The CD8α+ Dendritic Cell Is Responsible for Inducing Peripheral Self-Tolerance to Tissue-associated Antigens

We previously described a mechanism for the maintenance of peripheral self-tolerance. This involves the cross-presentation of tissue-associated antigens by a bone marrow–derived cell type that stimulates the proliferation and ultimate deletion of self-reactive CD8 T cells. This process has been referred to as cross-tolerance. Here, we characterize the elusive cell type responsible for inducing cross-tolerance as a CD8α+ dendritic cell (DC). To achieve this aim, transgenic mice were generated expressing yellow fluorescent protein (YFP) linked to CTL epitopes for ovalbumin and glycoprotein B (gB) of herpes simplex virus under the rat insulin promoter (RIP). Although tracking of YFP was inconclusive, the use of a highly sensitive gB-specific hybridoma that produced β-galactosidase on encounter with antigen, enabled detection of antigen presentation by cells isolated from the pancreatic lymph node. This showed that a CD11c+CD8α+ cell was responsible for cross-tolerance, the same DC subset as previously implicated in cross-priming. These data indicate that CD8α+ DCs play a critical role in both tolerance and immunity to cell-associated antigens, providing a potential mechanism by which cytotoxic T lymphocyte can be immunized to viral antigens while maintaining tolerance to self

Altered Metabolic Signature in Pre-Diabetic NOD Mice

Altered metabolism proceeding seroconversion in children progressing to Type 1 diabetes has previously been demonstrated. We tested the hypothesis that non-obese diabetic (NOD) mice show a similarly altered metabolic profile compared to C57BL/6 mice. Blood samples from NOD and C57BL/6 female mice was collected at 0, 1, 2, 3, 4, 5, 6, 7, 9, 11, 13 and 15 weeks and the metabolite content was analyzed using GC-MS. Based on the data of 89 identified metabolites OPLS-DA analysis was employed to determine the most discriminative metabolites. In silico analysis of potential involved metabolic enzymes was performed using the dbSNP data base. Already at 0 weeks NOD mice displayed a unique metabolic signature compared to C57BL/6. A shift in the metabolism was observed for both strains the first weeks of life, a pattern that stabilized after 5 weeks of age. Multivariate analysis revealed the most discriminative metabolites, which included inosine and glutamic acid. In silico analysis of the genes in the involved metabolic pathways revealed several SNPs in either regulatory or coding regions, some in previously defined insulin dependent diabetes (Idd) regions. Our result shows that NOD mice display an altered metabolic profile that is partly resembling the previously observation made in children progressing to Type 1 diabetes. The level of glutamic acid was one of the most discriminative metabolites in addition to several metabolites in the TCA cycle and nucleic acid components. The in silico analysis indicated that the genes responsible for this reside within previously defined Idd regions

HSC70 is a novel binding partner involved in the capture of immunoglobulins on B cells in the NOD mouse

B cells have been shown to be essential for Type 1 diabetes development in the non-obese diabetic mouse, where their contribution as antigen presenting cells has been emphasised. Other important functions for B cells include surface capture of immunoglobulins and transportation of immune complexes, with subsequent endocytosis, antigen processing and antigen presentation. We have previously demonstrated that NOD B cells capture IgM and IgG immune complexes through an unknown surface molecule. In this study, we revealed the presumptive immunoglobulin-binding molecule to be HSC70. Moreover, we detected increased levels of HSC70 on NOD B cells. HSC70 has been shown to play a role in antigen processing and presentation as well as being important in several autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. Due to its protein stabilising properties, increased HSC70 could contribute to enhanced self-antigen collection and presentation and thereby contribute to the development of Type 1 diabetes

Jämställt arbetsliv i skogssektorn

Föreliggande rapport syftar till att identifiera strukturella fenomen och faktorer som näringen själv kan åtgärda för att skogsbrukssektorns arbetsgivare och arbetsplatser skall vara attraktiva för både kvinnor och män. I enlighet med uppdragsbeskrivningen har arbete fokuserats på arbetskraft med akademisk skogsutbildning. Arbetet består av 1) En litteraturgenomgång i syftet att kartlägga det aktuella kunskapsläget inom fältet 2) En analys av kvinnors och mäns erfarenheter av sin akademiska skogsutbildning och arbetsliv baserat på brevundersökningsdata 3) Skattning av andelen kvinnor verksamma inom skogsentreprenadföretag 4) Djupintervjuer med fyra kvinnor med erfarenheter av att vara kvinna i olika delar av skogsnäringen. Kontakter och information med representanter för olika delar av skogsbrukssektorn har genomförts vid några tillfällen. Förtroendet för sektorn, och dess attraktionskraft är avgörande för att kompetent arbetskraft, i en ökad konkurrenssituation med andra sektorer och näringar, ska söka sig till de skogliga näringarna. Informanter från såväl brevundersökningen som djupintervjuerna understryker att målet för jämställdhetsarbetet är att det ska vara arbetet och kompetensen som uppmärksammas och värderas, inte om det är en man eller en kvinna som utför detta. Innan vi når dit krävs ett strategiskt förändringsarbete på alla nivåer och i alla delar av skogssektorn, eftersom kopplingarna mellan arbetsliv, utbildning och skogsägande är så starka. Hela sektorn genomsyras av en utpräglad skoglig kultur; som får konsekvenser för rekrytering till utbildningarna, vilka kunskaper som förmedlas och värderingar som reproduceras inom ramen för dessa, hur arbetslivet organiseras och på vilket sätt som företagets och organisationens verksamhet kommuniceras med skogsägare och det omgivande samhället. Med andra ord handlar det om arbetsmiljö i vid bemärkelse. Genom ökad mångfald, inte bara i fråga om kön, utan även ålder, etnicitet och sexuell läggning ges förutsättningar för ett mer tillåtande och inkluderande kultur. Till en del handlar det om att rekrytera in fler kvinnor på alla nivåer för den manliga dominansen ska brytas. Dessutom måste dessa kvinnor ges föreutsättningar att verka på lika villkor som sina manliga kollegor. För detta krävs att kunskapen och medvetenheten om genus och jämställdhetsfrågor integreras i hela sektorns alla organisationer. Som ansvarig för merparten av de skogliga utbildningarna har SLU ett särskilt ansvar i formandet av framtidens skogliga kompetens. Utbildning om genus och jämställdhet måste därför integreras i grundutbildningens nuvarande kursutbud. På motsvarande sätt bör SLU tillsammans med Skogforsk och Linnéuniversitetet utveckla fortbildningskurser för redan yrkesverksamma. Liksom inom andra kunskapsområden måste kunskapsförmedlingen bygga på en vetenskaplig grund. Forskning inom andra delar av arbetslivet visar på en koppling mellan jämställdhet, hållbarhet, konkurrenskraft

Decreased levels of T follicular helper (CD4+CXCR5+) cells and CD27+CD38+ and CD27+CD38− B cells in ankylosing spondylitis patients correlate with markers of inflammation

The purpose of this study was to study CD4+CXCR5+ T follicular helper (TFH) cells, CD27+CD38+ plasmablasts and CD27+CD38− memory B cells, as well as disease-related factors in patients with ankylosing spondylitis (AS) from northern Sweden. Peripheral blood mononuclear cells (PBMC) from 50 patients with AS (mean age 52 ± 9 years, 66% men, 100% HLA-B27 positive) and 50 pairwise matched blood donor controls (mean age 54 ± 9 years, 66% men) were stained with antibodies for CD27, CD38, CD19, CD3, CD4 and CXCR5 markers and analysed by flow cytometry. Patients with AS were examined with spinal x-ray for radiographic alterations (mSASSS), and plasma levels of C-reactive protein, erythrocyte sedimentation rate, as well as selected proinflammatory and regulatory cytokines were determined. Physical mobility, function and disease activity were registered by BASMI, BASFI and ASDAS-CRP, BASDAI, respectively. Comparing AS patients and controls pairwise, we observed a 56% reduction of TFH cells in PBMCs from AS patients (P =.000008). Furthermore, a 20%-30% reduction in plasmablasts and B memory cells (P ≤.002 and P ≤.007, respectively) was observed. In female patients, negative correlations between ESR and TFH, plasmablasts and B memory cells were observed; Rs = −0.551, P ≤.02; Rs = −0.476, P ≤.05 and Rs = −0.522, P ≤.03, respectively. In addition, positive correlations between the regulatory cytokine IL-10 and the proportion of B cells, IL-22, and the proportion of plasmablasts as well as a negative correlation between levels of the proinflammatory cytokine IL-6 and TFH were detected. Our observations indicate a role of an aberrant humoral immune response related to inflammation in AS

Jämställt arbetsliv i skogssektorn : Underlag för åtgärder

Godkänd; 2011; 20120124 (krijoh

Protein profiling and network enrichment analysis in individuals before and after the onset of rheumatoid arthritis

Background: Antibodies and upregulated cytokines and chemokines predate the onset of rheumatoid arthritis (RA) symptoms. We aimed to identify the pathways related to the early processes leading to RA development, as well as potential novel biomarkers, using multiple protein analyses. Methods: A case-control study was conducted within the Biobank of northern Sweden. The plasma samples from 118 pre-symptomatic individuals (207 samples; median predating time 4.1 years), 79 early RA patients, and 74 matched controls were analyzed. The levels of 122 unique proteins with an acknowledged relationship to autoimmunity were analyzed using 153 antibodies and a bead-based multiplex system (FlexMap3D; Luminex Corp.). The data were analyzed using multifactorial linear regression model, random forest, and network enrichment analysis (NEA) based on the 10 most significantly differentially expressed proteins for each two-by-two group comparison, using the MSigDB collection of hallmarks. Results: There was a high agreement between the different statistical methods to identify the most significant proteins. The adipogenesis and interferon alpha response hallmarks differentiated pre-symptomatic individuals from controls. These two hallmarks included proteins involved in innate immunity. Between pre-symptomatic individuals and RA patients, three hallmarks were identified as follows: apical junction, epithelial mesenchymal transition, and TGF-beta signaling, including proteins suggestive of cell interaction, remodulation, and fibrosis. The adipogenesis and heme metabolism hallmarks differentiated RA patients from controls. Conclusions: We confirm the importance of interferon alpha signaling and lipids in the early phases of RA development. Network enrichment analysis provides a tool for a deeper understanding of molecules involved at different phases of the disease progression