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  • 1
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    Online Resource
    Binding of Complement Inhibitor C4b-Binding Protein Contributes to Serum Resistance of Porphyromonas gingivalis
    The American Association of Immunologists ; 2008
    In:  The Journal of Immunology Vol. 181, No. 8 ( 2008-10-15), p. 5537-5544
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 181, No. 8 ( 2008-10-15), p. 5537-5544
    Abstract: The periodontal pathogen Porphyromonas gingivalis is highly resistant to the bactericidal activity of human complement, which is present in the gingival crevicular fluid at 70% of serum concentration. All thirteen clinical and laboratory P. gingivalis strains tested were able to capture the human complement inhibitor C4b-binding protein (C4BP), which may contribute to their serum resistance. Accordingly, in serum deficient of C4BP, it was found that significantly more terminal complement component C9 was deposited on P. gingivalis. Moreover, using purified proteins and various isogenic mutants, we found that the cysteine protease high molecular weight arginine-gingipain A (HRgpA) is a crucial C4BP ligand on the bacterial surface. Binding of C4BP to P. gingivalis appears to be localized to two binding sites: on the complement control protein 1 domain and complement control protein 6 and 7 domains of the α-chains. Furthermore, the bacterial binding of C4BP was found to increase with time of culture and a particularly strong binding was observed for large aggregates of bacteria that formed during culture on solid blood agar medium. Taken together, gingipains appear to be a very significant virulence factor not only destroying complement due to proteolytic degradation as we have shown previously, but was also inhibiting complement activation due to their ability to bind the complement inhibitor C4BP.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.181.8.5537
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2008
    detail.hit.zdb_id: 1475085-5
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  • 2
    Online Resource
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    Antibodies to Porphyromonas gingivalis Indicate Interaction Between Oral Infection, Smoking, and Risk Genes in Rheumatoid Arthritis Etiology
    Wiley ; 2016
    In:  Arthritis & Rheumatology Vol. 68, No. 3 ( 2016-03), p. 604-613
    Details
    In: Arthritis & Rheumatology, Wiley, Vol. 68, No. 3 ( 2016-03), p. 604-613
    Abstract: To investigate the role of the periodontal pathogen Porphyromonas gingivalis in the etiology of rheumatoid arthritis (RA) by analyzing the antibody response to the P gingivalis virulence factor arginine gingipain type B (RgpB) in relation to anti–citrullinated protein antibodies (ACPAs), smoking, and HLA–DRB1 shared epitope (SE) alleles in patients with periodontitis, patients with RA, and controls. Methods Anti‐RgpB IgG was measured by enzyme‐linked immunosorbent assay in 65 periodontitis patients and 59 controls without periodontitis, and in 1,974 RA patients and 377 controls without RA from the Swedish population‐based case–control Epidemiological Investigation of Rheumatoid Arthritis (EIRA) study. Autoantibody status, smoking habits, and genetic data were retrieved from the EIRA database. Differences in antibody levels were examined using the Mann‐Whitney U test. Unconditional logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (95% CIs) for the association of anti‐RgpB IgG with different subsets of RA patients. Results Anti‐RgpB antibody levels were significantly elevated in periodontitis patients compared to controls without periodontitis, in RA patients compared to controls without RA, and in ACPA‐positive RA patients compared to ACPA‐negative RA patients. There was a significant association between anti‐RgpB IgG and RA (OR 2.96 [95% CI 2.00, 4.37]), which was even stronger than the association between smoking and RA (OR 1.37 [95% CI 1.07, 1.74] ), and in ACPA‐positive RA there were interactions between anti‐RgpB antibodies and both smoking and the HLA–DRB1 SE. Conclusion Our study suggests that the previously reported link between periodontitis and RA could be accounted for by P gingivalis infection, and we conclude that P gingivalis is a credible candidate for triggering and/or driving autoimmunity and autoimmune disease in a subset of RA patients.
    Type of Medium: Online Resource
    ISSN: 2326-5191 , 2326-5205
    URL: Issue
    URL: Article
    DOI: 10.1002/art.v68.3
    DOI: 10.1002/art.39491
    RVK:
    XA 10000
    RVK:
    XA 30325
    Language: English
    Publisher: Wiley
    Publication Date: 2016
    detail.hit.zdb_id: 2754614-7
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  • 3
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    Online Resource
    A Novel Biological Role for Peptidyl-Arginine Deiminases: Citrullination of Cathelicidin LL-37 Controls the Immunostimulatory Potential of Cell-Free DNA
    The American Association of Immunologists ; 2018
    In:  The Journal of Immunology Vol. 200, No. 7 ( 2018-04-01), p. 2327-2340
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 200, No. 7 ( 2018-04-01), p. 2327-2340
    Abstract: LL-37, the only human cathelicidin that is released during inflammation, is a potent regulator of immune responses by facilitating delivery of oligonucleotides to intracellular TLR-9, thereby enhancing the response of human plasmacytoid dendritic cells (pDCs) to extracellular DNA. Although important for pathogen recognition, this mechanism may facilitate development of autoimmune diseases. In this article, we show that citrullination of LL-37 by peptidyl-arginine deiminases (PADs) hindered peptide-dependent DNA uptake and sensing by pDCs. In contrast, carbamylation of the peptide (homocitrullination of Lys residues) had no effect. The efficiency of LL-37 binding to oligonucleotides and activation of pDCs was found to be inversely proportional to the number of citrullinated residues in the peptide. Similarly, preincubation of carbamylated LL-37 with PAD2 abrogated the peptide’s ability to bind DNA. Conversely, LL-37 with Arg residues substituted by homoarginine, which cannot be deiminated, elicited full activity of native LL-37 regardless of PAD2 treatment. Taken together, the data showed that citrullination abolished LL-37 ability to bind DNA and altered the immunomodulatory function of the peptide. Both activities were dependent on the proper distribution of guanidinium side chains in the native peptide sequence. Moreover, our data suggest that cathelicidin/LL-37 is citrullinated by PADs during NET formation, thus affecting the inflammatory potential of NETs. Together this may represent a novel mechanism for preventing the breakdown of immunotolerance, which is dependent on the response of APCs to self-molecules (including cell-free DNA); overactivation may facilitate development of autoimmunity.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1701391
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2018
    detail.hit.zdb_id: 1475085-5
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  • 4
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    Online Resource
    Inactivation of Epidermal Growth Factor by Porphyromonas gingivalis as a Potential Mechanism for Periodontal Tissue Damage
    American Society for Microbiology ; 2013
    In:  Infection and Immunity Vol. 81, No. 1 ( 2013-01), p. 55-64
    Details
    In: Infection and Immunity, American Society for Microbiology, Vol. 81, No. 1 ( 2013-01), p. 55-64
    Abstract: Porphyromonas gingivalis is a Gram-negative bacterium associated with the development of periodontitis. The evolutionary success of this pathogen results directly from the presence of numerous virulence factors, including peptidylarginine deiminase (PPAD), an enzyme that converts arginine to citrulline in proteins and peptides. Such posttranslational modification is thought to affect the function of many different signaling molecules. Taking into account the importance of tissue remodeling and repair mechanisms for periodontal homeostasis, which are orchestrated by ligands of the epidermal growth factor receptor (EGFR), we investigated the ability of PPAD to distort cross talk between the epithelium and the epidermal growth factor (EGF) signaling pathway. We found that EGF preincubation with purified recombinant PPAD, or a wild-type strain of P. gingivalis , but not with a PPAD-deficient isogenic mutant, efficiently hindered the ability of the growth factor to stimulate epidermal cell proliferation and migration. In addition, PPAD abrogated EGFR-EGF interaction-dependent stimulation of expression of suppressor of cytokine signaling 3 and interferon regulatory factor 1. Biochemical analysis clearly showed that the PPAD-exerted effects on EGF activities were solely due to deimination of the C-terminal arginine. Interestingly, citrullination of two internal Arg residues with human endogenous peptidylarginine deiminases did not alter EFG function, arguing that the C-terminal arginine is essential for EGF biological activity. Cumulatively, these data suggest that the PPAD-activity-abrogating EGF function in gingival pockets may at least partially contribute to tissue damage and delayed healing within P. gingivalis -infected periodontia.
    Type of Medium: Online Resource
    ISSN: 0019-9567 , 1098-5522
    URL: Article
    DOI: 10.1128/IAI.00830-12
    RVK:
    XA 10000
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2013
    detail.hit.zdb_id: 1483247-1
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  • 5
    Online Resource
    Online Resource
    Citrullination Alters Immunomodulatory Function of LL-37 Essential for Prevention of Endotoxin-Induced Sepsis
    The American Association of Immunologists ; 2014
    In:  The Journal of Immunology Vol. 192, No. 11 ( 2014-06-01), p. 5363-5372
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 192, No. 11 ( 2014-06-01), p. 5363-5372
    Abstract: Cathelicidin LL-37 plays an essential role in innate immunity by killing invading microorganisms and regulating the inflammatory response. These activities depend on the cationic character of the peptide, which is conferred by arginine and lysine residues. At inflammatory foci in vivo, LL-37 is exposed to peptidyl arginine deiminase (PAD), an enzyme released by inflammatory cells. Therefore, we hypothesized that PAD-mediated citrullination of the arginine residues within LL-37 will abrogate its immunomodulatory functions. We found that, when citrullinated, LL-37 was at least 40 times less efficient at neutralizing the proinflammatory activity of LPS due to a marked decrease in its affinity for endotoxin. Also, the ability of citrullinated LL-37 to quench macrophage responses to lipoteichoic acid and poly(I:C) signaling via TLR2 and TLR3, respectively, was significantly reduced. Furthermore, in stark contrast to native LL-37, the modified peptide completely lost the ability to prevent morbidity and mortality in a mouse model of d-galactosamine–sensitized endotoxin shock. In fact, administration of citrullinated LL-37 plus endotoxin actually exacerbated sepsis due to the inability of LL-37 to neutralize LPS and the subsequent enhancement of systemic inflammation due to increased serum levels of IL-6. Importantly, serum from septic mice showed increased PAD activity, which strongly correlated with the level of citrullination, indicating that PAD-driven protein modification occurs in vivo. Because LL-37 is a potential treatment for sepsis, its administration should be preceded by a careful analysis to ensure that the citrullinated peptide is not generated in treated patients.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1303062
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2014
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  • 6
    Online Resource
    Online Resource
    Carbamylation of immunoglobulin abrogates activation of the classical complement pathway
    Wiley ; 2014
    In:  European Journal of Immunology Vol. 44, No. 11 ( 2014-11), p. 3403-3412
    Details
    In: European Journal of Immunology, Wiley, Vol. 44, No. 11 ( 2014-11), p. 3403-3412
    Abstract: Post‐translational modifications of proteins significantly affect their structure and function. The carbamylation of positively charged lysine residues to form neutral homoitrulline occurs primarily under inflammatory conditions through myeloperoxidase‐dependent cyanate (CNO − ) formation. We analyzed the pattern of human IgG 1 carbamylation under inflammatory conditions and the effects that this modification has on the ability of antibodies to trigger complement activation via the classical pathway. We found that the lysine residues of IgG 1 are rapidly modified after brief exposure to CNO − . Interestingly, modifications were not random, but instead limited to only few lysines within the hinge area and the N‐terminal fragment of the CH2 domain. A complement activation assay combined with mass spectrometry analysis revealed a highly significant inverse correlation between carbamylation of several key lysine residues within the hinge region and N‐terminus of the CH2 domain and the proper binding of C1q to human IgG 1 followed by subsequent complement activation. This severely hindered complement‐dependent cytotoxicity of therapeutic IgG 1 . The reaction can apparently occur in vivo, as we found carbamylated antibodies in synovial fluid from rheumatoid arthritis patients. Taken together, our data suggest that carbamylation has a profound impact on the complement‐activating ability of IgG 1 and reveals a pivotal role for previously uncharacterized lysine residues in this process.
    Type of Medium: Online Resource
    ISSN: 0014-2980 , 1521-4141
    URL: Issue
    URL: Article
    DOI: 10.1002/eji.v44.11
    DOI: 10.1002/eji.201444869
    RVK:
    XA 10000
    Language: English
    Publisher: Wiley
    Publication Date: 2014
    detail.hit.zdb_id: 1491907-2
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  • 7
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    Online Resource
    Apolipoprotein E Triggers Complement Activation in Joint Synovial Fluid of Rheumatoid Arthritis Patients by Binding C1q
    The American Association of Immunologists ; 2020
    In:  The Journal of Immunology Vol. 204, No. 10 ( 2020-05-15), p. 2779-2790
    Details
    In: The Journal of Immunology, The American Association of Immunologists, Vol. 204, No. 10 ( 2020-05-15), p. 2779-2790
    Abstract: We identified apolipoprotein E (ApoE) as one of the proteins that are found in complex with complement component C4d in pooled synovial fluid of rheumatoid arthritis (RA) patients. Immobilized human ApoE activated both the classical and the alternative complement pathways. In contrast, ApoE in solution demonstrated an isoform-dependent inhibition of hemolysis and complement deposition at the level of sC5b-9. Using electron microscopy imaging, we confirmed that ApoE interacts differently with C1q depending on its context; surface-bound ApoE predominantly bound C1q globular heads, whereas ApoE in a solution favored the hinge/stalk region of C1q. As a model for the lipidated state of ApoE in lipoprotein particles, we incorporated ApoE into phosphatidylcholine/phosphatidylethanolamine liposomes and found that the presence of ApoE on liposomes increased deposition of C1q and C4b from serum when analyzed using flow cytometry. In addition, posttranslational modifications associated with RA, such as citrullination and oxidation, reduced C4b deposition, whereas carbamylation enhanced C4b deposition on immobilized ApoE. Posttranslational modification of ApoE did not alter C1q interaction but affected binding of complement inhibitors factor H and C4b-binding protein. This suggests that changed ability of C4b to deposit on modified ApoE may play an important role. Our data show that posttranslational modifications of ApoE alter its interactions with complement. Moreover, ApoE may play different roles in the body depending on its solubility, and in diseased states such as RA, deposited ApoE may induce local complement activation rather than exert its typical role of inhibition.
    Type of Medium: Online Resource
    ISSN: 0022-1767 , 1550-6606
    URL: Article
    DOI: 10.4049/jimmunol.1900372
    RVK:
    XA 54100
    RVK:
    XA 10000
    Language: English
    Publisher: The American Association of Immunologists
    Publication Date: 2020
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  • 8
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    Online Resource
    Degradation of Human Antimicrobial Peptide LL-37 by Staphylococcus aureus -Derived Proteinases
    American Society for Microbiology ; 2004
    In:  Antimicrobial Agents and Chemotherapy Vol. 48, No. 12 ( 2004-12), p. 4673-4679
    Details
    In: Antimicrobial Agents and Chemotherapy, American Society for Microbiology, Vol. 48, No. 12 ( 2004-12), p. 4673-4679
    Abstract: Cathelicidin LL-37 is one of the few human bactericidal peptides with potent antistaphylococcal activity. In this study we examined the susceptibility of LL-37 to proteolytic degradation by two major proteinases produced by Staphylococcus aureus , a metalloproteinase (aureolysin) and a glutamylendopeptidase (V8 protease). We found that aureolysin cleaved and inactivated LL-37 in a time- and concentration-dependent manner. Analysis of the generated fragments by mass spectroscopy revealed that the initial cleavage of LL-37 by aureolysin occurred between the Arg19-Ile20, Arg23-Ile24, and Leu31-Val32 peptide bonds, instantly annihilating the antibacterial activity of LL-37. In contrast, the V8 proteinase hydrolyzed efficiently only the Glu16-Phe17 peptide bond, rendering the C-terminal fragment refractory to further degradation. This fragment (termed LL-17-37) displayed antibacterial activity against S. aureus at a molar level similar to that of the full-length LL-37 peptide, indicating that the antibacterial activity of LL-37 resides in the C-terminal region. In keeping with LL-37 degradation by aureolysin, S. aureus strains that produce significant amounts of this metalloprotease were found to be less susceptible to LL-17-37 than strains expressing no aureolysin activity. Taken together, these data suggest that aureolysin production by S. aureus contributes to the resistance of this pathogen to the innate immune system of humans mediated by LL-37.
    Type of Medium: Online Resource
    ISSN: 0066-4804 , 1098-6596
    URL: Article
    DOI: 10.1128/AAC.48.12.4673-4679.2004
    RVK:
    XA 24552
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2004
    detail.hit.zdb_id: 1496156-8
    SSG: 12
    SSG: 15,3
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  • 9
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    Apoptotic cell clearance in chronic inflammation of lateral neck cysts
    Springer Science and Business Media LLC ; 2012
    In:  European Archives of Oto-Rhino-Laryngology Vol. 269, No. 3 ( 2012-3), p. 965-970
    Details
    In: European Archives of Oto-Rhino-Laryngology, Springer Science and Business Media LLC, Vol. 269, No. 3 ( 2012-3), p. 965-970
    Type of Medium: Online Resource
    ISSN: 0937-4477 , 1434-4726
    URL: Article
    DOI: 10.1007/s00405-011-1703-y
    RVK:
    XA 26650
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2012
    detail.hit.zdb_id: 1459042-6
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  • 10
    Online Resource
    Online Resource
    Purification and Characterization of an Arginine-specific Peptidase from Ragweed ( Ambrosia artemisiifolia ) Pollen
    American Thoracic Society ; 1998
    In:  American Journal of Respiratory Cell and Molecular Biology Vol. 18, No. 3 ( 1998-03-01), p. 363-369
    Details
    In: American Journal of Respiratory Cell and Molecular Biology, American Thoracic Society, Vol. 18, No. 3 ( 1998-03-01), p. 363-369
    Type of Medium: Online Resource
    ISSN: 1044-1549 , 1535-4989
    URL: Article
    DOI: 10.1165/ajrcmb.18.3.2825
    RVK:
    XA 20260
    Language: English
    Publisher: American Thoracic Society
    Publication Date: 1998
    detail.hit.zdb_id: 1473629-9
    SSG: 12
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