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Last updated: 13th August 2010

Antimicrobial Peptides as a Major Part of the Innate Immune Defense at the Ocular Surface.
Garreis F, Gottschalt M, Paulsen FP
Department of Anatomy and Cell Biology, Martin Luther University Halle-Wittenberg, Halle/Saale, Germany.
Developments in ophthalmology 2010 ;45 16-22
The ocular surface is in constant contact with the environment (e.g. when using one´s fingers to insert a contact lens) and thus also with diverse bacteria, bacterial components and their pathogen associated molecules. Dysfunctions of the tear film structure or decreased moistening of the ocular surface, as in dry eye (keratoconjunctivitis sicca) for example, often lead to inflammatory and infectious complications resulting in severe functional disorders, particularly concerning the cornea. Besides different protective antimicrobial substances in the tear fluid (mucins, lysozyme, lactoferrin), the epithelia of cornea and conjunctiva can also protect themselves from microbial invasion by producing an arsenal of antimicrobial peptides (AMPs). A number of different studies have revealed that small cationic AMPs, which display antimicrobial activity against a broad spectrum of microorganisms, are a major component of the innate immune system at the human ocular surface. Furthermore, several AMPs modulate cellular activation processes like migration, proliferation, chemotaxis and cytokine production, and in this way also affect the adaptive immune system. In this article, we have summarized current knowledge of the mechanisms of activity and functional roles of AMPs, with a focus on potential multifunctional roles of human beta-defensins and S100 peptide psoriasin (S100A7) at the ocular surface.
Cationic Amino Acid Transporters and beta-Defensins in Dry Eye Syndrome.
Jger K, Garreis F, Dunse M, Paulsen FP
Department of Anatomy and Cell Biology, Martin Luther University of Halle-Wittenberg, Halle/Saale, Germany.
Developments in ophthalmology 2010 ;45 12-15
Several diseases concomitant with L-arginine deficiency (diabetes, chronic kidney failure, psoriasis) are significantly associated with dry eye syndrome. One important factor that has so far been neglected is the y(+) transporter. In humans, y(+) accounts for nearly 80% of arginine transport, exclusively carrying the cationic amino acids L-arginine, L-lysine and L-ornithine. y(+) is represented by CAT(cationic amino acid transporter) proteins. L-arginine is a precursor of the moisturizer urea, which has been used in the treatment of dry skin diseases. Although urea has also been shown to be part of the tear film, little attention has been paid to it in this role. Moreover, L-arginine and L-lysine are major components contributing to synthesis of the antimicrobially active beta-defensins induced under dry eye conditions. The first results have demonstrated that transport of L-arginine and L-lysine into epithelial cells is limited by the y(+) transporter at the ocular surface.
In vitro antimicrobial efficacy of beta-defensin 3 against Staphylococcus pseudintermedius isolates from healthy and atopic canine skin.
Fazakerley J, Crossley J, McEwan N, Carter S, Nuttall T
The University of Liverpool School of Veterinary Science, Leahurst Campus, Neston, Cheshire CH64 7TE, UK.
Veterinary dermatology 2010 May
Abstract beta-Defensins (BDs) are highly conserved antimicrobial peptides important in innate defence against bacteria. beta-Defensin 3 has a specific role in protecting the skin. This study quantified the minimal inhibitory concentration (MIC) of human (h)BD3 against Staphylococcus pseudintermedius isolates from atopic and healthy dogs. Single colony isolates (1 x 10(5) colony-forming units/mL log phase) were cultured with doubling dilutions of hBD3 in sodium phosphate buffer from 0.8 to 50 mug/mL at 37 degrees C for 2 h, before adding 100 muL of tryptone soy broth and incubating for a further 20 h. Bacterial growth was assessed as the mean optical density at 540 nm corrected for background. The median MIC was 12.5 mug hBD3/mL (range 3.125-25 mug/mL; n = 22). Forty-five percent of the isolates were inhibited at
TLR9-dependent induction of intestinal alpha-defensins by Toxoplasma gondii.
Foureau DM, Mielcarz DW, Menard LC, Schulthess J, Werts C, Vasseur V, Ryffel B, Kasper LH, Buzoni-Gatel D
Department of Medicine, Dartmouth Medical School, Lebanon, NH 03756, USA.
J Immunol. 2010 Jun 15;184(12):7022-9.
alpha-Defensins (or Cryptdins [Crps]) are a group of antimicrobial peptides produced as a component of Paneth cell (PC) secretory granules in the small intestine. In vivo ligation of TLR9 by synthetic agonists leads to PC degranulation, although the mechanism by which this occurs remains uncertain. In this report, we investigated TLR9-dependent mechanisms, triggered by the parasite Toxoplasma gondii, inducing Crp release in the lumen. Oral challenge of C57BL/6J (B6) wild-type (WT) mice with T. gondii induced TLR9 mRNA upregulation associated with a marked increase of type I IFN mRNA expression. PC secretory granules were released, and Crp-3/-5 mRNA expression by purified epithelial cells was increased following oral challenge of B6 WT mice. Although PCs failed to degranulate in infected B6 TLR9(-/-) mice, i.p. injection of mouse IFN-beta alone led to Crp-3/-5 mRNA upregulation in B6 WT and TLR9(-/-) mice. In addition, modulation of Crp mRNA expression in response to T. gondii infection was abrogated in B6 IFNAR(-/-) mice, which lack a functional type I IFN receptor. Taken together, these data demonstrate that T. gondii induces Crp-3/-5 production and release by PCs via a TLR9-dependent production of type I IFNs. Crps have a limited direct effect against T. gondii but may indirectly affect the early control of T. gondii invasiveness by promoting the initiation of a protective Th1 response against the parasite.
Human beta-defensin 2 and 3 and their mouse orthologs induce chemotaxis through interaction with CCR2.
Rhrl J, Yang D, Oppenheim JJ, Hehlgans T
Laboratory of Molecular Immunoregulation, Cancer and Inflammation Program, Division of Basic Science, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702, USA.
J Immunol. 2010 Jun 15;184(12):6688-94.
Beta-defensins play a dual role during immune response. Their direct antimicrobial properties contribute to the local innate immune response by combating microbial invasions. Furthermore, previous studies revealed the capacity of certain beta-defensin family members to chemoattract immature dendritic cells and CD45RO(+) CD4(+) T cells through chemokine receptor CCR6. However, because beta-defensins also chemoattract macrophages and monocytes, which do not express CCR6, efforts have been made to identify other receptors for these polypeptides. In this study, we demonstrate the capacity of human beta-defensin (hBD)2 and 3 and their mouse orthologs, beta-defensin 4 and 14, to interact with CCR2, a chemokine receptor expressed on monocytes, macrophages, and neutrophils. These beta-defensins, fused to the Fc region of human IgG(1), showed binding to CCR2-transfected HEK293 cells, as revealed by flow cytometry. The beta-defensin fusion proteins also induced CCR2-specific chemotaxis of transfected HEK293 cells, human peripheral blood monocytes, and mouse peritoneal exudate cells in a dose-dependent manner. Preincubation of human monocytes with CCL2/MCP-1, the chemokine ligand for CCR2, abolished migration induced by beta-defensins. Conversely, preincubation with hBD2:Ig or hBD3:Ig inhibited MCP-1 induced migration. Peritoneal exudate cells from CCR2-deficient mice failed to migrate toward these fusion proteins. In conclusion, the beta-defensins used in this study contribute to the innate and adaptive immune response in their role as chemoattractants. Our data indicate that hBD2 and hBD3, together with their mouse orthologs (beta-defensin 4 and 14), are chemotactic for a broad spectrum of leukocytes in a CCR6- and CCR2-dependent manner.
Analysis of beta-defensin and Toll-like receptor gene copy number variation in Celiac disease.
Fernandez-Jimenez N, Castellanos-Rubio A, Plaza-Izurieta L, Gutierrez G, Castao L, Vitoria JC, Bilbao JR
Endocrinology, Diabetes and Nutrition Research Group, Hospital de Cruces, Barakaldo-Bizkaia, Basque Country, Spain; Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Bilbao, Basque Country, Spain.
Hum Immunol. 2010 Aug;71(8):833-836.
Celiac disease (CD) is an immune-mediated disorder of the gut in which innate and adaptive responses are involved. Toll-like Receptor (TLR) 2 and TLR4 participate in host defense through antigen recognition, and show altered expression in CD gut mucosa. Beta-defensins are inducible antimicrobial peptides and DEFB gene copy number polymorphisms have been associated with autoimmune and inflammatory disorders. We performed copy number analysis of TLR2, TLR4 and the beta-defensin cluster (DEFB4, DEFB103 and DEFB104) by gene-specific real-time PCR in 376 CD patients and 376 controls. TLR genes did not show copy number variation and all samples presented 2 copies. Beta-defensin cluster varied between 2 and 9 copies per genome, and when grouped into bins, high copy numbers (>4) were underrepresented among patients [p=0.023; OR=0.69 (95% CI: 0.50-0.96)] suggesting that increased copy numbers could protect from CD, possibly by impeding bacterial infiltration more efficiently and preserving gut epithelial integrity.
Defensin-barbed innate immunity: clinical associations in the pediatric population.
Underwood MA, Bevins CL
UC Davis School of Medicine, 2516 Stockton Blvd, Sacramento, CA 95817, USA.
Pediatrics. 2010 Jun;125(6):1237-47.
Defensins and related antimicrobial peptides serve a central role in innate immunity in all species of plants and animals. In humans, defensins are widely expressed, including in neutrophils, skin, and mucosal epithelia. Most defensins are potent antibiotics, and some have chemotactic and toxin-neutralizing activities. Results of recent studies on the homeostatic and disease-fighting activities of human defensins point to a key relevance in several pediatric disorders. Inherited variation in defensin gene expression may contribute to susceptibility to several diseases, including psoriasis and Crohn disease. We review here the recent discoveries in innate immunity that shed light on the potential roles of defensins, and other antimicrobial molecules, in the pathophysiology of common pediatric diseases such as atopic dermatitis, necrotizing enterocolitis, cystic fibrosis, and otitis media.
Current understanding of the genetic basis of psoriasis.
Gudjonsson JE, Johnston A
Department of Dermatology, University of Michigan, Room 6427, Medical Science Building I, 1301 Catherine, Ann Arbor, MI, USA.
Expert Rev Clin Immunol 2009 Jul;5 (4):433-43
Psoriasis is a common, immunologically mediated, inflammatory and hyperproliferative disease of the skin and joints, with a multifactorial genetic basis. Recently, the association of psoriasis with loci at HLA-Cw*0602, IL12B, IL23A, IL23R, TNFAIP3, TNIP1, ZNF313 and IL4/IL13, and copy number variations in the beta-defensin and late-cornified envelope (LCE) gene loci were described. Here, we discuss the advances in the technology that has lead to the identification of these genes and their presumed role in the pathogenesis of psoriasis. Although it is now generally accepted that psoriatic lesions are caused by abnormal reactivity of specific T cells in the skin, these findings suggest that alterations in the epidermal barrier, innate defenses and processing of inflammatory signals may all contribute to the triggering of nonspecific innate immune mechanisms, which, in combination with altered IL-23 signaling, may lead to the dysregulation of T-cell-driven immune responses.
[HBD-1 and hBD-2 are expressed in cervico-vaginal lavage in female genital tract due to microbial infections]
Wiechula B, Cholewa K, Ekiel A, Romanik M, Dolezych H, Martirosian G
Katedra i Zaklad Mikrobiologii Lekarskiej Slaskiego Uniwersytetu Medycznego.
Ginekol. Pol. 2010 Apr;81 (4):268-71
OBJECTIVES: The aim of this study was to evaluate and compare concentration of selected human beta-defensins (hBD-1, hBD-2) in cervico-vaginal lavage (CVL), obtained from women with candidiasis, chlamydiasis and other bacterial infections. MATERIAL AND METHODS: beta-defensins were detected quantitatively by RT-PCR (7000 Taqman, Applied Biosystems) in cervico-vaginal lavage collected from 120 (79 women in the study group and 41 controls) non-pregnant women, aged 18-40 (mean age 28.5 +/- 6.29). The study group patients were divided into three subgroups on the basis of clinical and microbiological diagnosis: women with candidiasis (n=13); with chlamydiasis (n=13), and with other bacterial infections (n=12). RESULTS: The highest count of hBD-1 RNA copies was found in women with bacterial infections and candidiasis (335.84 and 320.10 respectively), and hBD-2--with chlamydiasis. The difference between RNA copies of hBD-1/microg in candidiasis, chlamydiasis and bacterial pathogens was statistically significant; for hBD-2 only in case of chlamydiasis. CONCLUSIONS: Chlamydia trachomatis infection activates the production of hBD-2. Candida albicans, Chlamydia trachomatis, and bacterial pathogens induced variable increases of hBD-1 concentration.
Beta2-agonists promote host defense against bacterial infection in primary human bronchial epithelial cells.
Gross CA, Bowler RP, Green RM, Weinberger AR, Schnell C, Chu HW
BMC pulmonary medicine 2010 May;10 (1):30
ABSTRACT: BACKGROUND: Airway epithelial cells are critical in host defense against bacteria including Mycoplamsa pneumoniae (Mp) in chronic obstructive pulmonary disease (COPD) and asthma. beta2-agonists are mainstay of COPD and asthma therapy, but whether beta2-agonists directly affect airway epithelial host defense functions is unclear. METHODS: Epithelial cells from bronchial brushings of normal (n = 8), asthma (n = 8) and COPD (n = 8) subjects were grown in air-liquid interface cultures, and treated with cigarette smoke extract (CSE) and/or Th2 cytokine IL-13, followed by Mp infection and treatment with beta2-agonists albuterol and formoterol for up to seven days. Mp and host defense proteins short palate, lung, and nasal epithelial clone 1 (SPLUNC1) and beta-defensin-2 were quantified. Expression of beta2-adrenergic receptors was also measured by real-time quantitative RT-PCR. RESULTS: (R)- or racemic albuterol and (R,R)- or racemic formoterol significantly decreased Mp levels in normal and asthma epithelial cells. Normal cells treated with Mp and (R)- or racemic albuterol showed an increase in SPLUNC1, but not in beta-defensin-2. COPD cells did not respond to drug treatment with a significant decrease in Mp or an increase in SPLUNC1. IL-13 attenuated drug effects on Mp, and markedly decreased SPLUNC1 and beta2-adrenergic receptors. CONCLUSIONS: These results for the first time show that beta2-agonists enhance host defense functions of primary bronchial epithelial cells from normal and asthma subjects, which is attenuated by IL-13.