Literature

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Last updated: 13th August 2010

Literature
Isoleucine/leucine(2) is essential for chemoattractant activity of beta-defensin Defb14 through chemokine receptor 6.
Tyrrell C, De Cecco M, Reynolds NL, Kilanowski F, Campopiano D, Barran P, Macmillan D, Dorin JR
MRC Human Genetics Unit, IGMM, Edinburgh EH4 2XU, Scotland, UK.
Mol Immunol. 2010 Mar;47(6):1378-1382.
Abstract
beta-Defensins are both antimicrobial and able to chemoattract various immune cells including immature dendritic cells and CD4 T cells through CCR6. They are short, cationic peptides with a highly conserved six-cysteine motif. It has been shown that only the fifth cysteine is critical for chemoattraction of cells expressing CCR6. In order to identify other residues essential for functional interaction with CCR6 we used a library of peptide deletion derivatives based on Defb14. Loss of the initial two amino acids from the Defb14-1C(V) derivative destroys its ability to chemoattract cells expressing CCR6. As the second amino acid is an evolutionarily conserved leucine, we make full-length Defb14-1C(V) peptides with substitution of the leucine(2) for glycine (L2G), lysine (L2K) or isoleucine (L2I). Defb14-1C(V) L2G and L2K and are unable to chemoattract CCR6 expressing cells but the semi-conservative change L2I has activity. By circular dichroism spectroscopy we can see no evidence for a significant change in secondary structure as a consequence of these substitutions and so cannot attribute loss of chemotactic activity with disruption of the N-terminal helix. We conclude that isoleucine/leucine in the N-terminal alpha-helix region of this beta-defensin is essential for CCR6-mediated chemotaxis.
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Demonstration of substances of innate immunity in the esophageal epithelium of domesticated mammals: Part II - Defence mechanisms, including species comparison.
Nina Hornickel I, Kacza J, Schnapper A, Beyerbach M, Schoennagel B, Seeger J, Meyer W
Institute for Anatomy, University of Veterinary Medicine Hannover Foundation, Bischofsholer Damm 15, 30173 Hannover, Germany.
Acta histochemica 2009 Dec
Abstract
The second part of our study deals with a comparative evaluation and discussion of the immunohistochemical results that were obtained. The cryoscanning electron microscopy (cryoSEM) observations confirmed a monolayer colonization of the esophageal surface with bacteria and fungi (yeasts); the latter in particular was prominent in the ruminant species studied. We demonstrated the existence of several innate immune parameters, including pathogen recognition receptors (PRRs), such as Toll-like receptor 2, which was primarily expressed in the stratum basale; however, the presence beta-glucan receptors remained inconclusive. Furthermore, the group of cationic antimicrobial peptides (CAPs) was shown, comprising beta-defensins 2 and 3 and cathelicidin. The less keratinized esophageal epithelium of the carnivorous cat was protected by high amounts of CAPs; whereas the more strongly keratinized epithelium of the herbivorous and omnivorous species with its characteristic layer structure exhibited clearly weaker reactions. Moreover, lysozyme could distinctly be demonstrated in the cells of the esophageal epithelium. It can be concluded that a first line of defence mechanisms of the innate immune system contributes to maintaining a microbial homeostasis on the surface of the esophageal epithelium of domesticated mammals. The results are discussed in comparison to findings from studies on the human esophagus.
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Defensins attenuate cytokine responses yet enhance antibody responses to Porphyromonas gingivalis adhesins in mice.
Kohlgraf KG, Ackermann A, Lu X, Burnell K, Blanger M, Cavanaugh JE, Xie H, Progulske-Fox A, Brogden KA
Dows Institute for Dental Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA. karl-kohlgraf@uiowa.edu
Future microbiology 2010 Jan;5 115-25
Abstract
AIM: Our aim is to assess the ability of human neutrophil peptide alpha-defensins (HNPs) and human beta-defensins (HBDs) to attenuate proinflammatory cytokine responses and enhance antibody responses to recombinant hemagglutinin B (rHagB) or recombinant fimbrillin A (rFimA) from Porphyromonas gingivalis 381 in mice. MATERIALS & METHODS: In the first study, C57BL/6 mice were given 10 microg rHagB or rFimA without and with 1 microg HNP1, HNP2, HBD1, HBD2 or HBD3. At 24 h, mice were euthanized and cytokine concentrations were determined in nasal wash fluid (NWF), bronchoalveolar lavage fluids, saliva and serum. In the second study, C57BL/6 mice were given 10 microg rHagB or rFimA without and with 1 microg HNPs or HBDs similarly on days 0, 7 and 14. At 21 days, mice were euthanized and rHagB- and rFimA-specific antibody responses were determined in NWF, bronchoalveolar lavage fluids, saliva and serum. RESULTS: Mice given rHagB + HNP2, rHagB + HBD1 and rHagB + HBD3 produced significantly lower (p < 0.05) IL-6 responses than mice given rHagB alone. Mice given rHagB + HNP1, rHagB + HNP2, rHagB + HBD1 and rHagB + HBD3 produced significantly lower (p < 0.05) keratinocyte-derived chemokine responses than mice given rHagB alone. Mice given rFimA produced very low levels of IL-6 and only moderate levels of keratinocyte-derived chemokine in NWF that were not attenuated by prior incubation of rFimA with any defensin. Mice given rHagB + HNP1 produced a significantly higher (p < 0.05) serum IgG antibody response than mice given rHagB alone and mice given rFimA + HNP2 produced a higher, but not significant, antibody response. CONCLUSION: The ability of HNPs and HBDs to attenuate proinflammatory cytokine responses in murine NWF and enhance IgG antibody responses in serum was dependent upon both the defensin and antigen of P. gingivalis.
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Defensins as anti-inflammatory compounds and mucosal adjuvants.
Kohlgraf KG, Pingel LC, Dietrich DE, Brogden KA
Dows Institute for Dental Research, College of Dentistry, The University of Iowa, Iowa City, IA 52242, USA. karl-kohlgraf@uiowa.edu
Future microbiology 2010 Jan;5 99-113
Abstract
Human neutrophil peptide alpha-defensins and human beta-defensins are small, well-characterized peptides with broad antimicrobial activities. In mixtures with microbial antigens, defensins attenuate proinflammatory cytokine responses by dendritic cells in culture, attenuate proinflammatory cytokine responses in the nasal fluids of exposed mice and enhance antibody responses in the serum of vaccinated mice. Although the exact mechanisms are unknown, defensins first start by binding to microbial antigens and adhesins, often attenuating toxic or inflammatory-inducing capacities. Binding is not generic; it appears to be both defensin-specific and antigen-specific with high affinities. Binding of defensins to antigens may, in turn, alter the interaction of antigens with epithelial cells and antigen-presenting cells attenuating the production of proinflammatory cytokines. The binding of defensins to antigens may also facilitate the delivery of bound antigen to antigen-presenting cells in some cases via specific receptors. These interactions enhance the immunogenicity of the bound antigen in an adjuvant-like fashion. Future research will determine the extent to which defensins can suppress early events in inflammation and enhance systemic antibody responses, a very recent and exciting concept that could be exploited to develop therapeutics to prevent or treat a variety of oral mucosal infections, particularly where inflammation plays a role in the pathogenesis of disease and its long-term sequelae.
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Defensins keep the peace too.
Menendez A, Ferreira RB, Finlay BB
Nat. Immunol. 2010 Jan;11 (1):49-50
Abstract
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A new avenue to investigate: the autophagic process. From Crohn´s disease to Chlamydia.
Pea AS, Karimi O, Crusius JB
Laboratory of Immunogenetics, Department of Pathology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands. pena.as@gmail.com
Drugs Today 2009 Nov;45 Suppl B 113-7
Abstract
The finding that a variant (T300A) of the autophagyrelated 16-like 1 (ATG16L1) gene is associated with Crohn´s disease suggests that the inability to eliminate intestinal intracellular microbes via (macro)autophagy may be involved in the pathogenesis of this disease. The variant induces an autophagy-associated defect in Paneth cells, specialized cells in the crypts of Lieberkuhn within the small intestine that secrete defensins and other antimicrobial peptides. Moreover, other loci, IRGM and LRRK2 involved in autophagy and implicated in clearance of intracellular bacteria have been found to be associated with Crohn´s disease. These unexpected findings have changed the focus of research in Crohn´s disease and have stimulated an in-depth study of the complex process of autophagy. Autophagy is regulated by many genes and is emerging as a central player in the immunologic control of intracellular bacteria. Chlamydia trachomatis is able to inhibit apoptosis and the production of nuclear factor kappa B (NFkappaB) in order to survive in the host. Extensive studies on association of genes regulating the inflammatory response in experimental models and in humans as revised in other sections of this supplement have failed to explain the longterm complications of C. trachomatis infection. The advances in the molecular pathways of Chlamydia infection and their effects on the Golgi apparatus and other cytoplasmic organelles suggests that defects in autophagic genes may predispose the host to chronic infection and be responsible for the long-term complications. A new genomic approach of the complete autophagic pathway may reveal new insight to understand the presence of a complication in affected individuals, even if at present there is no evidence that C. trachomatis is affected by this pathway.
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Plant defensins: defense, development and application.
Stotz HU, Thomson JG, Wang Y
Julius-von-Sachs-Institut fuer Biowissenschaften, Pharmazeutische Biologie, Biozentrum, Universitaet Wuerzburg, Wuerzburg, Germany.
Plant Signal Behav 2009 Nov;4 (11):1010-2
Abstract
Plant defensins are small, highly stable, cysteine-rich peptides that constitute a part of the innate immune system primarily directed against fungal pathogens. Biological activities reported for plant defensins include antifungal activity, antibacterial activity, proteinase inhibitory activity and insect amylase inhibitory activity. Plant defensins have been shown to inhibit infectious diseases of humans and to induce apoptosis in a human pathogen. Transgenic plants overexpressing defensins are strongly resistant to fungal pathogens. Based on recent studies, some plant defensins are not merely toxic to microbes but also have roles in regulating plant growth and development.
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Klebsiella pneumoniae capsule polysaccharide impedes the expression of {beta}-defensins by airway epithelial cells.
Moranta D, Regueiro V, March C, Llobet E, Margareto J, Larrate E, Garmendia J, Bengoechea JA
Program Infection and Immunity, Fundacin Caubet-CIMERA Illes Balears; Area Molecular basis of microbial pathogenesis, Centro de Investigacin Biomdica en Red Enfermedades Respiratorias (CibeRes) Bunyola; Unidad de Genmica, LEIA-Salud, Miano; Area de Microbiologa, Facultad Biologa, Universitat Illes Balears, Palma Mallorca, Consejo Superior de Investigaciones Cientficas (CSIC), Spain.
Infect Immun. 2010 Mar;78(3):1135-46.
Abstract
Human beta-defensins (hBDs) contribute to protect the respiratory tract against pathogens. It is reasonable to postulate that pathogens have developed countermeasures to resist them. Klebsiella pneumoniae capsule polysaccharide (CPS), but not the lipopolysaccharide O-antigen, mediated resistance against hBD1 and hBD2. hBD3 was the most potent hBD against Klebsiella. We investigated the possibility that as a strategy to survive in the lung K. pneumoniae may not activate the expression of hBDs. Infection of A549 and normal human bronchial cells with 52145-DeltawcaK2, CPS mutant, increased the expression of hBD2 and hBD3. Neither the wild-type nor the lipopolysaccharide O-antigen mutant increased the expression of hBDs. In vivo, 52145-DeltawcaK2 induced higher levels of mBD4 and mBD14, possible mouse orthologues of hBD2 and hBD3 respectively, than the wild-type. 52145-DeltawcaK2-dependent up-regulation of hBD2 was via NF-kappaB and mitogen-activated kinases (MAPKs) p44/42, JNK -dependent pathways. hBD3 increased expression was dependent on MAPK JNK. 52145-DeltawcaK2 engaged Toll-like receptors (TLRs) 2 and 4 to activate hBD2, whereas hBD3 expression was dependent on NOD1. K. pneumoniae induced the expressions of CYLD and MKP-1 which act as negative regulators for 52145-DeltawcaK2-inducedexpression of hBDs. Bacteria engagement of pattern recognition receptors induced CYLD and MKP-1, which may initiate attenuation of pro-inflammatory pathways. The results of this study indicate that K. pneumoniae CPS not only protects the pathogen from the bactericidal action of defensins but also impedes their expression. These features of K. pneumoniae CPS may facilitate pathogen survival in the hostile environment of the lung.
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Antibacterial and lipopolysaccharide (LPS)-neutralising activity of human cationic antimicrobial peptides against periodontopathogens.
Lee SH, Jun HK, Lee HR, Chung CP, Choi BK
Department of Oral Microbiology and Immunology, School of Dentistry, Seoul National University, Seoul, Republic of Korea.
Int J Antimicrob Agents. 2010 Feb;35(2):138-145.
Abstract
In this study, we investigated the antibacterial activity of eight antimicrobial peptides (AMPs), comprising four human beta-defensins (HBDs), three human neutrophil defensins (HNPs) and the cathelicidin LL-37, against two representative periodontopathogens, Prevotella intermedia and Tannerella forsythia. The neutralising effect of these AMPs on expression of interleukin (IL)-1beta, IL-8 and intercellular adhesion molecule 1 (ICAM-1) induced by lipopolysaccharide (LPS) from P. intermedia and T. forsythia was also tested in THP-1 cells and human gingival fibroblasts. Prevotella intermedia was susceptible to HBD-3 and LL-37 but was resistant to HBD-1, HBD-2, HBD-4, HNP-1, HNP-2 and HNP-3 at concentrations up to 10muM. However, all of the AMPs except HNP-2 at 5muM significantly inhibited the expression of IL-1beta, IL-8 and ICAM-1 induced by P. intermedia LPS. Tannerella forsythia showed marked susceptibility to the AMPs tested in the following order: LL-37, HBD-3, HBD-2, HBD-1, HNP-1 and HBD-4. All of the AMPs except HNP-3 had significant neutralising effects on T. forsythia LPS activity. The AMPs showing LPS-neutralising activity inhibited LPS binding to the cells. These results suggest that AMPs may be considered as preventive and therapeutic agents against mixed bacterial infections such as periodontitis by eliminating the pathogens themselves as well as reducing the activity of LPS.
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Manual annotation and analysis of the defensin gene cluster in the C57BL/6J mouse reference genome.
Amid C, Rehaume LM, Brown KL, Gilbert JG, Dougan G, Hancock RE, Harrow JL
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridgeshire CB10 1SA, UK. ca1@sanger.ac.uk
BMC Genomics 2009 ;10 606
Abstract
BACKGROUND: Host defense peptides are a critical component of the innate immune system. Human alpha- and beta-defensin genes are subject to copy number variation (CNV) and historically the organization of mouse alpha-defensin genes has been poorly defined. Here we present the first full manual genomic annotation of the mouse defensin region on Chromosome 8 of the reference strain C57BL/6J, and the analysis of the orthologous regions of the human and rat genomes. Problems were identified with the reference assemblies of all three genomes. Defensins have been studied for over two decades and their naming has become a critical issue due to incorrect identification of defensin genes derived from different mouse strains and the duplicated nature of this region. RESULTS: The defensin gene cluster region on mouse Chromosome 8 A2 contains 98 gene loci: 53 are likely active defensin genes and 22 defensin pseudogenes. Several TATA box motifs were found for human and mouse defensin genes that likely impact gene expression. Three novel defensin genes belonging to the Cryptdin Related Sequences (CRS) family were identified. All additional mouse defensin loci on Chromosomes 1, 2 and 14 were annotated and unusual splice variants identified. Comparison of the mouse alpha-defensins in the three main mouse reference gene sets Ensembl, Mouse Genome Informatics (MGI), and NCBI RefSeq reveals significant inconsistencies in annotation and nomenclature. We are collaborating with the Mouse Genome Nomenclature Committee (MGNC) to establish a standardized naming scheme for alpha-defensins. CONCLUSIONS: Prior to this analysis, there was no reliable reference gene set available for the mouse strain C57BL/6J defensin genes, demonstrating that manual intervention is still critical for the annotation of complex gene families and heavily duplicated regions. Accurate gene annotation is facilitated by the annotation of pseudogenes and regulatory elements. Manually curated gene models will be incorporated into the Ensembl and Consensus Coding Sequence (CCDS) reference sets. Elucidation of the genomic structure of this complex gene cluster on the mouse reference sequence, and adoption of a clear and unambiguous naming scheme, will provide a valuable tool to support studies on the evolution, regulatory mechanisms and biological functions of defensins in vivo.
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