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PubMed2006

alpha-Defensin: link between inflammation and atherosclerosis.

BACKGROUND: Several markers of inflammation predict the risk of thrombotic cardiovascular events in patients with atherosclerosis. However, the mechanism by which vascular inflammation promotes atherothrombotic disease is incompletely understood. Human neutrophil peptides 1-3, also known as alpha-defensins, are found in human atherosclerotic arteries, inhibit LDL metabolism and fibrinolysis and promote Lp(a) binding. We asked, therefore, if alpha-defensins are risk factors for the presence and severity of atherosclerosis. METHODS: alpha-Defensin was measured in skin biopsies taken from 53 male patients (age 58.7+/-11.3 years, mean+/-S.D.) immediately prior to coronary artery catheterization. Other established risk factors were measured concurrently. The correlation between alpha-defensin deposition in the skin and the severity of the coronary artery disease (CAD) was examined. RESULTS: A statistically significant correlation was observed between the amount of alpha-defensin in skin and the severity of CAD (R=0.40, p=0.003). Multiple regression analysis showed that skin alpha-defensin is an independent predictor for CAD severity (F=4.68, p=0.035). Logistic regression analysis confirmed that skin alpha-defensin independently predicted the likelihood for CAD (p=0.016, odds estimate 5.97, 95% CL 1.4-24.2). CONCLUSIONS: The deposition of alpha-defensin in the skin is a strong independent predictor of CAD in men. These results suggest a link between neutrophil activation and progression of atherosclerosis and provide a novel approach to assessment of risk factors for CAD.

Aged↗
PubMed1997

Defensins purified from human granulocytes bind C1q and activate the classical complement pathway like the transmembrane glycoprotein gp41 of HIV-1.

The transmembrane glycoprotein gp41 of HIV-1 contains a C1q binding domain (HIVenv 583-610) and activates the human complement system through the classical pathway. Based on structural and functional similarities between human defensins (human neutrophil peptide, HNP 1-3) and synthetic peptides representing the env 583-610 region of HIV-1, we found it interesting to investigate the C1q binding and complement activating ability of human defensins. Human defensins were purified and characterized by size exclusion chromatography, ultrafiltration, gel electrophoresis and HPLC. The complement activating ability of the purified peptides was assessed in a solid-phase immunoassay. Defensins, fixed to an ELISA plate, were able to bind the C1q subcomponent of the first complement component (C1), triggering the classical pathway of complement activation which led to C4b binding to the plate. Reduction and subsequent alkylation of disulfide bridges of defensins greatly decreased the C1q binding ability but complement activation (C4b binding) remained high. Further acetylation of the reduced defensin peptide resulted in a molecule which bound very little or no C1q but still activated the complement cascade. These phenomena indicate that defensins interact with the complement system via C1q-dependent and C1q-independent mechanisms, and extend the number of functional similarities between defensins and gp41 of HIV-1 to include C1q binding and complement activation.

Anti-Infective Agents↗
PubMed2004

Two novel non-cationic defensin-like antimicrobial peptides from haemolymph of the female tick, Amblyomma hebraeum.

Two non-cationic defensin-like antimicrobial peptides, named Amblyomma defensin peptide 1 and Amblyomma defensin peptide 2, were identified from the hard tick, Amblyomma hebraeum, by a combination of suppression subtractive hybridization for differentially expressed genes and proteomics. cDNA clones encoding each of these two defensin-like antimicrobial peptides were isolated from the differentially expressed cDNA library of the tick synganglia (central nervous system). The preproproteins deduced from the cDNA sequences each have 92 amino acid residues. Amblyomma defensin peptide 2 was purified from the haemolymph of fed female ticks. The purified peptide displayed antibacterial activity against Gram-negative and Gram-positive bacteria. Amblyomma defensin peptide 1 was further identified by protein chip capture combined with SELDI-TOF (surface-enhanced laser desorption/ionization-time-of-flight) MS. By screening for differentially expressed proteins, it was found that the expression of Amblyomma defensin peptide 1 was upregulated during 4 days post-feeding. Our findings firstly provide two defensin-like antimicrobial peptides that are particularly novel in being anionic, together with corresponding cDNA sequences, in hard ticks, and prove that the combination of suppression subtractive hybridization and protein profiling is a powerful method to study differentially expressed proteins, especially for organisms without available genome sequence information.

Amino Acid Sequence↗
PubMed2006

Structural and functional studies of defensin-inspired peptides.

Mammals have evolved complex self-defence mechanisms to protect themselves from infection. This innate immune system comprises a large family of hundreds of peptides and proteins which have potent antibiotic activity at nanomolar concentrations. The defensins are a group of small cationic peptides which contain a high proportion of positively charged and hydrophobic amino acids. Their exact mechanism of antimicrobial action is unclear, but it is thought that the defensins bind to and disrupt the outer cell membrane which ultimately causes lysis and cell death. They are characterized by six conserved cysteine residues which oxidize to form three intramolecular disulphide (S-S) bonds. The human and mouse defensins have been subdivided into classes based on their sequence, site of expression and the S-S bond connectivity of the cysteine residues. Alpha-defensins are connected by cysteines 1 and 6, 2 and 4, and 3 and 5, whereas beta-defensins have a 1-5, 2-4 and 3-6 cysteine S-S connectivity. We present our structural and functional studies of a novel mouse beta-defensin-related peptide (Defr1) which contains only five cysteine residues. Synthetic Defr1 was more active than its six-cysteine analogue against a large panel of pathogens. High-resolution MS techniques revealed that Defr1 contains an unusual defensin structure. These studies have guided the design of novel peptides to explore the roles of defensins as antibiotics and as stimulants of the immune response.

Animals↗
PubMed1996

Human enteric defensins. Gene structure and developmental expression.

Paneth cells, secretory epithelial cells of the small intestinal crypts, are proposed to contribute to local host defense. Both mouse and human Paneth cells express a collection of antimicrobial proteins, including members of a family of antimicrobial peptides named defensins. In this study, data from an anchored polymerase chain reaction (PCR) strategy suggest that only two defensin mRNA isoforms are expressed in the human small intestine, far fewer than the number expressed in the mouse. The two isoforms detected by this PCR approach were human defensin family members, HD-5 and HD-6. The gene encoding HD-6 was cloned and characterized. HD-6 has a genomic organization similar to HD-5, and the two genes have a striking pattern of sequence similarity localized chiefly in their proximal 5'-flanking regions. Analysis of human fetal RNA by reverse transcriptase-PCR detected enteric defensin HD-5 mRNA at 13.5 weeks of gestation in the small intestine and the colon, but by 17 weeks HD-5 was restricted to the small intestine. HD-6 mRNA was detectable at 13.5-17 weeks of gestation in the small intestine but not in the colon. This pattern of expression coincides with the previously described appearance of Paneth cells as determined by ultrastructural approaches. Northern analysis of total RNA from small intestine revealed quantifiable enteric defensin mRNA in five samples from 19 24 weeks of gestation at levels approximately 40-250-fold less than those observed in the adult, with HD-5 mRNA levels greater than those of HD-6 in all samples. In situ hybridization analysis localized expression of enteric defensin mRNA to Paneth cells at 24 weeks of gestation, as is seen in the newborn term infant and the adult. Consistent with earlier morphological studies, the ratio of Paneth cell number per crypt was reduced in samples at 24 weeks of gestation compared with the adult, and this lower cell number partially accounts for the lower defensin mRNA levels as determined by Northern analysis. Low levels of enteric defensin expression in the fetus may be characteristic of an immaturity of local defense, which is thought to predispose infants born prematurely to infection from intestinal microorganisms.

Amino Acid Sequence↗
PubMed2000

A novel murine beta -defensin expressed in tongue, esophagus, and trachea.

beta-Defensins are broad spectrum antimicrobial peptides expressed at epithelial surfaces. Two human beta-defensins, HBD-1 and HBD-2, have been identified. In the lung, HBD-2 is an inducible product of airway epithelia and may play a role in innate mucosal defenses. We recently characterized rat homologs (RBD-1, RBD-2) of the human genes and used these sequences to identify novel mouse genes. Mouse beta-defensin-4 (MBD-4) was amplified from lung cDNA using polymerase chain reaction primers designed from conserved sequences of RBD-2 and HBD-2. A full-length cDNA was cloned which encodes a putative peptide with the sequence MRIHYLLFTFLLVLLSPLAAFTQIINNPITCMTNGAICWGPCPTAFRQIGNCGHFKVRCCKIR. The peptide shares approximately 40% identity with HBD-2. MBD-4 mRNA was expressed in the esophagus, tongue, and trachea but not in any of 20 other tissues surveyed. Cloning of the genomic sequence of MBD-4 revealed two nearly (>99%) identical sequences encoding MBD-4 and the presence of numerous additional highly similar genomic sequences. Radiation hybrid mapping localized this gene to a region of chromosome 8 near several other defensins, MBD-2, MBD-3, and alpha-defensins (cryptdins)-3 and -17, consistent with a gene cluster. Our genomic cloning and mapping data suggest that there is a large beta-defensin gene family in mice. Identification of murine beta-defensins provides an opportunity to understand further the role of these peptides in host defense through animal model studies and the generation of beta-defensin-deficient animals by gene targeting.

Amino Acid Sequence↗
PubMed2006

A chromosome 8 gene-cluster polymorphism with low human beta-defensin 2 gene copy number predisposes to Crohn disease of the colon.

Defensins are endogenous antimicrobial peptides that protect the intestinal mucosa against bacterial invasion. It has been suggested that deficient defensin expression may underlie the chronic inflammation of Crohn disease (CD). The DNA copy number of the beta-defensin gene cluster on chromosome 8p23.1 is highly polymorphic within the healthy population, which suggests that the defective beta-defensin induction in colonic CD could be due to low beta-defensin-gene copy number. Here, we tested this hypothesis, using genomewide DNA copy number profiling by array-based comparative genomic hybridization and quantitative polymerase-chain-reaction analysis of the human beta-defensin 2 (HBD-2) gene. We showed that healthy individuals, as well as patients with ulcerative colitis, have a median of 4 (range 2-10) HBD-2 gene copies per genome. In a surgical cohort with ileal or colonic CD and in a second large cohort with inflammatory bowel diseases, those with ileal resections/disease exhibited a normal median HBD-2 copy number of 4, whereas those with colonic CD had a median of only 3 copies per genome (P=.008 for the surgical cohort; P=.032 for the second cohort). Overall, the copy number distribution in colonic CD was shifted to lower numbers compared with controls (P=.002 for both the surgical cohort and the cohort with inflammatory bowel diseases). Individuals with < or = 3 copies have a significantly higher risk of developing colonic CD than did individuals with > or = 4 copies (odds ratio 3.06; 95% confidence interval 1.46-6.45). An HBD-2 gene copy number of < 4 was associated with diminished mucosal HBD-2 mRNA expression (P=.033). In conclusion, a lower HBD-2 gene copy number in the beta-defensin locus predisposes to colonic CD, most likely through diminished beta-defensin expression.

Chromosomes, Human, Pair 8↗
PubMed1998

Amniotic fluid defensins: potential markers of subclinical intrauterine infection.

Human neutrophil peptides 1-3 (defensins) are granule constituents released from activated neutrophils. We hypothesized that amniotic fluid (AF) defensin levels are elevated in preterm labor (PTL) patients with subclinical intrauterine infection (IUI). AF samples were obtained from 203 pregnant patients with varying clinical characteristics. Defensin levels were measured by enzyme-linked immunosorbent assay. Median AF defensin levels were fourfold to 24-fold higher in patients with IUI than in preterm and term controls. Among patients with subclinical IUI, the degree of AF defensin elevation was greater in those with a positive AF culture. AF defensin levels increased exponentially with increasing severity of histologic chorioamnionitis. An AF defensin level of > 2,500 ng/mL identified 88% of patients with a positive AF culture, whereas a level of > 400 ng/mL identified 85% of all infected patients. AF defensin levels accurately identify patients with subclinical IUI, as defined by a positive AF culture or placental histology.

Amniotic Fluid↗
PubMed1997

A study of interleukin-8 and defensins in urine and plasma of patients with pyelonephritis and glomerulonephritis.

BACKGROUND: Interleukin-8 (IL-8) plays a crucial role in the recruitment and activation of polymorphonucleated leukocytes (PMN) in the site of inflammation. Defensins are specific cationic proteins from azurophil PMN granules which exert antimicrobial, cytotoxic and proinflammatory activities. METHODS: Urine and plasma levels of IL-8 and defensins were studied using specific enzyme-linked immunosorbent assays. IL-8 was determined in 107 patients, including 45 with chronic glomerulonephritis (GN) and 62 with chronic pyelonephritis (PN). Urine and plasma levels of defensins were studied simultaneously in 29 patients with GN and 29 with PN. None of the patients examined showed any evidence of renal insufficiency. A group of 24 healthy volunteers was used as a control. RESULTS: Urinary IL-8 was significantly increased in all groups of patients comparing with healthy control (< 30 pg/ml). The level of IL-8 in the urine of patients with PN (477 +/- 114 pg/ml, mean +/- SEM) was significantly (P < 0.001) higher than in patients with GN (53 +/- 7 pg/ml). The concentration of defensins in urine of patients with GN was slightly increased in comparison with the normal level (21 +/- 3.5 ng/ml versus 15.7 +/- 2.8 ng/ml). Urinary defensins were significantly elevated in patients with PN (134 +/- 118 ng/ml, P < 0.001), and were significantly higher than in the GN group (P < 0.001). A close correlation was observed between IL-8 and defensin concentrations in urine (r = 0.62), and between the urinary leukocyte count and IL-8 level (r = 0.72). The highest levels of IL-8 were observed in patients with PN, associated with nephrolithiasis (14 patients, 822 +/- 219 pg/ml versus 367 +/- 72 pg/ml in patients with PN alone, P < 0.05). IL-8 and defensin levels increased in older patients with PN, but not in older patients with GN. CONCLUSIONS: The levels of IL-8 and defensins in urine were 6-10-fold higher in patients with PN than in patients with GN. Thus, there is a significant difference in IL-8 production between septic and aseptic chronic inflammatory processes in kidney. It is possible to speculate that the timing and progression of kidney inflammation is mediated by an IL-8 dependent mechanism at least in the case of PN.

Adolescent↗
PubMed2004

Paneth cell alpha-defensins from rhesus macaque small intestine.

Antimicrobial peptides are secreted by small intestinal Paneth cells as components of innate immunity. To investigate the role of alpha-defensins in enteric host defenses in nonhuman primates, alpha-defensin cDNAs were isolated, alpha-defensin peptides were purified from rhesus macaque small bowel, and the bactericidal activities of the peptides were measured. Six rhesus enteric alpha-defensin (RED) cDNAs, RED-1 to RED-6, were identified in a jejunum cDNA library; the deduced RED peptides exhibited extensive diversity relative to the primary structures of rhesus myeloid alpha-defensins. RED-4 was purified from monkey jejunum, and N-terminal peptide sequencing of putative RED-4 peptides identified two N termini, RTCYCRTGR. and TCYCRTGRC.; these corresponded to alternative N termini for the RED-4 molecules, as deduced from their molecular masses and RED cDNAs. In situ hybridization experiments localized RED mRNAs exclusively to small intestinal Paneth cells. Recombinant RED-1 to RED-4 were purified to homogeneity and shown to be microbicidal in the low micromolar range (</=10 micro g/ml) against gram-positive and gram-negative bacteria, with individual peptides exhibiting variable target cell specificities. Thus, compared to myeloid alpha-defensins from rhesus macaques, enteric alpha-defensin peptides are highly variable in both primary structure and activity. These studies should facilitate further analyses of the role of alpha-defensins in primate enteric immunity.

Amino Acid Sequence↗
PubMed1997

Effect of defensins on interleukin-8 synthesis in airway epithelial cells.

Neutrophils play an important role in inflammatory processes in the lung and may cause tissue injury through, for example, release of proteinases such as neutrophil elastase. In addition to neutrophil elastase, stimulated neutrophils also release small nonenzymatic and cationic polypeptides termed defensins. The aim of the present study was to investigate whether defensins induce interleukin (IL)-8 expression in cells of the A549 lung epithelial cell line and in human primary bronchial epithelial cells (PBEC). Supernatants of defensin-treated A549 cells contained increased neutrophil chemotactic activity (16-fold) that was inhibited by antibodies against IL-8. Concurrently, within 3 and 6 h, defensins significantly increased the IL-8 levels in supernatants of both A549 cells (n = 6, P < 0.05 and P < 0.01, respectively) and PBEC (n = 4, P < 0.001 and P < 0.001, respectively). This defensin-induced increase was fully inhibited by the serine proteinase inhibitor alpha 1-proteinase inhibitor. In addition, defensins also increased IL-8 mRNA levels (12-fold); this increase was dependent on de novo mRNA synthesis and did not require protein synthesis. Furthermore, defensins did not affect IL-8 mRNA stability, indicating that the enhanced IL-8 expression was due to increased transcription. Our findings suggest that defensins, released by stimulated neutrophils, stimulate IL-8 synthesis by airway epithelial cells and thus may mediate the recruitment of additional neutrophils into the airways.

Aged↗
PubMed2002

Expression of human beta defensin (HBD-1 and HBD-2) mRNA in nasal epithelia of adult cystic fibrosis patients, healthy individuals, and individuals with acute cold.

BACKGROUND: Lack or inactivation of defensins may facilitate chronic bacterial colonization in the cystic fibrosis (CF) lung. CF nasal epithelium exhibits typical biochemical abnormalities and can be used to study defensin expression in CF. OBJECTIVES: To evaluate the expression of beta defensin (HBD-1 and HBD-2) mRNA and the presence of inflammatory markers (percentage of neutrophils and IL-8 mRNA expression) in CF and non-CF nasal mucosa. METHODS: Case-control study. Nasal brushing samples were obtained from 22 stable adult CF patients and 32 non-CF controls (25 healthy individuals and 7 individuals with acute cold). Samples were subjected to analysis involving mRNA expression (semiquantitative RT-PCR) and differential cell counting. RESULTS: Defensins and inflammatory markers were expressed at low levels in healthy individuals and at high levels in subjects with acute cold. In non-CF controls, defensin expression correlated significantly with inflammatory parameters (p < 0.001). In CF, defensin mRNA expression was comparable to healthy individuals (p = 0.2). In contrast to non-CF controls, in CF patients high levels of inflammatory markers did not correlate with defensin mRNA levels. CONCLUSIONS: Defensin expression is not upregulated in CF epithelium in response to inflammatory stimuli. Further studies are necessary to elucidate whether this is a consequence of the CF gene mutation.

Acute Disease↗
PubMed1995

Human neutrophil defensin and serpins form complexes and inactivate each other.

Defensins, antimicrobial and cytotoxic peptides of neutrophils, bind to and are inactivated by blood proteins. We identified defensin interactions with alpha 1-proteinase inhibitor (alpha 1-PI), alpha 1-antichymotrypsin (alpha 1-ACT), alpha 2-antiplasmin (alpha 2-AP), and antithrombin III (AT III) and examined defensin binding to alpha 1-PI and alpha 1-ACT in more detail. Defensin interactions with either alpha 1-PI or alpha 1-ACT were not affected by iodoacetamide or high salt concentration. Preincubation of alpha 1-ACT or alpha 1-PI with increasing concentrations of defensin resulted in a progressive decrease of antiprotease activity of both inhibitors against cathepsin G and antiprotease activity of alpha 1-PI against human neutrophil elastase. At higher concentrations, defensin also ablated the inhibitory effect of normal human serum on cathepsin G and human neutrophil elastase. Both alpha 1-PI and alpha 1-ACT inhibited defensin cytotoxicity toward the human lung carcinoma cell line A549, whereas the elastase inhibitor antileukoprotease did not. Complex interactions between serpins and defensin may have a role in regulating inflammatory processes.

Blood Proteins↗
PubMed1998

Elevated pleural fluid levels of defensins in patients with empyema.

BACKGROUND: Defensins, also known as human neutrophil peptides, are antimicrobial peptides present in the azurophil granules of neutrophils. We measured their level in pleural effusion in various pulmonary diseases to investigate whether they could be used as a diagnostic marker in the differential diagnosis of specific pleural diseases. PATIENTS AND PARTICIPANTS: We analyzed pleural effusion samples collected from 61 patients, including 50 exudates (11 with empyema, 3 parapneumonic, 15 tuberculous, 18 neoplastic, 3 miscellaneous) and 11 transudates as controls. MEASUREMENTS: Defensins were measured by radioimmunoassay and also analyzed by reverse-phase high-performance liquid chromatography. The concentrations of interleukin (IL)-8 and granulocyte colony-stimulating factor (G-CSF) in pleural effusion fluid were measured by enzyme-linked immunosorbent assay to examine the correlation between these cytokines and defensins. RESULTS: The concentration of defensins in all samples of empyema was >5,100 ng/mL and the mean concentration (13,265.8+/-1,895.2 ng/mL) in these samples was the highest among other groups. The concentration in the other 50 pleural effusion samples tested was <2,800 ng/mL. Defensins were mostly of the mature type in empyema. Pleural effusion levels of IL-8 and G-CSF in patients with empyema were also significantly higher than those in other samples. There was a significant correlation between defensins and IL-8 or G-CSF in pleural effusion fluid (r=0.762, and 0.827, respectively). CONCLUSIONS: Our results suggest that the high effusion concentrations of defensins in pleural effusion may constitute an important component of the host defense system or may have a cytotoxic role in empyema. Our results also indicate that the high levels of IL-8 and G-CSF in empyema may indirectly explain the elevated levels of defensins by increasing the number of neutrophils in the pleural space.

Biomarkers↗
PubMed2002

Human neutrophil defensins induce lung epithelial cell proliferation in vitro.

Repair of injured airway epithelium is often accompanied by an influx of leukocytes, and these cells have been suggested to contribute to the repair process. The aim of the present study was to investigate the effect of neutrophil defensins--antimicrobial peptides present in large amounts in the neutrophil--on proliferation of cultured lung epithelial cells. Neutrophil defensins at 4-10 microg/ml enhanced proliferation of the A549 lung epithelial cell line as assessed using cell counting, BrdU incorporation, and the tetrazolium salt MTT assay. Higher, cytotoxic concentrations of defensins decreased cell proliferation. Whereas defensin-induced cell proliferation was not inhibited by the EGF receptor tyrosine kinase inhibitor AG1478, it was completely inhibited by the mitogen-activated protein (MAP) kinase kinase (MEK) inhibitor U0126, suggesting that defensins mediate cell proliferation via an EGF receptor-independent, MAP kinase signaling pathway. Although the cytotoxic effect of defensins was inhibited by alpha1-proteinase inhibitor, the defensin-induced cell proliferation was not affected. These data suggest that neutrophil defensins may possibly be involved in epithelial repair in the airways by inducing lung epithelial cell proliferation.

Cell Division↗
PubMed1986

In vitro tumor cell cytolysis mediated by peptide defensins of human and rabbit granulocytes.

We examined the activity of defensins, cysteine-rich cationic peptides that are abundant in the cytoplasmic granules of human and rabbit granulocytes, against various tumor targets. The three human defensins, HNP-1, HNP-2, and HNP-3, lysed human and murine targets in chromium release and dye exclusion assays. Defensin-mediated tumor cell lysis was concentration-dependent, inhibited by serum, and dependent on temperature-sensitive events. Lysis was first detected by three hours of incubation and it reached a plateau between eight and 14 hours. In vitro exposure of murine teratocarcinoma cells to HNP 1-3 abrogated their oncogenicity in vivo. Nonmalignant target cells were also susceptible to defensin-mediated lysis. Four rabbit granulocyte defensins exerted marked (NP-1, NP-2) or moderate (NP-3a, NP-3b) cytotoxic activity, whereas defensin NP-5 was not cytotoxic. When tumor cells were incubated with human defensins in combination with hydrogen peroxide, synergistic cytotoxicity was detected. As defensins are released from granulocytes by various stimuli, their release could contribute to extracellular cytotoxicity which is independent of reactive oxygen intermediates.

Animals↗
PubMed2001

[Defensins as a mechanism of host defense and innate immunity].

Antimicrobial peptides, including beta-defensins, are thought to be effective agents against opportunistic infections. In humans, three beta-defensins have been identified. The first human beta-defensin, hBD-1, is predominantly expressed in epithelia of the urogenital tract and has been reported to be constitutive. The second and third human beta-defensins, hBD-2 and hBD-3, were isolated from psoriatic skin and found to be predominantly expressed in skin and respiratory tract. Of note, the hBD-2 gene expression is inducible by various proinflammatory agents such as TNF-alpha, IL-1 beta, IL-8, LPS, bacteria, and yeasts. It has been shown that LPS-induced expression of hBD-2 in human tracheobronchial epithelial cells requires CD14, which may complex with Toll-like receptors (TLRs) to ultimately activate NF-kappa B. In addition, beta-defensins have been recently reported to promote immune responses by recruiting dendritic and T cells. Defensins may play a key role in the mechanism of host defense and innate immunity. These defensins, including hBD-2, might provide a new therapeutic approach to infectious diseases.

Animals↗
PubMed2005

Immunofluorescence deconvolution microscopy and image reconstruction of human defensins in normal and burned skin.

OBJECTIVE: The aim of this study was visualization and localization of the human antimicrobials human beta defensins 1, 2, and 3, neutrophil defensin alpha (human neutrophil peptide), and the cathelicidin LL-37 in normal and burned skin, and determination of the cell types in which these antimicrobials were localized. METHODS: Tissue sections were probed with antimicrobial antibodies, tagged with fluorescently labeled secondary antibodies, and subjected to fluorescence deconvolution microscopy and image reconstruction. Images were generated by stacking multiple-section scans, which were then volume rendered by rotating stacks 360 degrees about an axis, or modeled in 3 dimensions. RESULTS: This technique yields a definitive image, providing a rapid basis for further quantification and manipulation from a full 3-dimensional aspect. In normal skin, human beta defensin-1 was localized to the perinuclear region of keratinocytes; human beta defensin-2 was primarily localized to the stratum germinativum; human beta defensin-3 was found in dendritic cells of the stratum spinosum; human neutrophil peptide was randomly distributed in the papillary dermis; and LL-37 was concentrated in the stratum corneum and along ducts. In burned skin, in which keratinocytes are lost or destroyed, human beta defensin-1 was present in dermal glandular structures including hair shafts; human beta defensin-2 and human beta defensin-3 were found in the remaining keratin layers and glands of the lower dermis; human neutrophil peptide was primarily localized to hair shafts, though visible in residual keratin layers; and LL-37 was evident in very high concentrations in the epithelium of sweat ducts. CONCLUSION: We conclude via this technique that cells in the lower dermal and subdermal regions of burned skin synthesize antimicrobials after burn injury, and maintain something of a barrier against infection. This methodology is discussed and explained in this article.

Journal Article↗