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  • 101.
    Schröder, Björn
    et al.
    Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany; University of Tuebingen, Tuebingen, Germany; Department of Microbiology and Immunology, School of Medicine, University of California, Davis, California, USA; Present address: Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
    Ehmann, D.
    Precht, J. C.
    Castillo, P. A.
    Küchler, R.
    Berger, J.
    Schaller, M.
    Stange, E. F.
    Wehkamp, J.
    Paneth cell α-defensin 6 (HD-6) is an antimicrobial peptide2015In: Mucosal Immunology, ISSN 1933-0219, E-ISSN 1935-3456, Vol. 8, no 3, p. 661-671Article in journal (Refereed)
    Abstract [en]

    Defensins protect human barriers from commensal and pathogenic microorganisms. Human α-defensin 6 (HD-6) is produced exclusively by small intestinal Paneth cells but, in contrast to other antimicrobial peptides (AMPs) for HD-6, no direct antibacterial killing activity has been detected so far. Herein, we systematically tested how environmental factors, like pH and reducing conditions, affect antimicrobial activity of different defensins against anaerobic bacteria of the human intestinal microbiota. Remarkably, by mimicking the intestinal milieu we detected for the first time antibacterial activity of HD-6. Activity was observed against anaerobic gut commensals but not against some pathogenic strains. Antibiotic activity was attributable to the reduced peptide and independent of free cysteines or a conserved histidine residue. Furthermore, the oxidoreductase thioredoxin, which is also expressed in Paneth cells, is able to reduce a truncated physiological variant of HD-6. Ultrastructural analyses revealed that reduced HD-6 causes disintegration of cytoplasmic structures and alterations in the bacterial cell envelope, while maintaining extracellular net-like structures. We conclude that HD-6 is an antimicrobial peptide. Our data suggest two distinct antimicrobial mechanisms by one peptide: HD-6 kills specific microbes depending on the local environmental conditions, whereas known microbial trapping by extracellular net structures is independent of the reducing milieu.

  • 102.
    Schröder, Björn O.
    et al.
    Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology; Stuttgart and University of Tübingen; Tübingen, Germany.
    Stange, Eduard F.
    Wehkamp, Jan
    Waking the wimp: Redox-modulation activates human beta-defensin 12011In: Gut microbes, ISSN 1949-0976, E-ISSN 1949-0984, Vol. 2, no 4, p. 262-266Article in journal (Refereed)
    Abstract [en]

    Antimicrobial peptides are key players of the innate immune system and form a primary barrier against infection by microorganisms. In humans, several classes of antimicrobial peptides are produced, including the defensins. These small, cationic peptides show broad spectrum antimicrobial activity against bacteria, some fungi and some viruses. Defensins are characterized by six conserved cysteine residues which are connected via three disulphide bridges. Depending on the pattern of connectivity, human defensins are either classified as α- or β-defensins. Human β-defensin 1 (hBD-1) is constitutively expressed by epithelia, but in comparison with other antimicrobial peptides the antimicrobial activity of hBD-1 was comparably low. We recently found that after reduction of hBD-1's three disulphide bonds its antimicrobial activity is strongly enhanced. Reduction can be either performed by a reducing environment, as it is present in parts of the human intestine, the oral cavity and other locations, or enzymatically by the thioredoxin-system, which is one of the major redox regulators. Reduced hBD-1 is able to kill Gram-positive anaerobic bacteria of the human normal flora as well as an opportunistic pathogenic fungus, whereas the oxidized peptide does not show activity against these microorganisms. Herein we provide additional data about reduced hBD-1 and discuss the biological context of our findings.

  • 103. Schröder, Björn
    et al.
    Stange, E F
    Wehkamp, J
    Human beta-defensin 1: from defence to offence2012In: Zeitschrift für Gastroenterologie - German Journal of Gastroenterology, ISSN 0044-2771, E-ISSN 1439-7803, Vol. 50, no 11, p. 1171-5Article in journal (Refereed)
    Abstract [de]

    The human gut is colonised by about one kilogram of commensal bacteria. These microorganisms are a potential threat, thus an efficient defence system is crucial in preventing bacterial translocation and infection. Besides other mechanisms of protection humans produce antimicrobial peptides (AMPs) that are able to kill a broad range of microorganisms. The human beta-defensin 1 (hBD-1) plays a major role because it is produced constitutively by all human epithelia and some immune cells. In contrast to other AMPs, however, the biological function of hBD-1 has remained unclear since the antibiotic activity of hBD-1 in vitro was only marginal. But still, several diseases have been associated with genetic polymorphisms in the hBD-1 encoding gene. Herein we discuss why the biological role of hBD-1 has been overlooked and how hBD-1 can be activated by chemical reduction. We elaborate on the biological significance of this activation and its importance for inflammatory bowel disease.

  • 104. Seiwert, Nina
    et al.
    Neitzel, Carina
    Stroh, Svenja
    Frisan, Teresa
    Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden.
    Audebert, Marc
    Toulany, Mahmoud
    Kaina, Bernd
    Fahrer, Jörg
    AKT2 suppresses pro-survival autophagy triggered by DNA double-strand breaks in colorectal cancer cells2017In: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 8, no 8, article id e3019Article in journal (Refereed)
    Abstract [en]

    DNA double-strand breaks (DSBs) are critical DNA lesions, which threaten genome stability and cell survival. DSBs are directly induced by ionizing radiation (IR) and radiomimetic agents, including the cytolethal distending toxin (CDT). This bacterial genotoxin harbors a unique DNase-I-like endonuclease activity. Here we studied the role of DSBs induced by CDT and IR as a trigger of autophagy, which is a cellular degradation process involved in cell homeostasis, genome protection and cancer. The regulatory mechanisms of DSB-induced autophagy were analyzed, focusing on the ATM-p53-mediated DNA damage response and AKT signaling in colorectal cancer cells. We show that treatment of cells with CDT or IR increased the levels of the autophagy marker LC3B-II. Consistently, an enhanced formation of autophagosomes and a decrease of the autophagy substrate p62 were observed. Both CDT and IR concomitantly suppressed mTOR signaling and stimulated the autophagic flux. DSBs were demonstrated as the primary trigger of autophagy using a DNase I-defective CDT mutant, which neither induced DSBs nor autophagy. Genetic abrogation of p53 and inhibition of ATM signaling impaired the autophagic flux as revealed by LC3B-II accumulation and reduced formation of autophagic vesicles. Blocking of DSB-induced apoptotic cell death by the pan-caspase inhibitor Z-VAD stimulated autophagy. In line with this, pharmacological inhibition of autophagy increased cell death, while ATG5 knockdown did not affect cell death after DSB induction. Interestingly, both IR and CDT caused AKT activation, which repressed DSB-triggered autophagy independent of the cellular DNA-PK status. Further knockdown and pharmacological inhibitor experiments provided evidence that the negative autophagy regulation was largely attributable to AKT2. Finally, we show that upregulation of CDT-induced autophagy upon AKT inhibition resulted in lower apoptosis and increased cell viability. Collectively, the findings demonstrate that DSBs trigger pro-survival autophagy in an ATM- and p53-dependent manner, which is curtailed by AKT2 signaling.

  • 105. Shirin, Tahmina
    et al.
    Rahman, Arman
    Danielsson, Åke
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Uddin, Taher
    Bhuyian, Taufiqur Rahman
    Sheikh, Alaullah
    Qadri, Syed Saleheen
    Qadri, Firdausi
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Antimicrobial peptides in the duodenum at the acute and convalescent stages in patients with diarrhea due to Vibrio cholerae O1 or enterotoxigenic Escherichia coli infection2011In: Microbes and infection, ISSN 1286-4579, E-ISSN 1769-714X, Vol. 13, no 12-13, p. 1111-1120Article in journal (Refereed)
    Abstract [en]

    Patients with acute watery diarrhea caused by Vibrio cholerae O1 or enterotoxigenic Escherichia coli (ETEC) were analyzed for innate immune factors produced by the epithelium during the disease process. Duodenal biopsies were obtained from study participants at the acute (day 2) and convalescent (day 21) stages of disease. Levels of alpha-defensin (HD-5 and -6), beta-defensin (hBD-1-4), and cathelicidin (LL-37) mRNAs were determined by real-time qRT-PCR. hBD-2, HD-5, LL-37 peptides were analyzed in duodenal epithelium by immunomorphometry. Concentration of hBD-2 in stool was determined by ELISA. Specimens from healthy controls were also analyzed. hBD-2 mRNA levels were significantly increased at acute stage of diarrhea; hBD-2 peptide was detected in fecal specimens but barely in duodenal epithelium at acute stage. Immunomorphometry analysis showed that Paneth cells contain significantly higher amounts of HD-5 pre/propeptide at convalescence (P < 0.01) and in healthy controls (P < 0.001) compared to acute stage, LL-37 peptide levels also decreased at acute stage while mRNA levels remained unchanged. mRNA expression levels of the other antimicrobial peptides remained unchanged with higher levels of alpha-defensins than beta-defensins. V cholerae induced an innate immune response at the acute stage of disease characterized by increased expression of hBD-2, and continued expression of hBD-1, HD-5-6, and LL-37.

  • 106.
    Singh, Bhupender
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mortezaei, Narges
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Savarino, Stephen J.
    Enteric Diseases Department, Naval Medical Research Center, Silver Spring, MD, 20910, USA.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Bullitt, Esther
    Department of Physiology and Biophysics, Boston University School of Medicine, Boston, MA 02118, USA.
    Andersson, Magnus
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Antibodies damage the resilience of fimbriae, causing them to be stiff and tangled2017In: Journal of Bacteriology, ISSN 0021-9193, E-ISSN 1098-5530, Vol. 199, no 1, article id e00665-16Article in journal (Refereed)
    Abstract [en]

    As adhesion fimbriae are a major virulence factor for many pathogenic Gram-negative bacteria, they are also potential targets for antibodies. Fimbriae are commonly required for initiating the colonization that leads to disease, and their success as adhesion organelles lies in their ability to both initiate and sustain bacte- rial attachment to epithelial cells. The ability of fimbriae to unwind and rewind their helical filaments presumably reduces their detachment from tissue surfaces with the shear forces that accompany significant fluid flow. Therefore, the disruption of func- tional fimbriae by inhibiting this resilience should have high potential for use as a vaccine to prevent disease. In this study, we show that two characteristic biome- chanical features of fimbrial resilience, namely, the extension force and the exten- sion length, are significantly altered by the binding of antibodies to fimbriae. The fimbriae that were studied are normally expressed on enterotoxigenic Escherichia coli, which are a major cause of diarrheal disease. This alteration in biomechanical properties was observed with bivalent polyclonal antifimbrial antibodies that recog- nize major pilin subunits but not with the Fab fragments of these antibodies. Thus, we propose that the mechanism by which bound antibodies disrupt the uncoiling of natural fimbria under force is by clamping together layers of the helical filament, thereby increasing their stiffness and reducing their resilience during fluid flow. In addition, we propose that antibodies tangle fimbriae via bivalent binding, i.e., by binding to two individual fimbriae and linking them together. Use of antibodies to disrupt physical properties of fimbriae may be generally applicable to the large number of Gram-negative bacteria that rely on these surface-adhesion molecules as an essential virulence factor.

    I M P O R T A N C E Our study shows that the resiliency of colonization factor antigen I (CFA/I) and coli surface antigen 2 (CS2) fimbriae, which are current targets for vac- cine development, can be compromised significantly in the presence of antifimbrial antibodies. It is unclear how the humoral immune system specifically interrupts in- fection after the attachment of enterotoxigenic Escherichia coli (ETEC) to the epithe- lial surface. Our study indicates that immunoglobulins, in addition to their well- documented role in adaptive immunity, can mechanically damage the resilience of fimbriae of surface-attached ETEC, thereby revealing a new mode of action. Our data suggest a mechanism whereby antibodies coat adherent and free-floating bacteria to impede fimbrial resilience. Further elucidation of this possible mechanism is likely to inform the development and refinement of preventive vaccines against ETEC diar- rhea. 

  • 107.
    Singh, Bhupender
    et al.
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Mortezaei, Narges
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Uhlin, Bernt Eric
    Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Savarino, Stephen
    Bullitt, Esther
    Andersson, Magnus
    Umeå University, Faculty of Science and Technology, Department of Physics.
    Antibody-mediated disruption of the mechanics of CS20 fimbriae of enterotoxigenic Escherichia coli2015In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 5, article id 13678Article in journal (Refereed)
    Abstract [en]

    Preventive vaccines against enterotoxigenic Escherichia coli (ETEC) are being developed, many of which target common fimbrial colonization factors as the major constituent, based on empirical evidence that these function as protective antigens. Particularly, passive oral administration of ETEC anti-fimbrial antibodies prevent ETEC diarrhea. Little is, however, known regarding the specific mechanisms by which intestinal antibodies against ETEC fimbriae function to prevent disease. Using coli surface antigen 20 (CS20) fimbriae as a model ETEC colonization factor, we show using force spectroscopy that anti-fimbrial antibodies diminish fimbrial elasticity by inhibiting their natural capacity to unwind and rewind. In the presence of anti-CS20 antibodies the force required to unwind a single fimbria was increased several-fold and the extension length was shortened several-fold. Similar measurements in the presence of anti-CS20 Fab fragments did not show any effect, indicating that bivalent antibody binding is required to reduce fimbrial elasticity. Based on these findings, we propose a model for an in-vivo mechanism whereby antibody-mediated disruption of the biomechanical properties of CS20 fimbriae impedes sustained adhesion of ETEC to the intestinal mucosal surface. Further elucidation of the role played by intestinal antibodies in mechanical disruption of fimbrial function may provide insights relevant to ETEC vaccine development.

  • 108.
    Sitohy, Basel
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry. Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hammarström, Sten
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Danielsson, Åke
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Medicine.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Basal lymphoid aggregates in ulcerative colitis colon: a site for regulatory T cell action2008In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 151, no 2, p. 326-333Article in journal (Refereed)
    Abstract [en]

    Regulatory T cells seem to play a central role in maintaining immune tolerance in the gut mucosa. Previously we have shown that interleukin (IL)-10 is produced at high levels in the inflamed colonic tissue of ulcerative colitis (UC) patients. The cellular source was CD4+ T cells, suggesting local activation of regulatory T cells. The present study was performed to determine whether the frequency of regulatory T cells is increased in UC colon and whether they are present in the basal lymphoid aggregates, the prominent microanatomical structure in UC colon. Colonic tissue specimens from UC and control patients were analysed for frequencies of lamina propria lymphocytes expressing the regulatory T cell markers forkhead box protein 3 (FoxP3), CD25 and glucocorticoid-induced tumour necrosis factor receptor family-related gene (GITR) as well as CD28, CD4 and CD3 by using marker specific reagents in immunomorphometry. Two-colour immunohistochemistry was used for detection of CD25/IL-10, FoxP3/IL-10 and CD25/FoxP3 double-positive cells. GITR+ and FoxP3+ cells were present in normal colon mucosa, although at a relatively low frequency, and were located preferentially within the solitary follicles. UC was associated with significantly increased frequencies of CD25+, GITR+ and FoxP3+ lamina propria lymphocytes both within the basal lymphoid aggregates and in the lamina propria outside. Many of the CD25+ cells co-expressed FoxP3 as well as IL-10, suggesting that these are indeed IL-10 secreting regulatory T cells, activated in an attempt to counteract the inflammation. Increased frequency of regulatory T cell subtypes seems insufficient to control the disease activity in UC.

  • 109. Slepenkin, Anatoly
    et al.
    Chu, Hencelyn
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Keyser, Pia
    Peterson, Ellena M
    Protection of mice from a chlamydia trachomatis vaginal infection using a salicylidene acylhydrazide, a potential Mmcrobicide2011In: Journal of Infectious Diseases, ISSN 0022-1899, E-ISSN 1537-6613, Vol. 204, no 9, p. 1314-1320Article in journal (Refereed)
    Abstract [en]

    The salicylidene acylhydrazide INP0341 inhibits growth of Chlamydia in HeLa cells, has negligible cell toxicity, and does not inhibit the growth of lactobacilli. The antichlamydial activity of INP0341 was retained when tested in vaginal and semen simulants. Vaginal tissue from INP0341-treated mice appeared similar to control sham-treated mice. To determine whether INP0341 can protect mice from a vaginal challenge, C3H/HeJ mice were either sham or INP0341 treated intravaginally pre- and postinoculation with 5 × 10(2) inclusion-forming units (IFUs) of Chlamydia trachomatis serovar D. Vaginal cultures taken over a month-long period showed a significant difference in the number of control mice that were culture positive versus the number in the INP0341-treated group, 100% (25/25) and 31% (8/26), respectively (P < .05). The quantity of IFUs shed and antibody titers to Chlamydia were significantly higher for the control group (P < .05). In summary, INP0341 is a promising compound to be considered for formulation as a vaginal microbicide.

  • 110.
    Sund, Malin
    et al.
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine. Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Surgery.
    Xu, Li Li
    Rahman, Arman
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Qian, Bi-Feng
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Danielsson, Åke
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine.
    Reduced susceptibility to dextran sulphate sodium-induced colitis in the interleukin-2 heterozygous (IL-2) mouse.2005In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 114, no 4, p. 554-564Article in journal (Refereed)
  • 111. Sundling, Christopher
    et al.
    Ronnberg, Caroline
    Yman, Victor
    Asghar, Muhammad
    Jahnmatz, Peter
    Lakshmikanth, Tadepally
    Chen, Yang
    Mikes, Jaromir
    Forsell, Mattias N.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Sonden, Klara
    Achour, Adnane
    Brodin, Petter
    Persson, Kristina E. M.
    Farnert, Anna
    B cell profiling in malaria reveals expansion and remodeling of CD11c+ B cell subsets2019In: JCI Insight, ISSN 2379-3708, Vol. 4, no 9, article id e126492Article in journal (Refereed)
    Abstract [en]

    Humoral immunity is important in limiting clinical disease in malaria, yet the longitudinal B cell response to infection remains unclear. We performed a 1-year prospective study in patients treated for acute Plasmodium fakiporum malaria for the first time or with previous exposure to the disease. Using an unbiased exploratory approach with mass cytometry, followed by targeted flow cytometry, we found that approximately 80% of mature B cells that proliferated in response to acute infection expressed CD11c. Only approximately 40% of CD11c+ B cells displayed an atypical B cell phenotype, with the remaining cells primarily made up of activated and resting memory B cells. The CD11c+ B cells expanded rapidly following infection, with previous exposure to malaria resulting in a significantly larger increase compared with individuals with primary infection. This was attributed to an expansion of switched CD11c+ B cells that was absent in primary infected individuals. The rate of contraction of the CD11c+ B cell compartment was independent of previous exposure to malaria and displayed a slow decay, with a half-life of approximately 300 days. Collectively, these results identify CD11c as a marker of B cells responding to malaria and further highlight differences in primary and secondary B cell responses during infection.

  • 112.
    Sundström, Mia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    B cell deviations and type 1 diabetes in the NOD mouse2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Type 1 diabetes (T1D) is a chronic autoimmune disease in which the insulin producing β-cells in the pancreatic islets of Langerhans are selectively attacked by the immune system. The β-cells are destroyed resulting in a reduced or eliminated insulin production, which in turn lead to a high blood glucose level. The non-obese diabetic (NOD) mouse is the most commonly used animal model for human T1D. NOD mice develop diabetes spontaneously through a process that closely resembles the human pathogenesis. In both humans and the NOD mouse, disease is caused by a combination of genetic and environmental factors. In the NOD mouse, more than 30 insulin-dependent diabetes (Idd) loci on 15 chromosomes have been linked to disease susceptibility, however, most of the Idd-regions lack identification of a disease associated gene. B cells are required for T1D development, although the underlying mechanisms are not fully revealed. The aim of this thesis was to dissect B cell-related immune deviations in the NOD mouse, including the underlying genetics of these traits.

    The TACI receptor binds two ligands, i.e. the cytokines BAFF and APRIL.TACI ligation by APRIL mediates class switch, drives plasma cell differentiation and increases immunoglobulin production. In Paper I, a novel NOD-specific B cell-related trait was identified, i.e. the increased percentage of TACIhigh-expressing splenic B cells, by comparing NOD mice with non-autoimmune disease prone C57BL/6 mice. To investigate if the described TACI trait was controlled by genes linked to any Idd-region, an Idd-focused linkage analysis was performed. The TACI-trait mapped to regions on chromosome 1 and 8, more specifically to the vicinity of the Idd5.4 and Idd22. Interestingly, the linkage to Idd22 was explained by mice ≥61 days of age, suggesting a temporal genetic regulation of TACI expression possibly influenced by the ongoing autoimmune process. In Paper II, the linkage of the TACI trait to chromosome 1 and 8 was confirmed by analyzing the percentage of TACIhigh-expressing B cells in congenic NOD.C1/Idd22 mice. Moreover, the functional consequence of TACI upregulation was investigated, with the focus on plasma cell development and immunoglobulin production. NOD splenic B cells stimulated with APRIL displayed increased numbers of plasma cells and produced higher amounts of IgG and IgA compared to B cells from C57BL/6 mice. Thus, the TACI upregulation on NOD B cells possibly contribute to a B cell compartment which is more disposed to plasma cell differentiation and isotype switch.

    NOD mice display enhanced and prolonged immune response towards several antigens, including non-self immunoglobulins. In Paper III, the genetic factor(s) controlling the altered immune response against a BALB/c derived monoclonal antibody were dissected. Significant linkage to the Idd1/Idd24, Idd12, and Idd18.1 regions as well as to a proximal region on chromosome 2 (33.5 Mb) was detected. The linkage to Idd1/24 was verified by analyzing a set of H2-congenic NOD and C57BL/6 mice, and the linked region was narrowed down to ~8 Mb. Candidate gene analysis revealed a significant difference in the transcription of the H2-O/DO molecule. This suggests that multiple mechanisms contribute to the loss of immune response control, including an altered MHC class II peptide loading on NOD B cells.

    In Paper IV, a novel B cell intrinsic receptor for IgM and IgG was revealed. The receptor appeared to be more abundant in NOD mice compared to C57BL/6 mice, as the level of extramembranous IgG monomers and IgM pentamers on peripheral blood B cells from NOD mice was significantly higher compared to C57BL/6 mice. In addition, analysis of immune complex binding using IgG- or IgM-opsonized bacterial particles revealed a higher degree of binding in NOD mice compared with C57BL/6 mice. The enhanced capture of immunoglobulins and immune complexes could thus contribute to the development of T1D by altering normal B cell functions such as activation and immune complex transportation.

  • 113.
    Sundström, Mia
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Banday, Viqar
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Lejon, Kristina
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology. Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Biomedical Laboratory Science.
    Increased expression of TACI in the NOD mouse results in enhanced plasma cell differentiation and immunoglobulin productionManuscript (preprint) (Other academic)
    Abstract [en]

    B cells have an important pathogenic role in the development of Type 1 diabetes in the NOD mouse. We have previously revealed a novel NOD-specific B cell-related trait, i.e. an increased percentage of TACIhigh-expressing B cells in NOD mice compared with C57BL/6 mice. In the NOD mouse the TACI trait is regulated by genes residing on chromosome 1 and 8, more specifically in the vicinity of the Idd5.4 and Idd22 regions. It has previously been demonstrated that TACI ligation by APRIL influences plasma cell differentiation, immunoglobulin production and isotype switch. In this paper the linkage of the TACI trait to chromosome 1 and 8 was confirmed by analyzing the percentage of TACIhigh-expressing B cells in congenic NOD.B6C1/Idd22 mice. Moreover, the functional concequence of TACI upregulation, with the focus on plasma cell development and immunoglobulin production, was investigated. NOD B cells stimulated with APRIL showed an increased plasma cell differentiation and enhanced IgM, IgG and IgA production compared to B cells from C57BL/6 mice. This supports the hypothesis that increased TACI expression on NOD B cells could contribute to the B cell involvement in the pathogenesis of T1D in the NOD mouse.

  • 114. Söderlund, A
    et al.
    Gabrielsson, S
    Paulie, S
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Rak, S
    Troye-Blomberg, M
    Allergen induced cytokine profiles in type I allergic individuals before and after immunotherapy.1997In: Immunology Letters, ISSN 0165-2478, E-ISSN 1879-0542, Vol. 57, no 1-3, p. 177-81Article in journal (Refereed)
    Abstract [en]

    Allergen immunotherapy (IT) involves subcutaneous injections of increasing doses of specific allergen over a period of time. It is recognised as highly effective in the treatment of patients with allergic rhinitis. However, the specific immunological mechanisms by which IT achieves its effect have not been fully elucidated. Recent studies, have shown that the clinical effects following IT of allergic individuals is concomitant with a reduced production of IL-4 by allergen specific CD4+ T-cells. The aim of the present study was to gain better knowledge about the immunological mechanisms by which IT exerts its beneficial effects. For this purpose, peripheral blood mononuclear cells (PBMC) from ten individuals receiving birch allergen or placebo in an IT-study performed in a double-blind manner, were analysed for IL-4, IFN-gamma, IL-5 and IL-10 mRNA expression at the onset of the study and during the pollen season, during treatment. Both spontaneous and in vitro allergen-induced cytokine mRNA expression was analysed using reverse transcriptase-polymerase chain reaction (RT-PCR). Spontaneous expression of IL-4 mRNA could be detected in most of the allergic patients, but not in healthy donors. The IT-treated patients showed a decrease in the spontaneous expression of IL-4 mRNA during the pollen season as compared to at the onset of the study, while in patients receiving placebo the IL-4 mRNA expression increased or remained unchanged. Similar results were obtained after in vitro stimulation with allergen. This was in contrast to the results for IFN-gamma, which was readily detected in both patient groups with no significant differences between the groups at either timepoint. IL-5 was shown to be increased during the pollen season in both groups and thereby presumably not affected by allergen IT. Taken together, these observations suggest that the cytokine profiles in circulating T lymphocytes change as a consequence of allergen IT.

  • 115. Söderström, K
    et al.
    Bucht, A
    Halapi, E
    Lundqvist, C
    Grönberg, A
    Nilsson, E
    Orsini, D L
    van de Wal, Y
    Koning, F
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    High expression of V gamma 8 is a shared feature of human gamma delta T cells in the epithelium of the gut and in the inflamed synovial tissue.1994In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 152, no 12, p. 6017-27Article in journal (Refereed)
    Abstract [en]

    We have analyzed the V-gene usage in gamma delta T cells of the human gut and joint by using a new mAb (B18) specific for V gamma 8 of human TCR-gamma delta+ T cells. The B18+ population constituted a minor subset of the gamma delta T cells in peripheral blood (PB) of healthy persons (6 +/- 5%) and only 1 of 35 gamma delta T cell clones analyzed was positive. In contrast, the B18+ subset was a dominant gamma delta T cell population among intraepithelial lymphocytes (IEL) derived from the human intestine (74 +/- 29, p < 0.002), and two of three IEL clones from patients with coeliac disease were B18+. Interestingly, a higher proportion of B18+ gamma delta T cells was found in the synovial fluid of patients with rheumatoid arthritis (RA) (21 +/- 18%, 0.02 < p < 0.05) compared with normal PB. Furthermore, the B18+ subset was more frequent among IL-2-expanded gamma delta T cells (42 +/- 20%) derived from synovial tissue than among IL-2-expanded cells derived from synovial fluid (p < 0.002) and PB from RA patients (p < 0.02) as well as normal PB (p < 0.002). The V-gene usage of 13 gamma delta T cell clones from the synovial fluid of arthritic patients was analyzed. All B18+ clones (n = 7) expressed mRNA for V gamma 8 together with mRNA for V delta 1 (n = 5) or mRNA for V delta 3 (n = 2). None of the B18- clones expressed V gamma 8 (n = 6). We conclude that the gamma delta T cell that expresses V gamma 8, together with mainly V delta 1, is a major gamma delta T cell subset among the IEL of the gut and a highly frequent subset in the synovial tissue of patients with RA. This subset may correspond to the mouse V gamma 7+ IEL, which has a high degree of amino acid sequence homology with the human V gamma 8 protein.

  • 116.
    Taheri, Nayyer
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Host-pathogen interactions during Campylobacter and Yersinia infections2019Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    The innate immune system is known for protecting the host against invading pathogens, for instance enteropathogens infecting the gastrointestinal tract. The production of e.g. antimicrobial peptides, cytokines, and chemokines by innate immune cells and intestinal epithelial cells contribute to bacterial clearance. Given the significance of this system in overall defense, pathogens affect and/or manipulate immune cells and responses in favor of their own survival. This thesis focuses on how the Gram-negative enteropathogenic bacteria Yersinia pseudotuberculosis and Campylobacter jejuni affect the host, either directly via type 3 secretion system (T3SS) effector proteins or via outer membrane vesicles (OMVs), and how host factors potentially affect their virulence.

    Yersinia pseudotuberculosis uses its T3SS to translocate virulence factors that disable various immune responses and subvert phagocytosis. Neutrophils are main target cells during Yersinia infection. They release granules that contain proteins with antimicrobial properties to the cell's exterior upon activation through a process called degranulation. We found that extracellular Y. pseudotuberculosis could prevent neutrophil degranulation upon cell contact. Prevention of degranulation was shown to be mediated via co-operative actions of the two anti-phagocytic Yersinia outer proteins YopH and YopE. Bacterial contact with neutrophils resulted in a transient inhibition of degranulation and further prevented degranulation upon subsequent contact with avirulent Y. pseudotuberculosis (lacking YopE and YopH) as well as Escherichia coli. Thus, Y. pseudotuberculosis impairs several neutrophil defense mechanisms to remain in the extracellular environment and to increase its survival during infection.

    Campylobacter jejuni lacks a T3SS and appears to use OMVs and flagella as its main secretion apparatus. During passage through the intestine C. jejuni is exposed to bile, an important physiological component and part of the natural barrier of the intestine, and ability to resist bile is advantageous for C. jejuni survival. We investigated how C. jejuni OMV production and protein content is affected by bile. The main invasion and colonization of C. jejuni occurs in the lower part of the intestine where the concentration of bile is low compared with the proximal intestine. The OMV proteomic profiles were radically altered when bacteria were grown in low concentration of bile corresponding to cecal concentrations. Twenty-five present of the detected proteins of OMVs showed an altered abundance in the presence of low concentration of bile. In contrast, the overall proteome of the bacteria was unaffected. Moreover, OMVs frombile-exposed bacteria could enhance adhesion as well as invasion of bacteria into intestinal epithelial cells, suggesting a role of OMVs to the virulence of C. jejuni in the gut. The body temperature differs between the asymptomatic avian carriers of C. jejuni and humans, which develop symptomatic disease. We investigated whether the bacterial growth temperature affects the OMV proteome and found that 59 proteins were differentially expressed at 37°C. Among the higher abundant proteins, significantly more proteins were predicted to be related to virulence. Thus, temperature has an impact on the property of the OMVs, and this might affect the outcome of infection by C. jejuni in different hosts.

    C. jejuni OMV interactions with innate immune cells were studied by analyses of OMV-mediated inflammasome activation. OMVs were found to induce ASC- and caspase-1-dependent inflammasome activation in murine and human macrophages and dendritic cells as well as in human neutrophils. While C. jejuni infection induced a low level of inflammasome-dependent cell death, OMV-induced inflammasome activation did not result in cell death. Thus, OMVs disseminate into tissue without bacteria can be a vehicle for virulence factors without inducing inflammatory cell death.

  • 117.
    Taheri, Nayyer
    et al.
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fahlgren, Anna
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Fällman, Maria
    Umeå University, Faculty of Medicine, Umeå Centre for Microbial Research (UCMR). Umeå University, Faculty of Medicine, Molecular Infection Medicine Sweden (MIMS). Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Yersinia pseudotuberculosis Blocks Neutrophil Degranulation2016In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 84, no 12, p. 3369-3378Article in journal (Refereed)
    Abstract [en]

    Neutrophils are essential components of immunity and are rapidly recruited to infected or injured tissue. Upon their activation, neutrophils release granules to the cell's exterior, through a process called degranulation. These granules contain proteins with antimicrobial properties that help combat infection. The enteropathogenic bacterium Yersinia pseudotuberculosis successfully persists as an extracellular bacterium during infection by virtue of its translocation of virulence effectors (Yersinia outer proteins [Yops]) that act in the cytosol of host immune cells to subvert phagocytosis and proinflammatory responses. Here, we investigated the effect of Y. pseudotuberculosis on neutrophil degranulation upon cell contact. We found that virulent Y. pseudotuberculosis was able to prevent secondary granule release. The blocking effect was general, as the release of primary and tertiary granules was also reduced. Degranulation of secondary granules was also blocked in primed neutrophils, suggesting that this mechanism could be an important element of immune evasion. Further, wild-type bacteria conferred a transient block on neutrophils that prevented their degranulation upon contact with plasmid-cured, avirulent Y. pseudotuberculosis and Escherichia coli Detailed analyses showed that the block was strictly dependent on the cooperative actions of the two antiphagocytic effectors, YopE and YopH, suggesting that the neutrophil target structures constituting signaling molecules needed to initiate both phagocytosis and general degranulation. Thus, via these virulence effectors, Yersinia can impair several mechanisms of the neutrophil's antimicrobial arsenal, which underscores the power of its virulence effector machinery.

  • 118. Tauriainen, Johanna
    et al.
    Maleki, Kimia
    Blom, Kim
    Bjorkstrom, Niklas
    Ahlm, Clas
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Infectious Diseases.
    Ljunggren, Hans-Gustaf
    Klingstrom, Jonas
    Inverse expression of the inhibitory/activating receptors TIGIT/CD226 on CD8 T cells in acute HFRS2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 291-291Article in journal (Other academic)
  • 119. Tran, Seav-Ly
    et al.
    Guillemet, Elisabeth
    Ngo-Camus, Maud
    Clybouw, Cyril
    Puhar, Andrea
    Unité PMM, INSERM U786, Institut Pasteur, 75724 Paris Cedex 15, France..
    Moris, Arnaud
    Gohar, Michel
    Lereclus, Didier
    Ramarao, Nalini
    Haemolysin II is a Bacillus cereus virulence factor that induces apoptosis of macrophages2011In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 13, no 1, p. 92-108Article in journal (Refereed)
    Abstract [en]

    Bacillus cereus is a Gram-positive spore-forming bacterium causing food poisoning and serious opportunistic infections. These infections are characterized by bacterial accumulation despite the recruitment of phagocytic cells. The precise mechanisms and the bacterial factors allowing B. cereus to circumvent host immune responses remain to be elucidated. We have previously shown that B. cereus induces macrophage cell death by an unknown mechanism. Here we identified the toxic component from the B. cereus supernatant. We report that Haemolysin II (HlyII) provokes macrophage cell death by apoptosis through its pore-forming activity. The HlyII-induced apoptotic pathway is caspase 3 and 8 dependent, thus most likely mediated by the death receptor pathway. Using insects and mice as in vivo models, we show that deletion of hlyII strongly reduces virulence. In addition, we show that after infection of Bombyx mori larvae, the immune cells are apoptotic, demonstrating that HlyII induces apoptosis of phagocytic cells in vivo. Altogether, our results clearly unravel HlyII as a novel virulence protein that induces apoptosis in phagocytic cells in vitro and in vivo.

  • 120. Tran, Seav-Ly
    et al.
    Puhar, Andrea
    Unité PMM, INSERM U786, Institut Pasteur, Paris, France, Universite de la Mediterranee, France.
    Ngo-Camus, Maud
    Ramarao, Nalini
    Trypan blue dye enters viable cells incubated with the pore-forming toxin HlyII of Bacillus cereus2011In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 6, no 9, article id e22876Article in journal (Refereed)
    Abstract [en]

    Trypan blue is a dye that has been widely used for selective staining of dead tissues or cells. Here, we show that the pore-forming toxin HlyII of Bacillus cereus allows trypan blue staining of macrophage cells, despite the cells remaining viable and metabolically active. These findings suggest that the dye enters viable cells through the pores. To our knowledge, this is the first demonstration that trypan blue may enter viable cells. Consequently, the use of trypan blue staining as a marker of vital status should be interpreted with caution. The blue coloration does not necessarily indicate cell lysis, but may rather indicate pore formation in the cell membranes and more generally increased membrane permeability.

  • 121. Troge, Anja
    et al.
    Scheppach, Wolfgang
    Schröder, Björn
    Rund, Stefan A
    Heuner, Klaus
    Wehkamp, Jan
    Stange, Eduard F
    Oelschlaeger, Tobias A
    More than a marine propeller--the flagellum of the probiotic Escherichia coli strain Nissle 1917 is the major adhesin mediating binding to human mucus.2012In: International Journal of Medical Microbiology, ISSN 1438-4221, E-ISSN 1618-0607, Vol. 302, no 7-8, p. 304-14, article id S1438-4221(12)00066-5Article in journal (Refereed)
    Abstract [en]

    The flagellum of the probiotic Escherichia coli strain Nissle 1917 (EcN) is not just responsible for motility, but also for EcN's ability to induce the production of human β-defensin 2. Here, we report a third function of this EcN organell. In this study we investigated the role of the EcN flagellum in adhesion to different host tissues by ex vivo and in vitro studies. Ex vivo studies with cryosections of human gut biopsies revealed that the flagellum of EcN is most likely important for efficient adhesion to the human intestinal tract. These results and in vitro studies with different epithelial cells indicated that the presence of mucus is important for efficient mediation of adhesion by the flagellum of EcN. We observed direct interaction between isolated flagella from EcN wild type and porcine mucin 2 as well as human mucus. However, we could not observe any interaction of the flagella with murine mucus. For the first time, we identified the mucus component gluconate as one receptor for the binding of flagella from EcN and were able to exclude the flagellin domain D3 as a responsible interaction partner. We propose that the flagellum of EcN is its major adhesin in vivo, which enables this probiotic strain to compete efficiently for binding sites on host tissue with several bacterial pathogens.

  • 122. Troye-Blomberg, Marita
    et al.
    Worku, S
    Tangteerawatana, P
    Jamshaid, R
    Söderström, K
    Elghazali, G
    Moretta, L
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Mincheva-Nilsson, Lucia
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Clinical Immunology.
    Human gamma delta T cells that inhibit the in vitro growth of the asexual blood stages of the Plasmodium falciparum parasite express cytolytic and proinflammatory molecules.1999In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 50, no 6, p. 642-50Article in journal (Refereed)
    Abstract [en]

    The functional properties, regarding parasite growth inhibition in vitro, the cytotoxic potential and cytokine profiles of human gammadelta+ and alphabeta+ T cells, T-cell lines and clones stimulated with Plasmodium falciparum-antigen-or T-cell mitogen in vitro were investigated. Using reverse transcriptase-polymerase chain reaction (RT-PCR) and specific primers, mRNA for the cytolytic molecules perforin, granzyme A and B, Fas and Fas ligand (FasL) were detected in both the gammadelta- and the alphabetaT cells. Despite this fact, only gammadeltaT cells inhibited, both Vdelta1+ and Vdelta2+, the in vitro growth of the asexual blood stages in a dose dependent manner. The inhibition required cell-to-cell contact and was not observed until the second parasite replication implied that the likely gammadeltaT-cell target was the extracellular merozoite or schizont. The failure of alphabetaT cells to inhibit the growth of the parasite suggests requirement of additional cytolytic molecules/signals or different receptor specificities exhibited by the gammadeltaT cells. Both the gammadelta- and alphabetaT cells expressed mRNA for a large number of cytokines. Interferon (IFN)-gamma, interleukin (IL) IL-5, IL-6, IL-8, tumour necrosis factor alpha (TNFalpha), tumour necrosis factor beta (TNF-beta)/lymphotoxin (LT) and T-cell growth factor beta-1 (TGF-beta1) were observed in all activated clones tested. No IL-3 was detected, while IL-1beta, IL-2, IL-4, IL-10 and GM-CSF were variably expressed. In conclusion, our data show that gammadeltaT cells in malaria nonimmune individuals inhibit the asexual blood stages of P. falciparum malaria, while similarly activated alphabetaT cells do not. Thus, it is likely that the gammadeltaT cells could play a mandatory role in the elimination of parasites and/or the regulation of the early immune response to malaria infection.

  • 123.
    Tükenmez, Hasan
    et al.
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Edström, Isabel
    Umeå University, Faculty of Science and Technology, Department of Molecular Biology (Faculty of Science and Technology).
    Kalsum, Sadaf
    Braian, Clara
    Ummanni, Ramesh
    Lindberg, Stina
    Umeå University, Faculty of Science and Technology, Department of Chemistry. Chemical Biology Consortium Sweden (CBCS).
    Sundin, Charlotta
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Lerm, Maria
    Elofsson, Mikael
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Larsson, Christer
    Corticosteroids protect infected cells against mycobacterial killing in vitro2019In: Biochemical and Biophysical Research Communications - BBRC, ISSN 0006-291X, E-ISSN 1090-2104, Vol. 511, no 1, p. 117-121Article in journal (Refereed)
    Abstract [en]

    The effect of corticosteroids on human physiology is complex and their use in tuberculosis patients remains controversial. In a high-throughput screening approach designed to discover virulence inhibitors, several corticosteroids were found to prevent cytolysis of fibroblasts infected with mycobacteria. Further experiments with Mycobacterium tuberculosis showed anti-cytolytic activity in the 10 nM range, but no effect on bacterial growth or survival in the absence of host cells at 20 mu M. The results from a panel of corticosteroids with various affinities to the glucocorticoid- and mineralocorticoid receptors indicate that the inhibition of cytolysis most likely is mediated through the glucocorticoid receptor. Using live-imaging of M. tuberculosis-infected human monocyte-derived macrophages, we also show that corticosteroids to some extent control intracellular bacteria. In vitro systems with reduced complexity are to further study and understand the interactions between bacterial infection, immune defense and cell signaling. (C) 2019 The Authors. Published by Elsevier Inc.

  • 124. Volk, Joana K.
    et al.
    Nyström, Elisabeth E. L.
    van der Post, Sjoerd
    Abad, Beatriz M.
    Schroeder, Bjoern
    Wallenberg Laboratory and Sahlgrenska Center for Cardiovascular and Metabolic Research, Department of Molecular and Clinical Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden.
    Johansson, Åsa
    Svensson, Frida
    Jäverfelt, Sofia
    Johansson, Malin E. V.
    Hansson, Gunnar C.
    Birchenough, George M. H.
    The Nlrp6 inflammasome is not required for baseline colonic inner mucus layer formation or function2019In: Journal of Experimental Medicine, ISSN 0022-1007, E-ISSN 1540-9538, Vol. 216, no 11, p. 2602-2618Article in journal (Refereed)
    Abstract [en]

    The inner mucus layer (IML) is a critical barrier that protects the colonic epithelium from luminal threats and inflammatory bowel disease. Innate immune signaling is thought to regulate IML formation via goblet cell Nlrp6 inflammasome activity that controls secretion of the mucus structural component Muc2. We report that isolated colonic goblet cells express components of several inflammasomes; however, analysis of IML properties in multiple inflammasome-deficient mice, including littermate-controlled Nlrp6−/−, detect a functional IML barrier in all strains. Analysis of mice lacking inflammasome substrate cytokines identifies a defective IML in Il18−/− mice, but this phenotype is ultimately traced to a microbiota-driven, Il18-independent effect. Analysis of phenotypic transfer between IML-deficient and IML-intact mice finds that the Bacteroidales family S24-7 (Muribaculaceae) and genus Adlercrutzia consistently positively covary with IML barrier function. Together, our results demonstrate that baseline IML formation and function is independent of inflammasome activity and highlights the role of the microbiota in determining IML barrier function.

  • 125.
    Waltraud, Schrottmaier
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Anna-Liisa, Luik
    Manuel, Salzmann
    Sigrun, Badrnya
    Susanne, Morava
    Julia, Kral-Pointner
    Mikael, Karlsson
    Alice, Assinger
    Mattias, Forsell
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology.
    Activation of circulating platelets leads to innate-like delivery of potent antiviral antibodies2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 278-278Article in journal (Other academic)
  • 126. Wareham, N. E.
    et al.
    Heilmann, C.
    Abrahamsson, J.
    Forestier, Erik
    Umeå University, Faculty of Medicine, Department of Medical Biosciences.
    Gustafsson, B.
    Ha, S-Y
    Heldrup, J.
    Jahnukainen, K.
    Jonsson, O. G.
    Lausen, B.
    Palle, J.
    Zeller, B.
    Hasle, H.
    Outcome of poor response paediatric AML using early SCT2012In: Biology of blood and marrow transplantation, ISSN 1083-8791, E-ISSN 1523-6536, Vol. 18, no 2, p. S235-S235Article in journal (Other academic)
  • 127. Wendler, J.
    et al.
    Ehmann, D.
    Courth, L.
    Schröder, Björn
    Malek, N.P.
    Wehkamp, J.
    Bacterial Periplasmic Oxidoreductases Control the Activity of Oxidized Human Antimicrobial β-Defensin 12018In: Infection and Immunity, ISSN 0019-9567, E-ISSN 1098-5522, Vol. 86, no 4, article id e00875-17Article in journal (Refereed)
    Abstract [en]

    The antimicrobial peptide human β-defensin 1 (hBD1) is continuously produced by epithelial cells in many tissues. Compared to other defensins, hBD1 has only minor antibiotic activity in its native state. After reduction of its disulfide bridges, however, it becomes a potent antimicrobial agent against bacteria, while the oxidized native form (hBD1ox) shows specific activity against Gram-negative bacteria. We show that the killing mechanism of hBD1ox depends on aerobic growth conditions and bacterial enzymes. We analyzed the different activities of hBD1 using mutants of Escherichia coli lacking one or more specific proteins of their outer membrane, cytosol, or redox systems. We discovered that DsbA and DsbB are essential for the antimicrobial activity of hBD1ox but not for that of reduced hBD1 (hBD1red). Furthermore, our results strongly suggest that hBD1ox uses outer membrane protein FepA to penetrate the bacterial periplasm space. In contrast, other bacterial proteins in the outer membrane and cytosol did not modify the antimicrobial activity. Using immunogold labeling, we identified the localization of hBD1ox in the periplasmic space and partly in the outer membrane of E. coli. However, in resistant mutants lacking DsbA and DsbB, hBD1ox was detected mainly in the bacterial cytosol. In summary, we discovered that hBD1ox could use FepA to enter the periplasmic space, where its activity depends on presence of DsbA and DsbB. HBD1ox concentrates in the periplasm in Gram-negative bacteria, which finally leads to bleb formation and death of the bacteria. Thus, the bacterial redox system plays an essential role in mechanisms of resistance against host-derived peptides such as hBD1.

  • 128. Wendler, Judith
    et al.
    Schröder, Björn
    Dr. Margarete FischerBosch-Institute of Clinical Pharmacology, Stuttgart and University of Tuebingen, Tuebingen, Germany; Present address: Wallenberg Laboratory, University of Gothenburg, Gothenburg, Sweden.
    Ehmann, Dirk
    Koeninger, Louis
    Mailänder-Sánchez, Daniela
    Lemberg, Christina
    Wanner, Stephanie
    Schaller, Martin
    Stange, Eduard F
    Malek, Nisar P.
    Weidenmaier, Christopher
    LeibundGut-Landmann, Salomé
    Wehkamp, Jan
    Proteolytic Degradation of reduced Human Beta Defensin 1 generates a Novel Antibiotic Octapeptide2019In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 9, article id 3640Article in journal (Refereed)
    Abstract [en]

    Microbial resistance against clinical used antibiotics is on the rise. Accordingly, there is a high demand for new innovative antimicrobial strategies. The host-defense peptide human beta-defensin 1 (hBD-1) is produced continuously by epithelial cells and exhibits compelling antimicrobial activity after reduction of its disulphide bridges. Here we report that proteolysis of reduced hBD-1 by gastrointestinal proteases as well as human duodenal secretions produces an eight-amino acid carboxy-terminal fragment. The generated octapeptide retains antibiotic activity, yet with distinct characteristics differing from the full-length peptide. We modified the octapeptide by stabilizing its termini and by using non-natural D-amino acids. The native and modified peptide variants showed antibiotic activity against pathogenic as well as antibiotic-resistant microorganisms, including E. coli, P. aeruginosa and C. albicans. Moreover, in an in vitro C. albicans infection model the tested peptides demonstrated effective amelioration of C. albicans infection without showing cytotoxity on human cells. In summary, protease degradation of hBD-1 provides a yet unknown mechanism to broaden antimicrobial host defense, which could be used to develop defensin-derived therapeutic applications.

  • 129.
    West, Christina E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Pediatrik.
    Gothefors, Leif
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Pediatrik.
    Granström, Marta
    Käyhty, Helena
    Hammarström, Marie-Louise K C
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics. Pediatrik.
    Effects of feeding probiotics during weaning on infections and antibody responses to diphtheria, tetanus and Hib vaccines.2008In: Pediatric Allergy and Immunology, ISSN 0905-6157, E-ISSN 1399-3038, Vol. 19, no 1, p. 53-60Article in journal (Other academic)
    Abstract [en]

    Microbial exposure is necessary for the development of normal immune function, which has driven the idea of using probiotics for treatment and prevention of immune-mediated diseases in infancy and childhood. Mounting evidence indicates that probiotics have immunomodulatory effects. However, the mechanisms are still poorly understood. Specific antibody response is a valuable proxy for immune system maturation status in infancy. We aimed at determining the impact of Lactobacillus F19 (LF19) during weaning on infections and IgG antibody responses to routine vaccines. In a double-blind, placebo-controlled randomized intervention trial, infants were fed cereals with (n = 89) or without LF19 (n = 90) from 4 to 13 months of age. Infants were immunized with DTaP (diphtheria and tetanus toxoid and acellular pertussis), polio and Hib-conjugate vaccines at (3), 5(1/2) and 12 months of age. We assessed the number of days with infections, antibiotic prescriptions and antibody concentrations to Hib capsular polysaccharide (HibPS), diphtheria toxin (D) and tetanus toxoid (T) before and after the second and third doses. Days with infectious symptoms did not differ between the groups. Days with antibiotic prescriptions were fewer in the LF19 group (p = 0.044). LF19 enhanced anti-D concentrations when adjusting for breastfeeding duration and colonization with LF19 (p = 0.024). There was an interaction of the intervention and colonization with LF19 on anti-T concentrations during the course of vaccination (p = 0.035). The anti-HibPS concentrations were higher after the first and second dose of Hib vaccine in infants breastfed <6 months compared with those breastfed > or =6 months (p < 0.05), with no effect by LF19. In conclusion, feeding LF19 did not prevent infections, but increased the capacity to raise immune responses to protein antigens, with more pronounced effects in infants breastfed <6 months.

  • 130.
    West, Christina E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Probiotics during weaning reduce the incidence of eczema.2009In: Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology, ISSN 1399-3038, Vol. 20, p. 430-7Article in journal (Refereed)
    Abstract [en]

    A reduced microbial load early in life has been suggested to be linked to the increasing prevalence of allergic diseases in the industrialized world. Some studies have indicated that probiotics may be effective in the prevention of eczema. In vitro studies indicate that probiotics have immunomodulatory effects. In the present study, we evaluated the effects of feeding Lactobacillus F19 during weaning on the incidence of eczema and Th1/Th2 balance. In a double-blind, placebo-controlled randomized intervention trial, infants were fed cereals with (n = 89) or without Lactobacillus F19 (n = 90) from 4 to 13 months of age. We assessed the cumulative incidence of eczema at 13 months of age. The ratio of interferon-gamma (IFN-gamma) to interleukin 4 (IL4) mRNA expression levels in polyclonally stimulated peripheral blood T cells was used as a proxy for immune balance. Total and specific IgE serum levels were also assessed. The cumulative incidence of eczema at 13 months was 11% (4-17%, 95% CI) and 22% (13-31%, 95% CI) in the probiotic and placebo groups, respectively (p < 0.05). The number needed to treat was 9 (6.5-11.5, 95% CI). At 13 months of age, the IFN-gamma/IL4 mRNA ratio was higher in the probiotic compared with the placebo group (p < 0.05). In contrast, there were no differences between groups in serum concentrations of IgE. In summary, feeding Lactobacillus F19 during weaning could be an effective tool in the prevention of early manifestation of allergy, e.g., eczema. The higher Th1/Th2 ratio in the probiotic compared with the placebo group suggests enhancing effects of Lactobacillus F19 on the T cell-mediated immune response.

  • 131.
    West, Christina E
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Hernell, Olle
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Andersson, Yvonne
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Sjöstedt, M
    Hammarström, Marie-Louise
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Immunology/Immunchemistry.
    Probiotic effects on T-cell maturation in infants during weaning.2012In: Clinical and Experimental Allergy, ISSN 0954-7894, E-ISSN 1365-2222, Vol. 42, no 4, p. 540-549Article in journal (Refereed)
    Abstract [en]

    Background: We previously reported that feeding the probiotic Lactobacillus paracasei ssp. paracasei F19 (LF19) during weaning reduced the cumulative incidence of eczema.

    Objective: To investigate the impact of feeding LF19 on T-cell maturation.

    Methods: One hundred and seventy-nine healthy, term infants with no prior allergic manifestations were randomized to daily intake of cereals with (n = 89) or without (n = 90) the addition of LF19 10colony forming units per serving from 4 to 13 months of age. Venous blood was drawn at 5.5 and 13 months of age. We used the cytokine response to polyclonal T-cell stimulation by anti-CD3 plus anti-CD28 monoclonal antibodies, and in vitro stimulation with the vaccine tetanus toxoid (TT) as measures of global adaptive immunity and capacity to raise a specific T-cell response, respectively. Expression levels of IL-2, IFN-γ, IL-4, IL-17A and IL-10 messenger RNAs (mRNAs) were used as proxies for general T-cell stimulation and naive Th0 cells, Th1-, Th2-, Th17- and T regulatory lineages.

    Results: There was no difference between the two groups at 5.5 months of age. At 13 months, the polyclonal IL-2 response was higher in the placebo group (P < 0.05), whereas the IFN-γ/IL-2 (P < 0.01) and IL-17A/IL-2 (P < 0.05) ratios after polyclonal stimulation were higher in the probiotic group, as was the TT-specific IL17-A response (P < 0.001). In both groups, the IFN-γ and IL-4 responses increased from 5.5 to 13 months upon both polyclonal and specific stimulation (P < 0.01), whereas the IL-10 response remained low (P > 0.05).

    Conclusion and Clinical Relevance: Our findings suggest modest effects by probiotics on T-cell maturation following 9 months of probiotic intake. Future studies should address if specific probiotics may drive immune development with possible preventive effects on the development of allergic disease.

  • 132.
    Westlund, Jessica
    et al.
    University of Gothenburg.
    Livingston, Megan
    University of Gothenburg.
    Fahlen-Yrlid, Linda
    University of Gothenburg.
    Oldenborg, Per-Arne
    Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Histology and Cell Biology.
    Yrlid, Ulf
    University of Gothenburg.
    CD47-deficient mice have decreased production of intestinal IgA following oral immunization but a maintained capacity to induce oral tolerance2012In: Immunology, ISSN 0019-2805, E-ISSN 1365-2567, Vol. 135, no 3, p. 236-244Article in journal (Refereed)
    Abstract [en]

    Signal regulatory protein a (SIRPa/CD172a), expressed by myeloid cells including CD11b+ dendritic cells, interacts with ubiquitously expressed CD47 to mediate cellcell signalling and therefore, may be pivotal in the development of tolerance or immunity. We show that in mice deficient in CD47 (CD47-/-) the cellularity in gut-associated lymphoid tissues is reduced by 50%. In addition, the frequency of CD11b+ CD172a+ dendritic cells is significantly reduced in the gut and mesenteric lymph nodes, but not in Peyers patches. Activation of ovalbumin (OVA)-specific CD4+ T cells in the mesenteric lymph nodes after feeding OVA is reduced in CD47-/- mice compared with wild-type however, induction of oral tolerance is maintained. The addition of cholera toxin generated normal serum anti-OVA IgG and IgA titres but resulted in reduced intestinal anti-OVA IgA in CD47-/- mice. Replacing the haematopoietic compartment in CD47-/- mice with wild-type cells restored neither the cellularity in gut-associated lymphoid tissues nor the capacity to produce intestinal anti-OVA IgA following immunization. This study demonstrates that CD47 signalling is dispensable for oral tolerance induction, whereas the expression of CD47 by non-haematopoietic cells is required for intestinal IgA B-cell responses. This suggests that differential CD4 T cell functions control tolerance and enterotoxin-induced IgA immunity in the gut.

  • 133.
    Williams, Michael J
    Umeå University, Faculty of Science and Technology, Umeå Centre for Molecular Pathogenesis (UCMP).
    Drosophila hemopoiesis and cellular immunity2007In: Journal of Immunology, ISSN 0022-1767, E-ISSN 1550-6606, Vol. 178, no 8, p. 4711-4716Article, review/survey (Refereed)
    Abstract [en]

    In Drosophila melanogaster larvae, three classes of circulating cellular immune surveillance cells (hemocytes) can be identified: plasmatocytes, crystal cells, and lamellocytes. Plasmatocytes are profiessional phagocytes most similar to the mammalian monocyte/macrophage lineage and make up similar to 95% of circulating hemocytes. The other similar to 5% of circulating hemocytes consists of crystal cells, which secrete components necessary for the melanization of invading organisms, as well as for wound repair. A third cell type known as lamellocytes are rarely seen in healthy larvae and are involved in the encapsulation of invading pathogens. There are no obvious mammalian counterparts for crystal cells or lamellocytes, and there is no equivalent to the lymphoid lineage in insects. In this review, I will discuss what is currently known about Drosophila hemopoiesis and the cellular immune response and where possible compare it to vertebrate mechanisms.

  • 134.
    Winberg, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Sciences, Paediatrics.
    Bjerg, A.
    Berthold, M.
    Lindback, J.
    Mattsson, L.
    Borres, M.
    Rönnmark, Eva
    Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Occupational and Environmental Medicine.
    Furry animal sensitisation to allergen components and asthma diagnosis in a child cohort from northern Sweden2012In: Allergy. European Journal of Allergy and Clinical Immunology, ISSN 0105-4538, E-ISSN 1398-9995, Vol. 67, no Suppl. 1, p. 539-539Article in journal (Other academic)
  • 135.
    Yang, Hairu
    et al.
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine).
    Hultmark, Dan
    Umeå University, Faculty of Medicine, Department of Molecular Biology (Faculty of Medicine). Institute of Biomedical Technology, University of Tampere, Tampere, Finland.
    Drosophila muscles regulate the immune response against wasp infection via carbohydrate metabolism2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 15713Article in journal (Refereed)
    Abstract [en]

    We recently found that JAK/STAT signaling in skeletal muscles is important for the immune response of Drosophila larvae against wasp infection, but it was not clear how muscles could affect the immune response. Here we show that insulin signaling is required in muscles, but not in fat body or hemocytes, during larval development for an efficient encapsulation response and for the formation of lamellocytes. This effect requires TOR signaling. We show that muscle tissue affects the immune response by acting as a master regulator of carbohydrate metabolism in the infected animal, via JAK/STAT and insulin signaling in the muscles, and that there is indirect positive feedback between JAK/STAT and insulin signaling in the muscles. Specifically, stimulation of JAK/STAT signaling in the muscles can rescue the deficient immune response when insulin signaling is suppressed. Our results shed new light on the interaction between metabolism, immunity, and tissue communication.

  • 136. Yin, Zhaojun
    et al.
    Wu, Xuanjun
    Kaczanowska, Katarzyna
    Sungsuwan, Suttipun
    Comellas Aragones, Marta
    Pett, Christian
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Yu, Jin
    Baniel, Claire
    Ulrika, Westerlind
    Umeå University, Faculty of Science and Technology, Department of Chemistry.
    Finn, M. G.
    Huang, Xuefei
    Antitumor Humoral and T Cell Responses by Mucin-1 Conjugates of Bacteriophage Qβ in Wild-type Mice2018In: ACS Chemical Biology, ISSN 1554-8929, E-ISSN 1554-8937, Vol. 13, no 6, p. 1668-1676Article in journal (Refereed)
    Abstract [en]

    Mucin-1 (MUC1) is one of the top ranked tumor associated antigens. In order to generate effective anti-MUC1 immune responses as potential anticancer vaccines, MUC1 peptides and glycopeptides have been covalently conjugated to bacteriophage Qβ. Immunization of mice with these constructs led to highly potent antibody responses with IgG titers over one million, which are among the highest anti-MUC1 IgG titers reported to date. Furthermore, the high IgG antibody levels persisted for more than six months. The constructs also elicited MUC1 specific cytotoxic T cells, which can selectively kill MUC1 positive tumor cells. The unique abilities of Qβ-MUC1 conjugates to powerfully induce both antibody and cytotoxic T cell immunity targeting tumor cells bode well for future translation of the constructs as anticancer vaccines.

  • 137. Zhang, Lu
    et al.
    Hu, Jin
    Zirakzadeh, Ali
    Rosvall, Jesper
    Hedlund, Mats
    Hu, Pingsheng
    Wallin, Robert
    Sherif, Amir
    Umeå University, Faculty of Medicine, Department of Surgical and Perioperative Sciences, Urology and Andrology.
    Winqvist, Ola
    Immune responses against Human Papilloma virus in draining lymph nodes from patients with penile cancer2017In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 86, no 4, p. 339-339Article in journal (Other academic)
  • 138.
    Överby, Anna
    et al.
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Nilsson, Emma
    Umeå University, Faculty of Medicine, Department of Clinical Microbiology, Virology.
    Det tidiga immunförsvaret nyckel i kampen mot TBE-virus2014In: Neurologi i Sverige, ISSN 2000-8538, Vol. 2, no 14, p. 68-74Article in journal (Other academic)
123 101 - 138 of 138
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