| 1. |
- Bergström, Beatrice, et al.
(författare)
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The Rheumatoid Arthritis Risk Gene AIRE Is Induced by Cytokines in Fibroblast-Like Synoviocytes and Augments the Pro-inflammatory Response
- 2019
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- The autoimmune regulator AIRE controls the negative selection of self-reactive T-cells as well as the induction of regulatory T-cells in the thymus by mastering the transcription and presentation of tissue restricted antigens (TRAs) in thymic cells. However, extrathymic AIRE expression of hitherto unknown clinical significance has also been reported. Genetic polymorphisms of AIRE have been associated with rheumatoid arthritis (RA), but no specific disease-mediating mechanism has been identified. Rheumatoid arthritis is characterized by a systemic immune activation and arthritis. Activated fibroblast-like synoviocytes (FLS) are key effector cells, mediating persistent inflammation, and destruction of joints. In this study, we identified AIRE as a cytokine-induced RA risk gene in RA FLS and explored its role in these pathogenic stroma cells. Using RNA interference and RNA sequencing we show that AIRE does not induce TRAs in FLS, but augments the pro-inflammatory response induced by tumor necrosis factor and interleukin-1 beta by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-gamma regulated genes. In particular, AIRE promoted the production and secretion of a set of chemokines, amongst them CXCL10, which have been associated with disease activity in RA. Finally, we demonstrate that AIRE is expressed in podoplanin positive FLS in the lining layer of synovial tissue from RA patients. These findings support a novel pro-inflammatory role of AIRE at peripheral inflammatory sites and provide a potential pathological mechanism for its association with RA.
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| 2. |
- Bergström, Beatrice, et al.
(författare)
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Methotrexate inhibits effects of platelet-derived growth factor and interleukin-1β on rheumatoid arthritis fibroblast-like synoviocytes
- 2018
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Ingår i: Arthritis Research and Therapy. - : Springer Science and Business Media LLC. - 1478-6354 .- 1478-6362. ; 20:49
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Tidskriftsartikel (refereegranskat)abstract
- Background: A key feature of joints in rheumatoid arthritis (RA) is the formation of hyperplastic destructive pannus tissue, which is orchestrated by activated fibroblast-like synoviocytes (FLS). We have demonstrated that the RA risk gene and tumor suppressor Limb bud and heart development (LBH) regulates cell cycle progression in FLS. Methotrexate (MTX) is the first-line treatment for RA, but its mechanisms of action remain incompletely understood. Here, we studied the effects of MTX on mitogen-induced FLS proliferation and expression of cell cycle regulators in vitro. Methods: Primary FLS from patients with RA or osteoarthritis were stimulated with the mitogen platelet-derived growth factor (PDGF) and the cytokine interleukin-1β (IL-1β) in the presence or absence of MTX. Cells were then subjected to qPCR for gene expression and cell cycle analysis by flow cytometry. Results: Stimulation with PDGF and IL-1β increased the percentage of FLS in the G2/M phase and shifted the cell morphology to a dendritic shape. These effects were inhibited by MTX. Furthermore, PDGF + IL-1β reduced LBH mRNA expression. However, MTX treatment yielded significantly higher transcript levels of LBH, and of CDKN1A (p21) and TP53 (p53), compared to untreated samples upon mitogen stimulation. The expression of DNA methyltransferase-1 (DNMT1) was also higher in the presence of MTX and there was strong correlation between DNMT1 and LBH expression. Conclusions: Therapeutic concentrations of MTX abolish the effects of PDGF and IL-1β on tumor suppressor expression and inhibit mitogen-promoted FLS proliferation. These data demonstrate novel and important effects of MTX on pathogenic effector cells in the joint, which might involve epigenetic mechanisms. © 2018 The Author(s).
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| 3. |
- Bierla, Joanna B., et al.
(författare)
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Sperm morphology of the Eurasian beaver, Castor fiber: An example of a species of rodent with highly derived and pleiomorphic sperm populations
- 2007
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Ingår i: Journal of morphology. - : Wiley-Blackwell. - 0362-2525 .- 1097-4687. ; 268:8, s. 683-689
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Tidskriftsartikel (refereegranskat)abstract
- The structural organization of the spermatozoon from the Eurasian beaver, Castor fiber (Family: Castoridae), was determined and compared to that of other sciuromorph rodents. The beaver spermatozoon has a head, which is variable in form but usually paddle-shaped, with a small nucleus and very large acrosome, and a tail that is relatively short compared to that of most other rodents. Transmission electron microscopy indicates that in most testicular spermatozoa the acrosome projects apically, although in a few it becomes partly flexed. During the final stages of maturation, however, the acrosome becomes highly folded so that the apical segment comes to lie alongside part of the acrosome that occurs lateral to the nucleus, with, in some cases, fusion taking place between the outer acrosomal membranes. The sperm nucleus is wedge-shaped, being broader basally and narrowing apically with an occasional large nuclear vacuole occurring. This spermatozoon structure is markedly different from that found in the other species of Geomyoidea, which is the sister group of the Castoridae. The findings thus emphasize the highly divergent nature of the beaver spermatozoon and demonstrate that, within the proposed Infraorder Castorimorpha, very large differences in sperm structure have evolved.
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| 4. |
- Caballero, Ignacio, et al.
(författare)
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Immunolocalization and possible functional role of PSP-I/PSP-II heterodimer in highly extended boar spermatozoa
- 2006
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Ingår i: Journal of Andrology. - : American Society of Andrology. - 0196-3635 .- 1939-4640. ; 27:6, s. 766-773
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Tidskriftsartikel (refereegranskat)abstract
- PSP-I/PSP-II heterodimer is a major protein of boar seminal plasma which is able to preserve, in vitro, the viability, motility, and mitochondrial activity of highly extended boar spermatozoa for at least 5 hours. However, little is known about the binding pattern of the heterodimer to the sperm plasma membrane and its eventual relation with the maintenance of the sperm functionality. The present study investigated the effect of exposing highly extended boar spermatozoa (11 million/mL) to 1.5 mg/mL of PSP-I/PSP-II for 0.5, 5, and 10 hours at 38 degrees C on sperm characteristics and the changes in PSP-I/PSP-II localization as a result of both the addition of PSP-I/PSP-II to the extender and the incubation time. Exposure of the spermatozoa to PSP-I/PSP-II preserved sperm viability, motility, and mitochondrial activity when compared to nonexposed spermatozoa. This protective effect lasted for 10 hours (P less than.05). After immunolabeling of highly extended semen with rabbit monospecific polyclonal antibody against PSP-I/PSP-11, the percentage of immunopositive spermatozoa declines over time from 71% (0.5 hours) to 49% (10 hours). However, more than 80% of spermatozoa remained labeled during the 10-hour incubation period if PSP-I/PSP-11 was added. Scanning electron microscopy revealed 4 different binding patterns. The heterodimer was mainly localized to the acrosomal area, being redistributed to the postacrosomal area or lost during in vitro incubation. In conclusion, the protective effect of the heterodimer appears to be related to its adhesion to the acrosomal area, and the loss of this protective effect coincides with a stepwise redistribution of PSP-I/PSP-II during incubation.
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| 5. |
- Drevinge, Christina, 1983, et al.
(författare)
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Intermediate monocytes correlate with CXCR3(+) Th17 cells but not with bone characteristics in untreated early rheumatoid arthritis
- 2021
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 16:3
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Tidskriftsartikel (refereegranskat)abstract
- Background Rheumatoid arthritis (RA) is associated with development of generalized osteoporosis. Bone-degrading osteoclasts are derived from circulating precursor cells of monocytic lineage, and the intermediate monocyte population is important as osteoclast precursors in inflammatory conditions. T cells of various subsets are critical in the pathogenesis of both RA and associated osteoporosis, but so far, no studies have examined associations between circulating intermediate monocytes, T cell subsets and bone characteristics in patients with RA. The aim of this study was to investigate the frequency of intermediate monocytes in patients with untreated early rheumatoid arthritis (ueRA) compared to healthy controls (HC), and to explore the correlation between intermediate monocytes and a comprehensive panel of T helper cell subsets, bone density and bone microarchitecture in ueRA patients. Methods 78 patients with ueRA fulfilling the ACR/EULAR 2010 criteria were included and compared to 29 age- and sex-matched HC. Peripheral blood samples were obtained before start of treatment and proportions of monocyte subsets and CD4(+) helper and regulatory T cell subsets were analyzed by flow cytometry. Bone densitometry was performed on 46 of the ueRA patients at inclusion using DXA and HR-pQCT. Results Flow cytometric analyses showed that the majority of ueRA patients had frequencies of intermediate monocytes comparable to HC. The intermediate monocyte population correlated positively with CXCR3(+) Th17 cells in ueRA patients but not in HC. However, neither the proportions of intermediate monocytes nor CXCR3(+) Th17 cells were associated with bone density or bone microarchitecture measurements. Conclusions Our findings suggest that in early RA, the intermediate monocytes do not correlate with bone characteristics, despite positive correlation with circulating CXCR3(+) Th17 cells. Future longitudinal studies in patients with longer disease duration are required to fully explore the potential of intermediate monocytes to drive bone loss in RA.
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| 6. |
- Ekwall, Hans, et al.
(författare)
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Cryo-scanning electron microscopy (Cryo-SEM) of boar semen frozen in medium-straws and MiniFlatPacks
- 2007
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Ingår i: Theriogenology. - : Elsevier. - 0093-691X .- 1879-3231. ; 67:9, s. 1463-1472
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Tidskriftsartikel (refereegranskat)abstract
- In this study we demonstrate, in the frozen state, the architecture of frozen boar spermatozoa collected from the sperm-rich fraction of ejaculates (n = 13) from four fertile boars packed and split-frozen in medium-straws (MS) and MiniFlatPacks (MFP), cross-sectioned in the frozen state and evaluated by image analysis on images obtained by use of cryo-scanning electron microscopy (Cryo-SEM). The tested hypothesis was that the degree of in situ dehydration and levels of homogeneity of boar semen either frozen in MSs or MFPs packages differ between them, with MFPs allowing for a more uniform dehydration of the spermatozoa and a higher cryosurvival, monitored by computer assisted sperm analysis (CASA) as proportion of linearly motile spermatozoa, compared to semen packaged and processed in MSs. The organization and relative surface of biological material (veins; e.g., frozen extender, bound water, solutes and spermatozoa) as well as free water (lakes) was measured as the degree of dehydration of the samples. The apparent organization of lakes and veins differed between packages, with the MFPs depicting larger lakes than the MSs. The sizes of the lakes in the latter appeared, moreover, highly asymmetrical depending on their position of the section. The relative surface of these lakes per section, respectively veins differed between packages (P less than 0.05), indicating a larger amount of free-water (lakes; 81.73 +/- 2.07% vs. 77.91 +/- 1.57%) in the MFPs and, consequently, thinner veins than in MSs. In conclusion, MFPs seem to allow for a more homogenous dehydration of the spermatozoa/frozen extender compared to MSs, which might account for their somewhat better sperm quality post-thaw. (C) 2007 Elsevier Inc. All rights reserved.
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| 7. |
- Ekwall, Hans
(författare)
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Cryo-scanning Electron Microscopy Discloses Differences in Dehydration of Frozen Boar Semen Stored in Large Containers
- 2009
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Ingår i: Reproduction in Domestic Animals. - : Wiley. - 0936-6768 .- 1439-0531. ; 44, s. 62-68
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Tidskriftsartikel (refereegranskat)abstract
- In general, freezing in flat plastic polyethylene terephthalate (PET) bags (FlatPacks) at 50 degrees C/min gives better post-thaw viability, in terms of sperm motility and membrane integrity, than does freezing in plastic maxi-straws, probably owing to differences in cryobiology. To test the hypothesis that this better survival post-thaw relates to the degree of sperm dehydration during freezing, the present study investigated the structure of boar semen in a frozen state using cryo-scanning electron microscopy (cryo-SEM) to compare two different packages (FlatPacks and maxi-straws) for single artificial insemination (AI) doses, and three different freezing rates. The semen was split-sample frozen in maxi-straws or FlatPacks (both holding 5 ml) using 3% glycerol as cryoprotectant. Three freezing rates were applied from -5 degrees C to -100 degrees C, namely 2 degrees C/min, 50 degrees C/min and 1200 degrees C/min, the lattermost by plunging the samples into liquid nitrogen (LN(2)). The samples were thereafter fractured into LN(2) and larger areas of extra-cellular, unbound frozen water ('ice lakes') were measured to determine the degree of dehydration of the spermatozoa. These areas decreased in size with an increase in cooling rate, the differences in size being more dramatic for maxi-straws than for FlatPacks. Size of ice lakes was also influenced by location within package in relation to cooling rate, the central values being always smaller in maxi-straws than in Flatpacks (p < 0.05 at 2 degrees C/min and 50 degrees C/min) but not at 1200 degrees C/min, which suggested the FlatPack allows for more homogenous freezing of boar semen.
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| 8. |
- Fagerström-Billai, Fredrik
(författare)
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Genome wide analysis of the Ssn6-Tup11/Tup12 co-repressor complex in the fission yeast Schizosaccharomyces pombe
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In this study, we have investigated the fission yeast Ssn6-Tup11 /Tup 12 transcriptional corepressor which is involved in regulation of many genes important for a wide variety of processes. In contrast to the well characterised budding yeast Tup1 protein there are two paralogous proteins present in fission yeast, namely Tup11 and Tup12. We have shown that the two proteins can interact with each other and are expressed at similar levels, which is in line with a reported redundant function. Sequence analysis shows that the intermediate proposed histone interacting domain is highly variable between Tup11 and Tup12 indicating a diversification. Interestingly, we show that tup11 and tup12 mutants have different phenotypes on media containing KC1 and CaC12. Consistent with this functional difference, we identify a number of target genes by genome wide expression profiling that are differentially affected by tup11 - and tup12. Many of these genes are Tup12 dependent and correlate with genes that have previously been shown to respond to a range of different environmental stress conditions. The observed different physiological roles of Tup11 and Tup12 can not be explained by differential recruitment of Ssn6 which can interact independently with both Tup11 and Tup12. Most interestingly we show that the Ssn6 protein is essential in fission yeast and therefore must have a distinct role separated from Tup11 and Tup12. Surprisingly, a conditional ssn6HA-ts mutant displays the same growth phenotype as tup12, indicating a role in Tup12 dependent stress response. Consistent with the diverse phenotypes of the individual co-repressor proteins, we identify a group of genes that requires Ssn6 for their regulation which is overlapping but distinct from the group of genes that depend on Tup11 or Tup12. Genome wide chromatin immunoprecipitation shows that Ssn6 is almost invariably found in the same genomic locations as Tup11 and/or Tup12. All three co-repressor subunits are generally bound to genes that are selectively regulated by Ssn6 or Tup11/12, and thus, likely in the context of a co-repressor complex containing all three subunits. The co-repressor binds to both the intergenic and coding regions of genes, but differential localization of the co-repressor within genes does not appear to account for the selective dependence of target genes on the Ssn6 or Tup11/12 subunits. Ssn6, Tup11, and Tup12 are preferentially found at genomic locations at which histones are deacetylated, primarily by the Clr6 class I HDAC. A subset of co-repressor target genes, including direct target genes affected by Ssn6 overexpression, is in addition associated with the function of class II (Clr3) and III (Hst4 and Sir2) HDACs. Interestingly, many specific Hst4 repressed ORF targets involved in amino acid biosynthesis are also direct targets for the Ssn6-Tup11/12 co-repressor, suggesting an association with the class ill sirtuins which has not been reported previously.
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| 9. |
- He, Yibo, et al.
(författare)
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A subset of antibodies targeting citrullinated proteins confers protection from rheumatoid arthritis.
- 2023
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Although elevated levels of anti-citrullinated protein antibodies (ACPAs) are a hallmark of rheumatoid arthritis (RA), the in vivo functions of these antibodies remain unclear. Here, we have expressed monoclonal ACPAs derived from patients with RA, and analyzed their functions in mice, as well as their specificities. None of the ACPAs showed arthritogenicity nor induced pain-associated behavior in mice. However, one of the antibodies, clone E4, protected mice from antibody-induced arthritis. E4 showed a binding pattern restricted to skin, macrophages and dendritic cells in lymphoid tissue, and cartilage derived from mouse and human arthritic joints. Proteomic analysis confirmed that E4 strongly binds to macrophages and certainRA synovial fluid proteins such as α-enolase. The protective effect of E4 was epitope-specific and dependent on the interaction between E4-citrullinated α-enolase immune complexes with FCGR2B on macrophages, resulting in increased IL-10 secretion and reduced osteoclastogenesis. These findings suggest that a subset of ACPAs have therapeutic potential in RA.
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| 10. |
- Hernandez, Marta, et al.
(författare)
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Cryo-scanning electron microscopy (Cryo-SEM) of semen frozen in medium-straws from good and sub-standard freezer AI-boars
- 2007
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Ingår i: Cryobiology. - : Elsevier. - 0011-2240 .- 1090-2392. ; 54:1, s. 63-70
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Tidskriftsartikel (refereegranskat)abstract
- A major limiting factor for commercial cryopreservation of boar semen for artificial insemination (AI) is the large individual variation to cooling, where the degree of cell dehydration during ice (re)shaping seems to play a major role. This study investigated, in the frozen state, the degree of dehydration and ice crystal distribution in boar semen doses whose spermatozoa displayed different viability after thawing. Cross-sectioned medium-straws (0.5 mL, n = 10) from a total of 10 stud boars classified as "good" (n = 5) or sub-standard (e.g., "bad" freezers, n = 5) by conventional analyses (computer assisted motility and sperm viability) were examined by Cryo-scanning electron microscopy (Cryo-SEM) to determine whether differences between groups could be already distinguishable prior to thawing. The degree of hydration was monitored in relation to the areas of ice crystal formed extracellularly (lakes), the areas of frozen, concentrated extender (veins) where spermatozoa were located and the degree of compartmentalization (number of lakes) present. Irrespectively of the region studied, the gradient of main dehydration (as lakes) observed along the cross-section area of the straws was very irregular. Most spermatozoa were enclosed in the freezing extender matrix and no obvious signs of external membrane damage were observed. None of the Cryo-SEM variables significantly correlated with post-thaw sperm parameters (p greater than 0.05). However, we identified significant differences (p less than 0.0001) among boars for all ultrastructure variables studied, including the size of the veins, where differences in solute concentration is expected. We concluded that despite the large variability in ice crystal formation during the conventional freezing process among boars, this is unrelated to inter-boar post-thaw sperm differences. (c) 2007 Elsevier Inc. All rights reserved.
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| 11. |
- Manry, Jérémy, et al.
(författare)
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The risk of COVID-19 death is much greater and age dependent with type I IFN autoantibodies.
- 2022
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 1091-6490. ; 119:21
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Tidskriftsartikel (refereegranskat)abstract
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection fatality rate (IFR) doubles with every 5 y of age from childhood onward. Circulating autoantibodies neutralizing IFN-α, IFN-ω, and/or IFN-β are found in ∼20% of deceased patients across age groups, and in ∼1% of individuals aged <70 y and in >4% of those >70 y old in the general population. With a sample of 1,261 unvaccinated deceased patients and 34,159 individuals of the general population sampled before the pandemic, we estimated both IFR and relative risk of death (RRD) across age groups for individuals carrying autoantibodies neutralizing type I IFNs, relative to noncarriers. The RRD associated with any combination of autoantibodies was higher in subjects under 70 y old. For autoantibodies neutralizing IFN-α2 or IFN-ω, the RRDs were 17.0 (95% CI: 11.7 to 24.7) and 5.8 (4.5 to 7.4) for individuals <70 y and ≥70 y old, respectively, whereas, for autoantibodies neutralizing both molecules, the RRDs were 188.3 (44.8 to 774.4) and 7.2 (5.0 to 10.3), respectively. In contrast, IFRs increased with age, ranging from 0.17% (0.12 to 0.31) for individuals <40 y old to 26.7% (20.3 to 35.2) for those ≥80 y old for autoantibodies neutralizing IFN-α2 or IFN-ω, and from 0.84% (0.31 to 8.28) to 40.5% (27.82 to 61.20) for autoantibodies neutralizing both. Autoantibodies against type I IFNs increase IFRs, and are associated with high RRDs, especially when neutralizing both IFN-α2 and IFN-ω. Remarkably, IFRs increase with age, whereas RRDs decrease with age. Autoimmunity to type I IFNs is a strong and common predictor of COVID-19 death.
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| 12. |
- Wilhelmson, Anna S K, et al.
(författare)
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Androgen Receptors in Epithelial Cells Regulate Thymopoiesis and Recent Thymic Emigrants in Male Mice
- 2020
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 11
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Tidskriftsartikel (refereegranskat)abstract
- Androgens have profound effects on T cell homeostasis, including regulation of thymic T lymphopoiesis (thymopoiesis) and production of recent thymic emigrants (RTEs), i. e., immature T cells that derive from the thymus and continue their maturation to mature naive T cells in secondary lymphoid organs. Here we investigated the androgen target cell for effects on thymopoiesis and RTEs in spleen and lymph nodes. Male mice with a general androgen receptor knockout (G-ARKO), T cell-specific (T-ARKO), or epithelial cell-specific (E-ARKO) knockout were examined. G-ARKO mice showed increased thymus weight and increased numbers of thymic T cell progenitors. These effects were not T cell-intrinsic, since T-ARKO mice displayed unaltered thymus weight and thymopoiesis. In line with a role for thymic epithelial cells (TECs), E-ARKO mice showed increased thymus weight and numbers of thymic T cell progenitors. Further, E-ARKO mice had more CD4(+)and CD8(+)T cells in spleen and an increased frequency of RTEs among T cells in spleen and lymph nodes. Depletion of the androgen receptor in epithelial cells was also associated with a small shift in the relative number of cortical (reduced) and medullary (increased) TECs and increased CCL25 staining in the thymic medulla, similar to previous observations in castrated mice. In conclusion, we demonstrate that the thymic epithelium is a target compartment for androgen-mediated regulation of thymopoiesis and consequently the generation of RTEs.
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| 13. |
- Wilhelmson, Anna S K, et al.
(författare)
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Testosterone Protects Against Atherosclerosis in Male Mice by Targeting Thymic Epithelial Cells.
- 2018
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Ingår i: Arteriosclerosis, thrombosis, and vascular biology. - 1524-4636. ; 38:7, s. 1519-1527
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Tidskriftsartikel (refereegranskat)abstract
- Androgen deprivation therapy has been associated with increased cardiovascular risk in men. Experimental studies support that testosterone protects against atherosclerosis, but the target cell remains unclear. T cells are important modulators of atherosclerosis, and deficiency of testosterone or its receptor, the AR (androgen receptor), induces a prominent increase in thymus size. Here, we tested the hypothesis that atherosclerosis induced by testosterone deficiency in male mice is T-cell dependent. Further, given the important role of the thymic epithelium for T-cell homeostasis and development, we hypothesized that depletion of the AR in thymic epithelial cells will result in increased atherosclerosis.Prepubertal castration of male atherosclerosis-prone apoE-/- mice increased atherosclerotic lesion area. Depletion of T cells using an anti-CD (cluster of differentiation) 3 antibody abolished castration-induced atherogenesis, demonstrating a role of T cells. Male mice with depletion of the AR specifically in epithelial cells (E-ARKO [epithelial cell-specific AR knockout] mice) showed increased thymus weight, comparable with that of castrated mice. E-ARKO mice on an apoE-/- background displayed significantly increased atherosclerosis and increased infiltration of T cells in the vascular adventitia, supporting a T-cell-driven mechanism. Consistent with a role of the thymus, E-ARKO apoE-/- males subjected to prepubertal thymectomy showed no atherosclerosis phenotype.We show that atherogenesis induced by testosterone/AR deficiency is thymus- and T-cell dependent in male mice and that the thymic epithelial cell is a likely target cell for the antiatherogenic actions of testosterone. These insights may pave the way for new therapeutic strategies for safer endocrine treatment of prostate cancer.
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