsets displayed a lower proportion of cells expressing the gut-homing integrin β7: naive BL (HC: 11.5%; qUC: 2.9%; aUC: 0.6%) and IgM memory BL type CD27+ (HC: 43%; qUC: 30%; aUC: 23%) and also CD27- (HC: 32% vs. aUC: 5%). Conclusion IBD patients have a diminished percentage of colonic IgA-producing PC, which is irrespective of the type of IBD or the inflammatory status; this reduction could compromise the correct microbiota regulation in IBD. The reduction of the percentage of β7-expressing BL in the blood of UC patients could potentially point to a specific pathogenic mechanism of UC.

Evidence for the Presence of Long-Lived Plasma Cells in Nasal Polyps.

PurposePlasma cells and immunoglobulins (Igs) play a pivotal role in the induction and maintenance of chronic inflammation in nasal polyps. During secondary immune responses, plasma cell survival and Ig production are regulated by the local environment. The purpose of the present study was to investigate the presence of long-lived plasma cells (LLPCs) and specific survival niches for LLPCs in human nasal polyps.MethodsNasal mucosal samples were cultured with an air-liquid interface system and the Ig levels in culture supernatants were analyzed by enzyme-linked immunosorbent assay. The characteristics of LLPCs in nasal polyps were determined by immunohistochemistry and immunofluorescence. The expression of neurotrophins as well as their receptors was detected by quantitative real-time polymerase chain reaction, immunohistochemistry, immunofluorescence, and Western blotting.ResultsThe numbers of CD138+ total plasma cells and BCL2+ plasma cells were increased in both eosinophilic and non-eosinophilic nasal polyps compared with those in normal tissues. The production of IgG, IgA, and IgE was detected in culture supernatants even after a 32-day culture of nasal polyps. Although the total numbers of plasma cells were decreased in nasal polyps after culture, the numbers of BCL2+ plasma cells remained stable. The expression of nerve growth factor (NGF) as well as tropomyosin receptor kinase (Trk) A, a high-affinity receptor for NGF, was upregulated in both eosinophilic and non-eosinophilic nasal polyps. In addition, BCL2+ plasma cell numbers were positively correlated with NGF and TrkA mRNA expression in nasal mucosal tissues. Polyp plasma cells had the expression of TrkA.ConclusionsHuman nasal polyps harbor a population of LLPCs and NGF may be involved in their prolonged survival. LLPCs may be a novel therapeutic target for suppressing the local Ig production in nasal polyps.

Sestrin2 Mediates IL-4-induced IgE Class Switching by Enhancing Germline ε Transcription in B Cells

Sestrin2 (Sesn2), a metabolic regulator, accumulates in response to a diverse array of cellular stresses. Sesn2 regulates cellular metabolism by inhibiting the mammalian target of rapamycin complex 1 through the AMP-activated protein kinase (AMPK) signaling pathway. Recently, researchers reported that Sesn2 regulates the differentiation and function of innate immune cells and T cells; however, the role of Sesn2 in B cells is largely unknown. In this study, we investigated the role of Sesn2 in Ig class switching and Ig production in mouse B cells. We observed that mouse B cells express Sesn2 mRNA. Interestingly, the expression of germline ε transcripts (GLTε) was selectively decreased in lipopolysaccharide-stimulated Sesn2−/− splenocytes. Overexpression of Sesn2 increased GLTε promoter activity in B cells. In addition, AICAR (an activator of AMPK) selectively increased IL-4-induced GLTε expression and surface IgE (sIgE) expression in splenocytes. Furthermore, AICAR selectively enhanced IL-4-induced GLTε expression, sIgE expression, and IgE production by anti-CD40-stimulated B cells. We observed that ovalbumin (OVA)-specific IgE concentration was reduced in OVA-challenged Sesn2−/− mice. Taken together, these results indicate that Sesn2-AMPK signaling selectively enhances IL-4-induced IgE class switching and IgE production by B cells, suggesting that this could be a therapeutic strategy targeting Sesn2 in IgE-mediated allergic diseases.

Receiver DCB analysis and calibration in geomagnetic storm-time using IGS products

Solar activity and geomagnetic storm cause ionospheric disturbance and affect the GNSS positioning accuracy, which this effect cannot be ignored. The reliability depends mainly on differential code bias (DCB), when estimating the total electron content (TEC) with GNSS pseudorange observations. This study analyzes the variation characteristics of receiver DCB (RDCB) during a strong geomagnetic storm to determine whether the RDCB estimation is affected by space weather. Results show that the RDCB dispersion of low-latitude stations is larger than that of other areas. On the storm day, the RDCB standard deviation (STD) exhibits a peak characteristic and the number of RDCB abnormal stations is significantly more than that on quiet day. Analysis shows that the RDCB abnormality is caused by the ionospheric model misalignment during the ionospheric disturbance. By correcting the RDCB, the RDCB STD is reduced by 43.10%. Thus, the model correction can improve the estimation accuracy of RDCB during geomagnetic storm.

Correction: T Cell-Dependent Maturation of Pathogen-Specific Igs in the Antrum of Chronically Helicobacter pylori-Infected Patients.

Mucosal plasma cells (PC) and Ig production are essential to fend pathogens and to maintain mucosal homeostasis. In human Helicobacter pylori infection, mucosal PC express inducible NO synthase (iNOS), which positively correlates with clearance of experimental human infection. To characterize Ig genes and specificities of antral mucosal iNOS+ and iNOS- PC in H. pylori infection, we sequenced rearranged Ig genes from single cell-sorted PC from biopsy specimens of chronically infected patients and analyzed them with respect to their molecular features. The binding specificity of individual PC's Ig was determined following recombinant expression. We identified high rates of somatic hypermutations, especially targeting RGYW/WRCY hotspot motifs in the individual Ig genes, indicating T cell-dependent maturation. For seven of 14 recombinantly expressed Ig, Ag specificity could be determined. Two clones reacted to H. pylori proteins, and five were found to be polyreactive against LPSs, dsDNA, and ssDNA. All specific Ig originated from iNOS+ PC. H. pylori-specific Ig are encoded by V and J family genes previously shown to be also used in rearranged Ig loci of MALT B cell lymphomas. In summary, mucosal iNOS+ PC producing H. pylori-specific Ig accumulate in infection and appear to be a product of T cell-dependent B cell maturation. Moreover, the Ig's molecular features partly resembled that of MALT B cell lymphoma Ig genes, suggestive of a mechanism in which a progressive molecular evolution of pathogen-specific B cells to MALT B cell lymphoma occurs.

Regulatory T Cell Adoptive Immunotherapy Promotes B Cell Immunity after Haploidentical Transplantation

Background: Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Tregs) effectively prevents conventional T cell (Tcons) mediated Graft versus Host Disease (GvHD) while it does not impair graft-versus-leukemia effect in haploidentical hematopoietic cell transplantation (haplo-HCT). Moreover Treg immunotherapy promotes fast donor T cell recovery after transplant. Recent studies showed that mouse bone marrow (BM) Tregs localize in the hematopoietic stem cell (HSC) niche, where they contribute to HSCs maintenance and promote donor engraftment and B cell lymphopoiesis. We are investigating if human Tregs promote B cell reconstitution and immunity in preclinical models and in haplo-HCT patients. Methods: Human sample analysis: B cell reconstitution was analysed monthly by FACS in BM and peripheral blood (PB) samples from 66 patients who underwent either Treg/Tcon haplo-HCT (45 patients), or T-cell depleted haplo-HCT (8 patients) or haplo-HCT with post-transplant cyclophosphamide (PTCy, 13 patients). Diagnosis was acute leukemia in 52 patients, lymphoma in 11 and multiple myeloma in 3. PB total immunoglobulin (Ig), anti-Cytomegalovirus (CMV) IgM and CMV viremia were monitored. Humanized mouse model: donor derived human Tregs and purified CD34+ HSCs were co-infused in sublethally irradiated (2 Gy) immune-deficient NSG mice. Donor engraftment and B cell reconstitution were analysed by FACS and histology. Results: B cell reconstitution was faster after Treg/Tcon haplo-HCT when compared to other haplo-HCT protocols. B cell counts were higher in PB of patients that received Treg/Tcon haplo-HCT (p<.05) and were comparable to those of healthy subjects by 4 months after transplant (117±148 cells/mm, Fig.1A). We could detect early frequencies of CD34+CD38+CD10+CD127+ common lymphoid progenitors, CD45+CD10+CD38+CD19- Pre/Pro-B, CD45+CD10+CD38+CD19+ Pre-B, and Pro-B cells in the BM of these patients, that resulted in an increased production of CD38+CD19+CD5-IgM+ immature B cells, CD38+CD19+CD5+IgM+ transitional B cells and CD19+CD20+ mature B cells. We used a mouse model of xenotransplantation to understand whether donor B cell reconstitution in Treg/Tcon haplo-HCT is boosted by a Treg-mediated effect on donor human HSCs. We found that infusion of human Tregs facilitated donor HSC engraftment. BM and PB human chimerism was increased (p<.05) in mice that received Treg infusion. BM histology revealed the presence of in vivo expanded human CXCR4+ Tregs in the femurs of Treg receiving mice 1 month after transplant. In the same samples we observed a lower number of CD34+ HSCs, suggesting BM Tregs facilitate donor HSC differentiation. Moreover, Treg treatment allowed human HSCs to localize preferentially in the epiphyseal areas of the femurs, where donor cells started to engraft (p<.04). When looking at donor B cell reconstitution, we found HSC-derived mature B cells rapidly abundant and easily detectable starting 30 days after HSC infusion in PB of Treg-treated animals (p<.05). To further assess whether HSC-derived B cells were functional in patients that received Treg/Tcon haplo-HCT, we analysed total Ig production and specific responses to CMV reactivation. Post-transplant hypogammaglobulinemia was rapidly corrected in Treg/Tcon haplo-HCT patients. Total IgM were higher compared to other haplo-HCT protocols and reached normal levels by 3 months after transplant (96±155 mg/dL, Fig.1B). CMV reactivation rate was lower (47% vs 79%) and it occurred later after Treg/Tcon immunotherapy (51±19 vs 40±48 days). New production of anti-CMV specific IgM was documented in 43% of CMV seropositive patients 98±48 days after Treg/Tcon haplo-HCT, while anti-CMV specific IgM were almost undetectable after other haplo-HCT protocols within the first 6 months after transplant (Fig.1C). Such potent B cell responses coupled with T cell reconstitution resulted in a reduction of CMV second reactivations (Fig.1D p<.05) with no patient that died with CMV disease. Conclusions: Adoptive transfer of human Tregs boosts donor HSC engraftment and facilitates the reconstitution of functional HSC-derived donor B cells. Such results suggest that Treg/Tcon haplo-HCT patients could be early vaccinated after transplant. Treg/Tcon immunotherapy promotes control of infections and B cell immunity in patients undergoing haplo-HCT. Disclosures No relevant conflicts of interest to declare.

PDB83 ANALYSIS OF PRESCRIPTION RATES OF INSULIN GLARGINE (IG), PER PRODUCT AND PRESENTATION TYPE, BY GENERAL PRACTITIONERS (GP) IN ENGLAND AND ITS ASSOCIATION WITH HEALTH DETERMINANTS (2013-2018)

To investigate GP prescription rates of IG in England, per product (including biosimilars), and potential associations with key demographic and socio-economic variables. The list of all IG prescriptions by GPs in England between April 2013 and December 2018 was extracted from UK Government databases. Age (mean years) and sex (percentage of females) of patients registered with each GP were retrieved. Socio-economic characteristics (income deprivation [percentage income-deprived], ethnicity [percentage of white people] and rural-urban classification [dichotomous]) of areas where GPs are located were collected. Insulin glargine prescription levels and their temporal trends were analysed. Mixed-effects Poisson regression models were implemented to understand potential associations between prescription rates and key variables. Concentration indices were calculated to evaluate potential inequalities in prescription rates according to income deprivation. Lantus SoloStar® was the most frequently prescribed IG product, with approximately constant levels since 2013. Toujeo SoloStar Pen® and Abasaglar KwikPen® (biosimilar) prescription levels steeply increased since the first prescribed in 2015. Regression analyses showed the association between IG prescription rates and the variables studied. Income deprivation had a positive effect on prescription levels of Lantus® (SoloStar®/cartridges) and Abasaglar KwikPen®, i.e. the more income-deprived the higher prescription levels were. Additionally, results from regression analyses implied that different prescribing behaviours may exist across Clinical Commissioning Groups (CCGs). Concentration indices did not indicate the existence of substantial inequalities in the distribution of IG prescriptions across the population. Results demonstrated that the way GPs in England prescribe IG are associated with the characteristics of the patients they serve. These relationships do not seem to vary greatly across products, including IG biosimilars. Potential variations in prescription levels across CCGs may be related to individual CCG prescribing policies. Understanding the cause of potential variations in prescription levels across GPs and CCGs can help ensure equitable healthcare.

Analysis of BDS Fractional Cycle Biases and PPP Ambiguity Resolution.

It is difficult to enable traditional precise point positioning (PPP) with ambiguity resolution (AR) due to fractional cycle biases (FCBs), which limit the accuracy and reliability of positioning results. The BeiDou Navigation Satellite System (BDS) has been providing continuous positioning, navigation, and timing (PNT) services in the global region since the end of 2018. The BDS constellation includes geostationary earth orbit (GEO), inclined geostationary orbit (IGSO), and medium earth orbit (MEO) satellites. However, its hybrid constellation structure and the satellite-side multipath effect have hindered the BDS PPP AR for two main reasons: (1) some receivers have half-cycle biases between GEO and non-GEO satellites, which result in the inconsistency of hardware delays for each satellite type; (2) the correction model for elevation-dependent satellite-side multipath effect is only applicable to IGSO and MEO, while in the case of GEO the effect cannot be effectively weakened or eliminated. To rectify these problems, a suitable strategy is proposed for estimating BDS FCBs, whereby the GEO FCBs and non-GEO FCBs are estimated independently. Results show that the FCBs estimated by the new strategy for GEO and non-GEO are more stable compared to the traditional strategy. The GEO wide-lane (WL) FCBs fluctuate less than 0.3 cycle in one month, except for C05, while the variation of non-GEO WL FCBs is about 0.1 cycle. In addition, compared to the traditional strategy, the fractions of GEO WL ambiguities after the removal of FCBs estimated by the new strategy can be improved noticeably from 53.5% to 78.5%, and from 71.8% to 92.3% for <0.15 cycle and <0.25 cycle respectively, which could be comparable with non-GEO. Simultaneously, the improvement of GEO narrow-lane (NL) ambiguities is from 28.9% to 40.2%, and from 40.4% to 53.3% for <0.10 cycle and <0.15 cycle respectively, are less noticeable. This is mainly due to the low precision IGS products for GEO. After PPP AR, the mean convergence time is shorted from 56.0 min to 43.6 min, and from 71.6 min to 62.7 min for static PPP and kinematic PPP, respectively.

The Probiotic Bacterium Isolated from Bekasam (Traditional Fermented Food), Lactobacillus Sp. Induces Activation of Gut Mucosal Immune System in Rat.

BACKGROUND:Bekasam is one of the traditional foods in South Sumatra, Indonesia, a mixture of fermented fish containing Lactic Acid Bacteria (LAB), Lactobacillus sp. Non-commensal bacteria and probiotics can induce intestinal mucosal immune responses.AIM:This pilot study aimed to see the efficacy of Lactobacillus sp. to the immune response of the intestinal mucosa by assessing the levels of IgA in the intestinal fluid and markers of T cell populations, such as CD4 and CD8 in the intestinal mucosa.METHODS:This study was an in vivo experimental study. As many as 30 rats were grouped into 3 treatment groups (doses 107, 108, and 109 CFU/rat/day, for 7 days) and 2 groups of controls (negative control, 10% non-fat milk, and positive control, Lactobacillus casei 108 CFU/rat/day for 7 days). At the end of the treatment, the intestinal mucosa was taken to examine the levels of IgA, CD4 and CD8 using the Enzyme-Linked Immunosorbent Assay (ELISA) method, according to the manuals of each ELISA kit. All displays of research data were presented with means ± SD. T-test was used to assess the significance of differences.RESULTS:Secretion of Ig A increased with the addition of Lactobacillus sp. from bekasam. Administration of Lactobacillus sp. yielded no effect on helper T cell level (CD4 markers), as well as on cytotoxic T cell levels (CD8 markers).CONCLUSION:Lactobacillus sp. probiotic from bekasam improved the intestinal mucosal immune system by increasing the production of Ig A, but exhibited no effect on T lymphocyte cells.

The Carrier Phase Time Transfer with Broadcast Ephemeris

Time transfer method PPP is restricted by the real-time and precision of IGS production, and the real-time application have not been widely implemented. Standard Point Positioning(SPP) can satisfy the application for the real-time customer, but the precision is low and is not satisfy the high precision customer. So a new algorithm which have real-time and high precision performance is given. The algorithm dose not need the external orbit and clock error, and can be used for the real-time time transfer because of getting rid of the reliance on IGS production. In this paper, the analysis for the new algorithm is given by using the real measurement data. The results show that the algorithm could improve the time transfer results and frequency stability significantly; the time transfer precision of the new algorithm relative to SPP is improved from 10 ns to 1-2 ns, and dose not need the external precise ephemeris production; the new algorithm can be realized in the receiver conveniently.

Functional nutrition modulates the early immune response against viral haemorrhagic septicaemia virus (VHSV) in rainbow trout

Although viruses represent a major threat for cultured fish worldwide, the commercialization of vaccines capable of providing effective and long-lasting protection is still lacking for most of these viral diseases. In this situation, the use of supplemented diets could be a suitable strategy to increase the immune status of the fish and reduce the impact of viral pathogens. Among possible immunostimulants that could be included in these functional feeds, some studies have previously shown that certain β-glucans can significantly increase certain immune parameters of fish and reduce the impact of viral diseases. However, the mechanisms through which β-glucans exert their activity have not been fully elucidated yet. In the current study, we have studied the immune response of different tissues to viral haemorrhagic septicaemia virus (VHSV) in rainbow trout fed with a non-supplemented control diet as well as in fish fed a commercial functional aquafeed (Protec™, Skretting) containing β-glucans, vitamin C, vitamin E and zinc. For this, after 30 days of feeding the fish with one of the two diets, they were subsequently infected with VHSV by bath or mock-infected. After 2 or 6 days post-infection, fish were sacrificed and the levels of transcription of different immune genes such as IgM, IgT, IgD, Mx, interferon γ (IFN γ) and perforin studied in different tissues (kidney, gut and gills). Additionally, the levels of natural IgMs in serum were also determined. Our results demonstrate that fish fed the functional diet were capable of mounting an increased IgM, IgT, IgD and Mx transcriptional response to the virus. Additionally, these fish also showed increased levels of natural IgMs in serum. These results reveal a previously undescribed effect of functional diets on fish Ig production and point to Protec™ as an adequate diet to be incorporated in holistic programs aimed at mitigating the effect of viral diseases.

Abstract P1108: Serum Immunoglobulins are Not Necessary for Experimental Hypertension

The role of B cells and serum immunoglobulins (Ig) in hypertension is unclear. Elevated serum IgG has been observed in some hypertensive patients and in animal models of hypertension. Mice with a severe B cell deficiency due to lack of B cell activating factor receptor (BAFF-R) and mice lacking the cytokine interleukin 21 (IL21) - which is a potent inducer of B cell Ig class switching and high affinity Ig production - are protected from Ang II-induced hypertension and exhibit reduced serum IgG levels. Thus, we sought to determine whether hypertensive IgGs play a causative role in hypertension and end-organ dysfunction. First, we purified serum IgG from normotensive and hypertensive wild type (WT) mice and adoptively transferred equal amounts of IgG by intraperitoneal injection into normotensive recipient mice followed by infusion of a sub-pressor dose of angiotensin II (Ang II) for 2 weeks. Flow cytometric analysis of aortas revealed a modest increase in F4/80+ macrophages (p=0.04) and CD8+ T cells (p=0.02) in mice that received hypertensive IgG. However, there was no difference in endothelial dependent relaxation, renal inflammation, albuminuria, and blood pressure (BP) between the two groups. As an alternative method to investigate the role of class-switched high affinity Igs, we studied mice with genetic deletion of activation-induced deaminase (AID) which is an enzyme necessary for somatic hypermutation (to generate high affinity Igs) and isotype class switching. AID -/- mice exhibit undetectable IgG and higher levels of IgM in serum compared to WT mice. Ang II infusion for 4 weeks revealed no difference in BP, aortic inflammation, renal inflammation, and albuminuria. We also studied mice with deficiency of the IgM heavy chain (uMT). These mice exhibit undetectable levels of all immunoglobulins and are severely deficient in mature B cells. uMT-/- mice are also not protected from hypertension induced by Ang II infusion or deoxycorticosterone acetate (DOCA-salt) treatment. Together, these results demonstrate that while elevated serum immunoglobulins seen in hypertensive animals and humans may represent a biomarker of aberrant immune activation, they are likely not playing a causal role in hypertension pathophysiology.

A distributed method to estimate RDCB and SDCB using a GPS receiver network

In this paper, a distributed method to estimate satellite and receiver differential code biases (DCBs) separately utilizing a network of global positioning system (GPS) receivers is proposed. The proposed method consists of many local filters and a single fusion module. Each local filter estimates vertical ionospheric delays (VIDs) and the combined DCBs (CDCBs) by utilizing dual-frequency code and carrier-phase measurements from each receiver. The fusion module gathers the combined DCB estimates and their estimation errors from all the local filters. Then it discriminates the satellite DCBs (SDCBs) and the receiver DCBs (RDCBs) separately. By an experiment, it is shown that the RMS difference of SDCBs and RDCBs between the proposed method and the IGS product are around 0.374 m and 0.424 m, respectively.

Circulating follicular regulatory T cells could inhibit Ig production in a CTLA-4-dependent manner but are dysregulated in ulcerative colitis

Ulcerative colitis (UC) is a chronic relapsing inflammatory disease that occurs in the gastrointestinal tract, characterized by an upregulation in autoantibody production and antimicrobial antibody production. The interaction between follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) is critical to the induction and regulation of antibody production. In this study, we investigated the characteristics of Tfr cells in UC patients. We gated circulating Tfr cells as CD4+CXCR5+CD25+CD127− T cells, of which approximately 73% on average were Foxp3+. The circulating Tfh (CD4+CXCR5+CD25−) cells from control subjects and UC patients presented a comparable capacity to induce IgM production from naive B cells and to mediate class switching to IgG. Tfr cells significantly reduced Tfh-mediated B cell help in both healthy controls and UC patients in a concentration-dependent manner. However, the suppression capacity of Tfr cells was significantly lower in UC patients than in healthy controls. Subsequently, we found that the frequency of CTLA-4-expressing cells was only slightly lower in UC patients, but the MFI of CTLA-4, however, was markedly lower in UC patients. CTLA-4 blockade nearly abrogated Tfr-mediated suppression of IgM, and significantly reduced Tfr-mediated suppression of IgG. Moreover, CTLA-4 blockade removed the relative advantage of Tfr suppression capacity in healthy controls compared to UC patients. Overall, this study demonstrated that CTLA-4 was required for Tfr-mediated suppression of B cell help, but was expressed at lower levels in UC patients.

Th17 cells in glaucoma patients promote Ig production in IL-17A and IL-21-dependent manner.

Elevated expression of autoantibodies is a hallmark of immune dysregulation in glaucoma and may cause retinal ganglion cell apoptosis and immune-mediated nerve damage, thus contributing to the development of blindness. The cause of autoantibody upregulation remains unclear. Th17 cells are shown to promote autoimmunity and Ig production. Here, we demonstrate that the serum levels of interleukin (IL)-17A and IL-21 are comparable between glaucoma patients and non-glaucoma controls. However, the levels of Th17-promoting cytokines, such as tumour necrosis factor (TNF) IL-6, are higher in glaucoma patients than in controls. Subsequently, we demonstrate that glaucoma patients present upregulated levels of Th17 cells that are quiescent directly ex vivo. Interestingly, compared to the Th17 cells from non-glaucoma subjects, the Th17 cells from glaucoma patients present similar IL-17A production capacity but significantly higher IL-21 production capacity. Given that IL-21 is also described as a specific cytokine of follicular helper T cells, the Ig production by B cells following co-incubation with circulating Th17 cells is investigated. Th17 cells from glaucoma patients present significantly enhanced potential to promote Ig production than the Th17 cells from controls. Both glaucoma patient Th17 cells and control Th17 cells require IL-17A and IL-21 for Ig production. Overall, results from this study suggest that Th17 cells from glaucoma patients present elevated capacity to stimulate Ig production.

The Method of Real-time PPP Time Transfer Research

The accuracy of precision point position (PPP) time transfer can achieve a value below 0.3 ns. Time transfer by precise point positioning has the defect of long latency resulting from IGS products, and cannot satisfied for the high real-tine user. A real-time precise point positioning time transfer algorithm using IGS products is proposed, which can improve the real-time, the feasibility of the algorithm is tested and verified in this paper. The time transfer results show that the accuracy of the new algorithm can be reach to 0.30 ns for RMS and 0.25 ns for STD. Moreover, the daily stability of the time transfer results is up to 2E-15. Experiments show that, the algorithm is real-time, and the time transfer results are coincident with IGS final clock products well.

T Cell-Dependent Maturation of Pathogen-Specific Igs in the Antrum of Chronically Helicobacter pylori-Infected Patients.

Mucosal plasma cells (PC) and Ig production are essential to fend pathogens and to maintain mucosal homeostasis. In human Helicobacter pylori infection, mucosal PC express inducible NO synthase (iNOS), which positively correlates with clearance of experimental human infection. To characterize Ig genes and specificities of antral mucosal iNOS+ and iNOS- PC in H. pylori infection, we sequenced rearranged Ig genes from single cell-sorted PC from biopsy specimens of chronically infected patients and analyzed them with respect to their molecular features. The binding specificity of individual PC's Ig was determined following recombinant expression. We identified high rates of somatic hypermutations, especially targeting RGYW/WRCY hotspot motifs in the individual Ig genes, indicating T cell-dependent maturation. For seven of 14 recombinantly expressed Ig, Ag specificity could be determined. Two clones reacted to H. pylori proteins, and five were found to be polyreactive against LPSs, dsDNA, and ssDNA. All specific Ig originated from iNOS+ PC. H. pylori-specific Ig are encoded by V and J family genes previously shown to be also used in rearranged Ig loci of MALT B cell lymphomas. In summary, mucosal iNOS+ PC producing H. pylori-specific Ig accumulate in infection and appear to be a product of T cell-dependent B cell maturation. Moreover, the Ig's molecular features partly resembled that of MALT B cell lymphoma Ig genes, suggestive of a mechanism in which a progressive molecular evolution of pathogen-specific B cells to MALT B cell lymphoma occurs.

Regulatory Roles of Pectin Oligosaccharides on Immunoglobulin Production in Healthy Mice Mediated by Gut Microbiota.

The prebiotic regulation of the gut microbiota is a promising strategy to induce protective humoral and mucosal immune responses. The potential immune-improving effects of pectin oligosaccharides (POS) in healthy mice and the potential mechanism mediated by specific intestinal bacteria are investigated. POS is prepared using a hydrogen-peroxide-assisted degradation. Mice that consumed diets containing POS are tested for microbial community shifts, short-chain fatty acids (SCFAs), and immunoglobulin (Ig) production using quantitative real-time polymerase chain reaction, gas chromatography, and ELISA kits. Pearson's correlation analyses are performed between Ig production and specific intestinal bacteria or SCFAs. POS treatment significantly improves the growth of healthy mice. Moreover, 4-week POS administration results in a profound change in intestinal microbial composition and a significantly higher fecal concentration of acetate, which leads to substantial increases of the levels of fecal secretory immunoglobulin A and serum IgG. The results suggest that the inclusion of POS in a diet can increase Ig production and optimize the composition of the gut microbiota. A significant correlation is observed between changes in Ig production and specific intestinal bacteria or acetate, providing insight into the mechanism of POS as a potential immune-enhancing supplement.

Critical role of Interleukin 21 and T follicular helper cells in hypertension and vascular dysfunction.

T and B cells have been implicated in hypertension, but the mechanisms by which they produce a coordinated response is unknown. T follicular helper (Tfh) cells that produce interleukin 21 (IL21) promote germinal center (GC) B cell responses leading to immunoglobulin (Ig) production. Here we investigate the role of IL21 and Tfh cells in hypertension. In response to angiotensin (Ang) II-induced hypertension, T cell IL21 production is increased, and Il21-/- mice develop blunted hypertension, attenuated vascular end-organ damage, and decreased interleukin 17A (IL17A) and interferon gamma production. Tfh-like cells and GC B cells accumulate in the aorta and plasma IgG1 is increased in hypertensive WT but not Il21-/-mice. Furthermore, Tfh cell deficient mice develop blunted hypertension and vascular hypertrophy in response to Ang II infusion. Importantly, IL21 neutralization reduces blood pressure (BP) and reverses endothelial dysfunction and vascular inflammation. Moreover, recombinant IL21 impairs endothelium-dependent relaxation ex vivo and decreases nitric oxide production from cultured endothelial cells. Finally, we show in humans that peripheral blood T cell production of IL21 correlates with systolic BP and IL17A production. These data suggest that IL21 may be a novel therapeutic target for the treatment of hypertension and its micro- and macrovascular complications.