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PubMed1997

Comparative studies on the extracellular release and biological activity of guinea pig neutrophil cationic antibacterial polypeptide of 11 kDa (CAP11) and defensins.

Neutrophils contain various antibacterial polypeptides and proteins in the granules. Defensins have been known as the major antimicrobial granular components. Recently, we have purified a novel cationic antibacterial polypeptide of 11 kDa (CAP11) from guinea pig neutrophil granules. In this study, we have examined the extracellular release and biological activity of CAP11, and compared with defensins. CAP11 was extracellularly released from neutrophils by N-formyl Met-Leu-Phe, phorbol 12-myristate 13-acetate, accompanied by the release of lysozyme, a specific and azurophil granule component, without release of beta-glucuronidase, an azurophil granule component, whereas defensins were released by phagocytosis, accompanied by the release of beta-glucuronidase, suggesting that the localization of CAP11 and defensins is different among neutrophil granules. Defensins increased neutrophil adhesion, and inhibited phagocytosis of opsonized zymosan particles and phagocytosis-associated superoxide anion generation. In contrast, CAP11 did not affect these neutrophil functions. Both CAP11 and defensins possessed the histamine-releasing activities for mast cells, but CAP11 was 10-fold less potent than defensins. CAP11 and defensins showed the antibacterial activities against both Escherichia coli and Staphylococcus aureus. However, the antibacterial activity of defensins was completely lost in the presence of physiological concentration of NaCl (0.15 M), although CAP11 retained the antibacterial activity even in the presence of NaCl. Furthermore, CAP11 exhibited the 10-fold more potent antiretroviral activity than defensins against Moloney murine leukemia viruses. Together these observations indicate that when released from neutrophils, CAP11 likely functions as an antimicrobial molecule in the extracellular milieu, whereas defensins may participate in the modulation of neutrophil function and mast cell histamine release.

Amino Acid Sequence↗
PubMed2001

Discovery of new human beta-defensins using a genomics-based approach.

Epithelial beta-defensins are broad-spectrum cationic antimicrobial peptides that also act as chemokines for adaptive immune cells. In the human genome, all known defensin genes cluster to a <1 Mb region of chromosome 8p22-p23. To identify new defensin genes, the DNA sequence from a contig of large-insert genomic clones from the region containing human beta-defensin-2 (HBD-2) was analyzed for the presence of defensin genes. This sequence survey identified a novel beta-defensin, termed HBD-3. The HBD-3 gene contains two exons, is located 13 kb upstream from the HBD-2 gene, and it is transcribed in the same direction. A partial HBD-3 cDNA clone was amplified from cDNA derived from IL-1beta induced fetal lung tissue. The cDNA sequence encodes for a 67 amino acid peptide that is approximately 43% identical to HBD-2 and shares the beta-defensin six cysteine motif. By PCR analysis of two commercial cDNA panels, HBD-3 expression was detected in adult heart, skeletal muscle, placenta and in fetal thymus. From RT-PCR experiments, HBD-3 expression was observed in skin, esophagus, gingival keratinocytes, placenta and trachea. Furthermore, in fetal lung explants and gingival keratinocytes, HBD-3 mRNA expression was induced by IL-1beta. Additional sequence analysis identified the HE2 (human epididymis secretory protein) gene 17 kb upstream from the HBD-3 gene. One splice variant of this gene (HE2beta1) encodes a beta-defensin consensus cysteine motif, suggesting it represents a defensin gene product. HE2beta1 mRNA expression was detected in gingival keratinocytes and bronchial epithelia using RT-PCR analysis. The discovery of these novel beta-defensin genes may allow further understanding of the role of defensins in host immunity at mucosal surfaces.

Adult↗
PubMed2005

Variability and evolution of bovine beta-defensin genes.

Defensins comprise an important family of antimicrobial peptides. Among vertebrates numerous defensin genes have been detected, but their evolutionary background is still discussed. We investigated the molecular evolution of bovine defensins via screening of different bovine species including the extinct ancestor of domestic cattle (Bos primigenius) for beta-defensin encoding genes. We detected a large variability of new defensin encoding sequences similar to previously published bovine neutrophil beta-defensin (bnbd), neutrophil beta-defensin 12 (nbd12), enteric beta-defensin (ebd), lingual antimicrobial peptide (lap), and tracheal antimicrobial peptide (tap). Our data suggest that variants of the same so-called subfamily (tap, lap, ebd, and nbd12) each share a common ancestry independent of their species origin, implicating several duplication events of tap, lap, ebd, and nbd12 before the different bovine lineages diverged. Variants of bovine neutrophil beta-defensins bnbd5 and bnbd9 were detected exclusively in domestic cattle and aurochs. Values of synonymous and nonsynonymous substitutions demonstrated lap, bnbd5, bnbd9 and nbd12 evolving under positive selection, whereas amino-acid altering substitutions among variants of ebd and tap are purified. Comparison of the amino-acid sequences with available structures of human and murine defensins suggested conservation of the typical secondary elements of defensins in the absence of high sequence similarity.

Animals↗
PubMed2001

Structure determination of human and murine beta-defensins reveals structural conservation in the absence of significant sequence similarity.

Defensins are cationic and cysteine-rich peptides that play a crucial role in the host defense against microorganisms of many organisms by their capability to permeabilize bacterial membranes. The low sequence similarity among the members of the large mammalian beta-defensin family suggests that their antimicrobial activity is largely independent of their primary structure. To investigate to what extent these defensins share a similar fold, the structures of the two human beta-defensins, hBD-1 and hBD-2, as well as those of two novel murine defensins, termed mBD-7 and mBD-8, were determined by nuclear magnetic resonance spectroscopy. All four defensins investigated share a striking similarity on the level of secondary and tertiary structure including the lack of a distinct hydrophobic core, suggesting that the fold is mainly stabilized by the presence of three disulfide bonds. In addition to the overall shape of the molecules, the ratio of solvent-exposed polar and hydrophobic side chains is also very similar among the four defensins investigated. It is significant that beta-defensins do not exhibit a common pattern of charged and hydrophobic residues on the protein surface and that the beta-defensin-specific fold appears to accommodate a wide range of different amino acids at most sequence positions. In addition to the implications for the mode of biological defensin actions, these findings are of particular interest because beta-defensins have been suggested as lead compounds for the development of novel peptide antibiotics for the therapy of infectious diseases.

Amino Acid Sequence↗
PubMed2006

Defensin expression in chronic pouchitis in patients with ulcerative colitis or familial adenomatous polyposis coli.

AIM: Pouchitis develops in ileoanal pouches in up to 50% of patients with ulcerative colitis during the first 10 years after pouch surgery while being rare in patients after proctocolectomy for familial adenomatous polyposis coli (FAP) syndrome. Defensins are major components of the innate immune system and play a significant role in gastrointestinal microbial homeostasis. Pouch defensin and cytokine expression were correlated with states of pouch inflammation to study their role in pouchitis. METHODS: Patients with ulcerative colitis and FAP syndrome were stratified into groups with pouches after surgery, pouches without or with pouchitis. Biopsies from terminal ileum from a healthy intestine or from normal terminal ileum of patients with ulcerative colitis served as controls. mRNA from pouches and controls was analysed for defensin and cytokine expression. RESULTS: Expression of defensins was increased in all pouches immediately after surgery, compared to ileum of controls. Initially, pouches in ulcerative colitis revealed higher defensin expression than FAP pouches. Defensin expression declined in both patient groups and increased again slightly in pouchitis in patients with ulcerative colitis. FAP pouches without pouchitis had strong expression of beta-defensin hBD-1, while all other defensins remained at low levels. Cytokine expression in ulcerative colitis pouches was high, while FAP pouches showed moderately elevated cytokines only after surgery. CONCLUSION: Development of pouchitis correlates with decreased defensin expression in ulcerative colitis in addition to high expression of cytokines. The low incidence of pouchitis in FAP pouches correlates with increased expression of hBD-1 beta-defensin in association with low cytokine levels.

Adenomatous Polyposis Coli↗
PubMed2006

Sequence analysis of a 212 kb defensin gene cluster on ECA 27q17.

Defensins are a family of evolutionary ancient antimicrobial peptides consisting of three sub-families: alpha-, beta- and theta-defensins. This investigation was focused on the genomic characterization of equine beta-defensins and the investigation of the potential clustering of beta-defensin genes in the equine genome. Six genomic BAC clones were isolated from the CHORI-241 library and one of these was mapped by FISH to ECA 27q17. This location was confirmed by RH-mapping. The contiguous 212 kb sequence of this clone was determined. Sequence analysis revealed the identification of ten pseudogenes and nine genes, six of which were highly homologous to human beta-defensin DEFB4. Clustering of the beta-defensin genes was confirmed and the order of the genes on the analyzed BAC was related to the corresponding defensin cluster on HSA 8. The knowledge about the sequence and the genomic structure of the equine beta-defensin genes will improve the classification of different paralogous defensin genes and is a prerequisite for subsequent functional studies. Additionally, the first alpha-defensin-like sequence outside the groups of primates, lagomorphs and rodents (glires) was identified.

Animals↗
PubMed2000

Expression of human beta-defensins in intraocular tissues.

PURPOSE: Defensins are naturally occurring antimicrobial peptides. Recently the authors published evidence of defensin production by the human ocular surface. A study was undertaken to look for intraocular defensins that may account for unexplained antimicrobial activity of intraocular fluids. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was performed on human postmortem ciliary body samples for beta defensins-1 (HBD-1) and beta defensin-2 (HBD-2), and alpha defensins 5 and 6. Induction of defensins by cytokines was analyzed in cultured human ciliary body epithelial (CBE) and retinal pigment epithelial (RPE) cells. Polyclonal antibodies were used to immunoblot aqueous and vitreous to detect HBD-1 and HBD-2 and to estimate their concentration. RESULTS: RT-PCR revealed constitutive HBD-1 message in ciliary body. HBD-2 and alpha defensin 5 and 6 messages were absent. HBD-2 message was induced by cytokine stimulation of both CBE and RPE cells. Immunoblots of vitreous and aqueous stained positively for HBD-1 but not HBD-2. The estimated aqueous concentration of HBD-1 was less than 16 ng/ml. CONCLUSIONS: This study demonstrates that HBD-1 is constitutively present in the aqueous and vitreous, probably at sub-bacteriocidal concentrations. HBD-2 was absent from aqueous, but cytokine stimulation studies suggest that it may be generated in response to inflammatory cytokines during infections. HBD-2 has a wider antibacterial spectrum, is 10-fold more potent, and may play a more significant role in antimicrobial defense than HBD-1. The use of defensins therapeutically may be indicated; however, caution is required because defensins also promote cell proliferation and fibrin formation, which are 2 key elements in ocular scarring processes such as proliferative vitreoretinopathy.

Aqueous Humor↗
PubMed1996

Evaluation of the effects of defensins on neutrophil functions.

Defensins are known to be the microbicidal components of neutrophil granules, which contribute to oxygen-independent antimicrobial mechanisms. In this study, we have examined the effect of defensins on neutrophil functions, such as adhesion, superoxide anion generation, phagocytosis and chemotaxis. Guinea-pig defensins increased the expression of CD11b, CD11c and CD54 (intercellular adhesion molecule ICAM-1) on human neutrophils, and induced adhesion of guinea-pig and human neutrophils. When the effect of guinea-pig defensins on superoxide anion generation was examined, defensins inhibited superoxide anion generation during phagocytosis of complement-opsonized particles. Furthermore, defensins inhibited complement-dependent phagocytosis. However, they did not inhibit the binding of complement-opsonized particles to neutrophils, suggesting that defensins possibly inhibit complement-dependent phagocytosis by affecting the ingestion step but not the binding step. Defensins exhibited neither chemotactic nor chemokine activity. Interestingly, 10-20% of total defensins were released extracellularly from phagocytosing neutrophils. Together these observations indicate that, in addition to their antimicrobial activity, defensins may have the ability to modulate the functions of neutrophils at sites of infection or inflammation.

Animals↗
PubMed2005

theta-Defensin pseudogenes in HIV-1-exposed, persistently seronegative female sex-workers from Thailand.

The leukocytes of rhesus monkeys contain cyclic octadecapeptides (theta;-defensins) that can protect cells from infection by HIV-1 in vitro. Although humans express mRNA from one or more theta;-defensin pseudogenes, these transcripts contain a premature stop codon that prevents formation of theta;-defensin peptides. We hypothesized that some highly exposed persistently seronegative (HEPS) individuals might have intact theta;-defensin (DEFT) genes and produce functional theta;-defensins that might account for their resistance to HIV-1 infection. We sequenced DEFT genes from 30 women in Chiang Rai, northern Thailand: 11 HEPS female sex-workers and 19 control women (10 HIV-1 infected and 9 HIV-1 uninfected). We found that theta;-defensin genes from all 11 HEPS women contained the crucial signal sequence stop codon, as did the 19 control women. Synthetic theta;-defensins based on the cDNA sequences to generate a human theta;-defensin (termed retrocyclin-1 and -2) were capable of inhibiting replication of Thai HIV-1 subtype B and CRF01_AE isolates regardless of the coreceptor utilization of the isolates. Although our study indicates that synthetic theta;-defensin peptides are effective in vitro against Thai subtype B and CRF01_AE isolates of HIV-1, the presence of premature stop codons in the DEFT genes of these HEPS women makes it unlikely that endogenous theta;-defensin production accounts for their resistance to HIV-1.

Amino Acid Sequence↗
PubMed2003

Bacterial vaginosis, vaginal fluid neutrophil defensins, and preterm birth.

OBJECTIVE: To examine the association between bacterial vaginosis, vaginal fluid neutrophil defensins, and preterm birth. METHODS: Vaginal fluid specimens were obtained at 24-29 weeks' gestation from 242 cases with preterm birth and 507 noncases sampled using a case-cohort study design. We tested for bacterial vaginosis by Gram staining and Nugent scores and assayed for neutrophil defensins by enzyme-linked immunosorbent assay. Bacterial vaginosis was studied as a categoric variable (negative, intermediate, and positive), whereas defensins were studied as a continuous, categoric (based on percentiles), and dichotomous measure (presence versus absence). Three gestational age cut points were used to define preterm birth. Modified Cox proportional hazard models were used to evaluate the associations between bacterial vaginosis, defensins, and degree (less than 32, less than 34, and less than 37 weeks) and type (premature rupture of membranes, preterm labor) of preterm birth. RESULTS: Elevated vaginal fluid neutrophil defensins were not associated with birth before 37 weeks. Compared with women who did not have measurable vaginal fluid defensins, women with higher defensin levels (0-2.8 micro g/mL, 2.8-8.2 micro g/mL, and greater than 8.2 micro g/mL) had a greater risk of delivering before 32 weeks. Hazard ratios adjusted for maternal race and vaginal bleeding during pregnancy and 95% confidence intervals for these defensin levels were 1.7 (0.4, 6.9), 2.4 (0.7, 7.9), and 3.1 (1.0, 9.8), respectively. Bacterial vaginosis status did not influence the association between defensins and preterm birth. CONCLUSION: Elevated concentrations of vaginal fluid neutrophil defensins at 24-29 weeks' gestation might predict preterm birth before 32 weeks.

Adult↗
PubMed2003

Involvement of lipooligosaccharides of Haemophilus influenzae and Neisseria meningitidis in defensin-enhanced bacterial adherence to epithelial cells.

Stimulated neutrophils release a variety of antimicrobial peptides, including neutrophil defensins (HNP1-4). We have previously reported that neutrophil defensins enhanced the adherence of Haemophilus influenzae and Neisseria meningitidis to cultured respiratory epithelial cells. In this study, the effect of defensins on the adherence of H. influenzae and N. meningitidis lipooligosaccharide (LOS) mutants to epithelial cells was tested. Neutrophil defensins enhanced the adherence of the oligosaccharide mutants of H. influenzae and N. meningitidis, whilst the adherence of the lipid A mutants B29 of H. influenzae and lpxL1 and lpxL2 of N. meningitidis was not or only moderately stimulated by neutrophil defensins. The adherence of the N. meningitidis LOS negative mutant lpxA was not enhanced by defensins. These findings suggested that the secondary fatty acids of lipid A were involved in the defensin-enhanced adherence. LOS from strain H44/76 or HNP-LOS complexes did not affect or stimulate the adherence of N. meningitidis, although the defensin-enhanced adherence is specific for certain bacterial species having LOS in their outer membrane. These results indicated that LOS is involved in the defensin-enhanced adherence. However, the mechanism by which defensins and LOS interact with epithelial cells to promote bacterial adherence remains to be resolved.

Bacterial Adhesion↗
PubMed2001

Expressions of beta-defensins in human keratinocyte cell lines.

BACKGROUND: Defensins, a major family of antimicrobial peptides, are small cationic, cysteine-rich peptides with a wide range of antimicrobial activity. In human, beta-defensin-1 was isolated from urine and cervical mucous suggesting that this peptide plays an antimicrobial role in the genitourinary tract. Beta-defensin-2 was identified in psoriatic scale produced by keratinocytes suggesting that this peptide contributes to defend the expansive surface of the integuments. OBJECTIVE: Current research was done to investigate the expression and modulation of beta-defensin mRNA in human keratinocyte cell lines. METHODS: HaCaT and A431 cell lines were used to all culture experiments. Cultured human keratinocytes were stimulated with ultraviolet (UV) B irradiation or tumor necrosis factor-alpha (TNF-alpha) or lipopolysaccharide (LPS) to determine whether defensin mRNA production occurred. Reverse transcription-polymerase chain reaction (RT-PCR) was performed to amplify defesin cDNA from stimulated keratinocytes, and southern blots were used to verify the specificity of RT-PCR amplication products. RESULTS: Expression of human beta-defensins was upregulated with UVB irradiation, TNF-alpha and LPS in HaCaT cells and in comparison to the control, significantly higher at 6 h post stimulation with UVB 100 mJ/cm2 and peak at 12 to 18 h post stimulation with UVB 30 mJ/cm2, TNF-alpha and LPS. A431 cells did not show expression of human beta-defensins in unstimulated state, even after irradiation with UVB or TNF-alpha or LPS. CONCLUSIONS: This report demonstrates the presence of defensin in human keratinocytes and capacity of human keratinocytes to produce defensin mRNA in response to UVB irradiation, TNF-alpha and LPS. Release of defensins by keratinocytes in response to cytokines elaborated in inflammation may contribute to the host defense responses.

Cells, Cultured↗
PubMed2001

Human beta defensin-1 and -2 expression in human pilosebaceous units: upregulation in acne vulgaris lesions.

A rich residential microflora is harboured by the distal outer root sheath of the hair follicle and the hair canal - normally without causing skin diseases. Although the basic mechanisms involved in the development of inflammation during acne vulgaris remain unclear, microbial agents might play an important role in this process. In this study we have analyzed by in situ hybridization and immunohistochemistry the expression patterns of two antimicrobial peptides, human beta defensin-1 and human beta defensin-2, in healthy human hair follicles as well as in perilesional and intralesional skin of acne vulgaris lesions such as comedones, papules, and pustules. Strong defensin-1 and defensin-2 immunoreactivity was found in all suprabasal layers of the epidermis, the distal outer root sheath of the hair follicle, and the pilosebaceous duct. Marked defensin-1 and defensin-2 immunoreactivity was also found in the sebaceous gland and in the basal layer of the central outer root sheath including the bulge region. The majority of acne biopsies displayed a marked upregulation of defensin-2 immunoreactivity in the lesional and perilesional epithelium - in particular in pustules - and a less marked upregulation of defensin-1 immunoreactivity. The upregulation of beta-defensin expression in acne vulgaris lesions compared to controls suggests that beta-defensins may be involved in the pathogenesis of acne vulgaris.

Acne Vulgaris↗
PubMed2002

Bacterial vaginosis and vaginal fluid defensins during pregnancy.

OBJECTIVE: The purpose of this study was to examine the association between Gram stain findings of vaginal fluid and the concentration of vaginal fluid neutrophil defensins. STUDY DESIGN: Vaginal fluid specimens obtained from 749 women at 24 to 29 weeks of gestation were tested for bacterial vaginosis and assayed for neutrophil defensins. Bacterial vaginosis was studied as a categoric variable (negative, intermediate, and positive), whereas defensins were examined as a continuous measure and dichotomized on the basis of presence versus absence and at the 90th percentile. Multiple linear and logistic regression models were used to assess the relationship between bacterial vaginosis and defensins. RESULTS: Women with intermediate bacterial vaginosis were more likely to have elevated vaginal fluid neutrophil defensins (>90th percentile) than women with normal vaginal flora (adjusted odds ratio, 2.3; 95% CI, 1.3, 4.2), whereas women with frank bacterial vaginosis were not (adjusted odds ratio, 1.3; 95% CI, 0.7, 2.6). Among women with any detectable defensin (69.5% of the study population), intermediate bacterial vaginosis was associated positively with defensin concentrations in multiple linear regression models (P =.007). Women with intermediate and frank bacterial vaginosis had 5.9 microg/mL and 2.2 microg/mL higher defensin concentrations, respectively, than women who did not have bacterial vaginosis. The presence of leukocytes in vaginal fluids was associated positively with defensin concentrations (P <.0001). CONCLUSION: Changes in vaginal microflora during mid pregnancy are associated with an increased concentration of vaginal fluid neutrophil defensins.

Adolescent↗
PubMed1996

Defensin modulates tissue-type plasminogen activator and plasminogen binding to fibrin and endothelial cells.

Defensins are naturally occurring antimicrobial peptides that may participate in host defense against microorganisms. We previously reported that the amino acid sequence of leukocyte defensins resembles the lysine-binding site in the kringles of plasminogen and that defensin inhibits fibrinolysis mediated by tissue-type plasminogen activator (tPA) and plasminogen. In the present paper we analyze the mechanisms of this inhibition. Defensin binds specifically to cultured human umbilical vein endothelial cells (HUVEC) (half-maximal binding = 3 microM) as well as to fibrin. At saturating concentrations (5-10 microM), defensin stimulates the maximum binding of plasminogen to HUVEC and to fibrin approximately 10-fold. However, defensin inhibits plasminogen binding to both surfaces at concentrations >10 microM. Defensin also inhibits tPA and plasminogen-mediated fibrinolysis in a dose-dependent manner at all concentrations tested. Fibrinolysis is almost totally inhibited by 6 microM defensin, a concentration that stimulates the binding of plasminogen to fibrin. Discordance between the enhancement of plasminogen binding and its activation cannot be explained by an inhibitory effect of defensin on tPA binding nor by inhibition of plasmin activity, each of which occur only at higher concentrations. Rather, these results suggest that plasminogen bound to fibrin in the presence of defensin is less susceptible to activation by tPA.

Anti-Infective Agents↗
PubMed2005

Why is the Arg5-Glu13 salt bridge conserved in mammalian alpha-defensins?

Mammalian alpha-defensins, expressed primarily in leukocytes and epithelia, kill a broad range of microbes, constituting one of the first lines of innate immune defense against infection. Nine amino acid residues, including six cysteines, one glycine, and a pair of oppositely charged residues Arg/Glu, are conserved in the otherwise diverse sequences of all known mammalian alpha-defensins. Structural analysis indicates that the two charged residues form a salt bridge, likely stabilizing a protruding loop in the molecule. To investigate the structural and functional roles of the conserved Arg5-Glu13 salt bridge in alpha-defensins, we chemically prepared human neutrophil alpha-defensin 2 (HNP2) and five HNP2 analogs, R5E/E13R, E13Q, E13R, R5T/E13Y, and R14A. In contrast to HNP2 and R14A-HNP2, none of the four salt bridge analogs was capable of folding into a native conformation in the context of isolated defensin domains. However, when covalently attached to the 45-residue pro-HNP2 propeptide, the salt bridge analogs of HNP2 in their pro-forms all folded productively, suggesting that the Arg5-Glu13 salt bridge is not required for correct pro-alpha-defensin folding. When assayed against both Escherichia coli and Staphylococcus aureus, the six alpha-defensins showed bactericidal activity that correlated with the number of net positive charges carried by individual molecules in the panel, irrespective of whether or not the Arg5-Glu13 salt bridge was decimated, suggesting that Arg5 and Glu13 are not functionally conserved. Proteolytic resistance analysis with human neutrophil elastase, one major protease contained in azurophils with HNPs, revealed that destabilization of the salt bridge dramatically accelerated defensin degradation by the enzyme. Thus, we propose that the Arg5-Glu13 salt bridge found in most mammalian alpha-defensins is conserved for defensin in vivo stability.

Alleles↗
PubMed2000

Defensins act as potent adjuvants that promote cellular and humoral immune responses in mice to a lymphoma idiotype and carrier antigens.

Defensins released by neutrophils are able to kill a broad spectrum of microbes. They also induce leukocyte migration in vitro and elicit inflammatory leukocyte responses at s.c. injection sites in mice. In vitro experiments showed that human defensins enhanced concanavalin A-stimulated murine spleen cell proliferation and IFN-gamma production. This led us to examine the effects of human defensins on specific immune responses in vivo. BALB/c mice were immunized with 50 microg of keyhole limpet hemocyanin (KLH) adsorbed to aluminum hydroxide and administered with defensins in aqueous solution. Intraperitoneal administration of defensins significantly increased the production of KLH-specific IgG1, IgG2a and IgG2b antibodies 14 days after immunization. In vitro splenic KLH-specific proliferative responses were higher in mice treated with KLH and defensins than in those treated with KLH alone. Increased IFN-gamma and, to a lesser extent, IL-4 production were also detected in the supernatants of ex vivoKLH-activated spleen cells from mice treated with defensins. Finally, defensins significantly enhanced the antibody response to a syngeneic tumor antigen, lymphoma Ig idiotype and also augmented resistance to tumor challenge. These results indicate that defensins act as potent immune adjuvants by inducing the production of lymphokines, which promote T cell-dependent cellular immunity and antigen-specific Ig production. Thus, defensins appear to function as neutrophil-derived signals that promote adaptive immune responses.

Adjuvants, Immunologic↗
PubMed2004

Human alpha defensin in HIV-exposed but uninfected individuals.

Human alpha defensins 1, 2, and 3 are produced by CD8 T cells of HIV-infected long-term nonprogressors and have an antiviral activity. alpha Defensins were examined in peripheral blood mononuclear cells (PBMCs), cervical-vaginal mononuclear cells (CVMCs), and cervical biopsies of 9 HIV-1-exposed but uninfected women (ESNs), 10 HIV-infected patients (HIV), and 13 low-risk healthy controls (HCs). Results showed that, whereas alpha defensin production and alpha defensin-expressing CD8 lymphocytes were comparable in ESNs and HIV patients, constitutive alpha defensin production by peripheral CD8 and CVMCs was augmented in ESNs compared with HCs (P = 0.001 and P = 0.058, respectively); alpha defensin mRNA was increased in PBMCs of ESNs; unstimulated, alpha defensin-expressing peripheral and mucosal CD8 lymphocytes were 10-fold higher in ESNs compared with HCs (P = 0.003 and P = 0.01, respectively); and alpha defensin mRNA and alpha defensin-expressing cells were augmented in cervical biopsies of ESN compared with HCs (mRNA:P = 0.03). The differences were reduced upon in vitro mitogen stimulation. A robust constitutive production of alpha defensin is seen in HIV-exposed uninfected individuals; these peptides could have a role in the potentially protective immune response that characterizes ESNs.

Biopsy↗