Interleukin-17 as a molecular target in immune-mediated arthritis: Immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin-4

Objective Our previous studies have shown that murine dendritic cells (DCs) genetically modified to express interleukin-4 (IL-4) reduce the incidence and severity of murine collagen-induced arthritis. The present studies were performed to assess the immunoregulatory mechanisms underlying this response, by assessing the effects of IL-4 DCs on cytokine production by subsets of T helper cells. Methods Male DBA mice ages 6–8 weeks old were immunized with type II collagen. Splenic T cells obtained during the initiation phase and the end stage of arthritis were cultured with IL-4 DCs or untransduced DCs in the presence of collagen rechallenge. Interferon-Γ (IFNΓ) and IL-17 responses were measured. Antibodies to IL-4, IL-12, and IL-23, and recombinant IL-4, IL-12, and IL-23 were used to further study the regulation of T cell cytokine production by IL-4 DCs. Results Splenic T cells obtained during the initiation phase of arthritis produced less IL-17 when cultured in the presence of IL-4 DCs, despite their production of increased quantities of other proinflammatory cytokines (IFNΓ and tumor necrosis factor). T cell IL-17 production after collagen rechallenge was not inhibited by a lack of IL-23, since IL-4–mediated suppression of IL-17 was not reconstituted by IL-23, an otherwise potent inducer of IL-17 production by T cells. Although IL-4 DCs can produce increased quantities of IL-12 and IFNΓ, suppression of IL-17 production by IL-4 DCs was independent of both. While IL-17 production by T cells obtained during the initiation phase of arthritis was regulated by IL-4 DCs, IL-17 production by T cells obtained during end-stage arthritis was not altered. Conclusion Our data suggest that IL-4 DCs exert a therapeutic effect on collagen-induced arthritis by targeting IL-17. IL-17 suppression by IL-4 DCs is robust and is not reversed by IL-23. Timing might be important in IL-17–targeted therapy, since IL-17 production by T cells obtained during end-stage arthritis did not respond to suppression by IL-4 DCs.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/55925/1/22311_ftp.pd

Inter-annual variability of transparent exopolymer particles in the Arctic Ocean reveals high sensitivity to ecosystem changes

Transparent exopolymer particles (TEP) are a class of marine gel particles and important links between surface ocean biology and atmospheric processes. Derived from marine microorganisms, these particles can facilitate the biological pumping of carbon dioxide to the deep sea, or act as cloud condensation and ice nucleation particles in the atmosphere. Yet, environmental controls on TEP abundance in the ocean are poorly known. Here, we investigated some of these controls during the first multiyear time-series on TEP abundance for the Fram Strait, the Atlantic gateway to the Central Arctic Ocean. Data collected at the Long-Term Ecological Research observatory HAUSGARTEN during 2009 to 2014 indicate a strong biological control with highest abundance co-occurring with the prymnesiophyte Phaeocystis pouchetii. Higher occurrence of P. pouchetii in the Arctic Ocean has previously been related to northward advection of warmer Atlantic waters, which is expected to increase in the future. Our study highlights the role of plankton key species in driving climate relevant processes; thus, changes in plankton distribution need to be accounted for when estimating the ocean’s biogeochemical response to global change

A polymorphism in the interleukin-4 receptor affects the ability of interleukin-4 to regulate Th17 cells: a possible immunoregulatory mechanism for genetic control of the severity of rheumatoid arthritis

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/94408/1/Wallis_2011_Polymorphism_interleukin-4_receptor.pdf165

Regulation of pathogenic IL-17 responses in collagen-induced arthritis: roles of endogenous interferon-gamma and IL-4

Abstract Introduction Interleukin (IL)-17 plays an important role in the pathogenesis of rheumatoid arthritis and the mouse model collagen-induced arthritis (CIA). Interferon(IFN)-γ and IL-4 have been shown to suppress Th17 development in vitro, but their potential immunoregulatory roles in vivo are uncertain. The goals of this study were to determine the relationship between Th17 responses and disease severity in CIA and to assess regulation of IL-17 by endogenous IFN-γ and IL-4. Methods DBA1/LacJ mice were immunized with type II collagen in complete Freund's adjuvant (CFA) to induce arthritis, and treated with neutralizing antibody to IFN-γ and/or IL-4. Systemic IL-17, IFN-γ, and IL-4 were measured in serum. At the peak of disease, cytokine production was measured by ELISA of supernatants from spleen, lymph node and paw cultures. Paws were also scored for histologic severity of arthritis. Results Joint inflammation was associated with a higher ratio of systemic IL-17/IFN-γ. Neutralization of IFN-γ accelerated the course of CIA and was associated with increased IL-17 levels in the serum and joints. The IFN-γ/IL-4/IL-17 responses in the lymphoid organ were distinct from such responses in the joints. Neutralization of IL-4 led to increased arthritis only in the absence of IFN-γ and was associated with increased bone and cartilage damage without an increase in the levels of IL-17. Conclusions IL-4 and IFN-γ both play protective roles in CIA, but through different mechanisms. Our data suggests that the absolute level of IL-17 is not the only determinant of joint inflammation. Instead, the balance of Th1, Th2 and Th17 cytokines control the immune events leading to joint inflammation.http://deepblue.lib.umich.edu/bitstream/2027.42/112787/1/13075_2009_Article_2675.pd

Inter-Annual Variability of Organic Carbon Concentration in the Eastern Fram Strait During Summer (2009–2017)

The Arctic Ocean plays a key role in regulating the global climate, while being highly sensitive to climate change. Temperature in the Arctic increases faster than the global average, causing a loss of multiyear sea-ice and affecting marine ecosystem structure and functioning. As a result, Arctic primary production and biogeochemical cycling are changing. Here, we investigated inter-annual changes in the concentrations of particulate and dissolved organic carbon (POC, DOC) together with biological drivers, such as phyto- and bacterioplankton abundance in the Fram Strait, the Atlantic gateway to the Central Arctic Ocean. Data have been collected in summer at the Long-Term Ecological Research observatory HAUSGARTEN during eight cruises from 2009 to 2017. Our results suggest that the dynamic physical system of the Fram Strait induces strong heterogeneity of the ecosystem that displays considerable intra-seasonal as well as inter-annual variability. Over the observational period, DOC concentrations were significantly negatively related to temperature and salinity, suggesting that outflow of Central Arctic waters carrying a high DOC load is the main control of DOC concentration in this region. POC concentration was not linked to temperature or salinity but tightly related to phytoplankton biomass as estimated from chlorophyll-a concentrations (Chl-a). For the years 2009–2017, no temporal trends in the depth-integrated (0–100 m) amounts of DOC and Chl-a were observed. In contrast, depth-integrated (0–100 m) amounts of POC, as well as the ratio [POC]:[TOC], decreased significantly over time. This suggests a higher partitioning of organic carbon into the dissolved phase. Potential causes and consequences of the observed changes in organic carbon stocks for food-web structure and CO2 sequestration are discussed

One-year follow-up-case report of secondary tension pneumothorax in a COVID-19 pneumonia patient

PURPOSE The Coronavirus Disease 2019 (COVID-19) may result not only in acute symptoms such as severe pneumonia, but also in persisting symptoms after months. Here we present a 1~year follow-up of a patient with a secondary tension pneumothorax due to COVID-19 pneumonia. CASE PRESENTATION In May 2020, a 47-year-old male was admitted to the emergency department with fever, dry cough, and sore throat as well as acute chest pain and shortness of breath. Sputum testing (polymerase chain reaction, PCR) and computed tomography (CT) confirmed infection with the severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2). Eleven days after discharge, the patient returned to the emergency department with pronounced dyspnoea after coughing. CT showed a right-sided tension pneumothorax, which was relieved by a chest drain (Buelau) via mini open thoracotomy. For a period of 3~months following resolution of the pneumothorax the patient complained of fatigue with mild joint pain and dyspnoea. After 1~year, the patient did not suffer from any persisting symptoms. The pulmonary function and blood parameters were normal, with the exception of slightly increased levels of D-Dimer. The CT scan revealed only discrete ground glass opacities (GGO) and subpleural linear opacities. CONCLUSION Tension pneumothorax is a rare, severe complication of a SARS-CoV-2 infection but may resolve after treatment without negative long-term sequelae. LEVEL OF EVIDENCE V

Oncogenic RET Kinase domain mutations perturb the autophosphorylation trajectory by enhancing substrate presentation in trans

To decipher the molecular basis for RET kinase activation and oncogenic deregulation, we defined the temporal sequence of RET autophosphorylation by label-free quantitative mass spectrometry. Early autophosphorylation sites map to regions flanking the kinase domain core, while sites within the activation loop only form at later time points. Comparison with oncogenic RET kinase revealed that late autophosphorylation sites become phosphorylated much earlier than wild-type RET, which is due to a combination of an enhanced enzymatic activity, increased ATP affinity, and surprisingly, by providing a better intermolecular substrate. Structural analysis of oncogenic M918T and wild-type RET kinase domains reveal a cis-inhibitory mechanism involving tethering contacts between the glycine-rich loop, activation loop, and αC-helix. Tether mutations only affected substrate presentation but perturbed the autophosphorylation trajectory similar to oncogenic mutations. This study reveals an unappreciated role for oncogenic RET kinase mutations in promoting intermolecular autophosphorylation by enhancing substrate presentation

Inter-Annual Variability of Organic Carbon Concentration in the Eastern Fram Strait During Summer (2009–2017)

The Arctic Ocean plays a key role in regulating the global climate, while being highly sensitive to climate change. Temperature in the Arctic increases faster than the global average, causing a loss of multiyear sea-ice and affecting marine ecosystem structure and functioning. As a result, Arctic primary production and biogeochemical cycling are changing. Here, we investigated inter-annual changes in the concentrations of particulate and dissolved organic carbon (POC, DOC) together with biological drivers, such as phyto- and bacterioplankton abundance in the Fram Strait, the Atlantic gateway to the Central Arctic Ocean. Data have been collected in summer at the Long-Term Ecological Research observatory HAUSGARTEN during eight cruises from 2009 to 2017. Our results suggest that the dynamic physical system of the Fram Strait induces strong heterogeneity of the ecosystem that displays considerable intra-seasonal as well as inter-annual variability. Over the observational period, DOC concentrations were significantly negatively related to temperature and salinity, suggesting that outflow of Central Arctic waters carrying a high DOC load is the main control of DOC concentration in this region. POC concentration was not linked to temperature or salinity but tightly related to phytoplankton biomass as estimated from chlorophyll-a concentrations (Chl-a). For the years 2009–2017, no temporal trends in the depth-integrated (0–100 m) amounts of DOC and Chl-a were observed. In contrast, depth-integrated (0–100 m) amounts of POC, as well as the ratio [POC]:[TOC], decreased significantly over time. This suggests a higher partitioning of organic carbon into the dissolved phase. Potential causes and consequences of the observed changes in organic carbon stocks for food-web structure and CO2 sequestration are discussed