Defensins and acne

Acne a disease of the pilosebaceous unit is characterised by hypercornification and hyperkeratosis of outer root sheath (ORS) and sebaceous duct and perilesional infiltrate. Lesions may be characterised as "non"-inflammatory versus inflammatory. Hypercornification of the distal ORS and the pilosebaceous duct in concert with increased sebum production and abnormalities of the microbial flora are considered to be major factors in the pathogenesis of acne vulgaris. However, the basic mechanisms involved in the development of inflammation during acne vulgaris remain unclear. We have investigated the expression patterns of two antimicrobial peptides, human beta-defensin 1 (hBD1) and human beta-defensin 2 (hBD2) in healthy human hair follicles as well as in peri- and intralesional skin of acne vulgaris lesions such as comedones, papules and pustules. Strong hBD1 and hBD2 immunoreactivity was found in all suprabasal layers of the epidermis, and all permanent compartments of the hair follicle including the distal ORS of the hair follicle and the pilosebaceous duct. Moreover, marked hBD1 and hBD2 expression was also detected in the hair follicle stem cell compartment. In contrast, the proximal follicle bulb which undergoes apoptotic regression and is also able to regenerate following injury did not express hBD1 or hBD2. The majority of acne biopsies displayed a marked upregulation of hBD2 IR in the lesional and perilesional epithelium; in particular in pustules, and a less marked upregulation of hBD1 IR. The upregulation of beta-defensins expression in acne vulgaris lesions when compared to controls suggests that beta-defensins may be involved in the pathogenesis of acne vulgaris.     

Defensins: Natural component of human innate immunity

The widespread use of antibiotics has contributed to a huge increase in the number of resistant bacteria. New classes of drugs are therefore being developed of which defensins are a potential source. Defensins are a group of antimicrobial peptides found in different living organisms, involved in the first line of defense in their innate immune response against pathogens. This review summarizes the results of studies of this family of human antimicrobial peptides (AMPs). There is a special emphasis on describing the entire group and individual peptides, history of their discovery, their functions and expression sites. The results of the recent studies on the use of the biologically active peptides in human medicine are also presented. The pharmaceutical potential of human defensins cannot be ignored, especially considering their strong antimicrobial activity and properties such as low molecular weight, reduced immunogenicity, broad activity spectrum and resistance to proteolysis, but there are still many challenges and questions regarding the possibilities of their practical application.     

Defensins of vertebrate animals.

During the past year, novel beta-defensins of mice and men have been identified, together with a novel defensin subfamily (the circular or 'theta' minidefensins) in primates. Insight into the evolution of defensins has been obtained from structural studies, and several mechanisms related to microbial resistance to defensins have been delineated. There is now convincing evidence that defensins augment adaptive immune responses.     

Antimicrobial peptides: natural effectors of the innate immune system

Antimicrobial peptides (AMPs) are an evolutionarily conserved component of the innate immune system that defend against invading bacteria, viruses, and fungi through membrane or metabolic disruption. The efficiency of host defense via AMPs derives from the ability of these peptides to quickly identify and eradicate foreign pathogens through precise biochemical mechanisms. Recent advances in this field have expanded the repertoire of activities for AMPs to include immunostimulatory and immunomodulatory capacity as a catalyst for secondary host defense mechanisms. Further scrutiny of the biochemical and regulatory mechanisms of AMPs will lead to novel alternative approaches to the treatment of human pathogenic disorders.     

Cancer immunotherapy: synthetic and natural peptides in the balance.

The identification of human tumor-associated antigens has opened new avenues for immune intervention in cancer. Clinical trials using synthetic peptides that match segments of known tumor-associated proteins are ongoing. Alternatively, naturally processed peptides, obtained by acid treatment of tumor cells can be used. Here, Matteo Bellone and colleagues discuss the advantages and disadvantages of synthetic versus natural tumor peptides in cancer immunotherapy.     

Synthetic peptides from a conserved region of gp120 induce broadly reactive anti-HIV responses.

In our efforts to identify products that might be used for active immunotherapy in human immunodeficiency virus (HIV) infection, we have studied synthetic peptides derived from the CD4 attachment site of gp120. Two peptides have emerged with particularly interesting properties. The first (B138) is linear and spans the envelope residues 421-438; the second (1005/45) encompasses amino acids 418-445 and is cyclized by way of a disulphide bond joining its terminal cysteines. Both species have been shown to inhibit syncytial formation in a conventional bioassay, B138 being the most efficient. Both peptides elicit high titres of anti-peptide antibodies in immunized mice, rabbits and goats, with titres exceeding 1:10(5) in many cases. A substantial portion of this response is directed against gp120 as determined by enzyme-linked immunosorbent assay (ELISA). Analysis by flow cytometry has demonstrated that the antisera are broadly reactive with multiple diverse strains of HIV. The anti-gp120 activity of the anti-peptide antiserum was further confirmed by radioimmuno-precipitation (RIP) assays. Furthermore, RIP analysis and inhibition experiments in a GD4-gp120 binding assay have revealed that anti-peptide sera contain antibodies directed against the CD4 attachment site on gp120 and interfere with this receptor-ligand interaction.     

Immunomodulatory significance of natural peptides in mammalians: Promising agents for medical application

Modulation of immune responses by immunoregulatory agents, such as the natural or synthetic immunomodulatory peptides, has been suggested as a potential strategy to modulate immune system against infection and other immune-related diseases. These compositionally simple peptides have attracted much attention for many drug developers, due to their high activity, low toxicity and clear target specificity. Host defence peptides and milk-derived peptides are two kinds of natural immunomodulatory peptides which have been widely studied in mammalians. They could participate at the interface of innate and adaptive immunity by regulating immune effector cells. This review summarizes the recent advances in host defence peptides and milk-derived peptides as well as their general characteristics, immunomodulatory functions and possible applications.     

Defensins in the immunology of bacterial infections

Defensins are a component of the host response against bacterial infections. Multiple studies suggest a linked upregulation of beta-defensins and pro-inflammatory cytokines expression in various tissues, as well as the possibility of mutual induction. Recent data demonstrate the importance of nucleotide-binding oligomerization proteins for the expression of defensins, and associate low levels of alpha-defensins expression by intestinal Paneth cells with susceptibility to Crohn's disease of the ileum. A novel anti-toxin activity has been identified for several alpha- and theta-defensins, expanding the repertoire of the antimicrobial functions of defensins. It has been shown that bacterial proteins can inactivate the action of defensins, and that pathogen type III secretion systems (T3SS) manipulate defensins expression via T3SS-mediated inhibition of the NF-kappaB pathway.     

Dynamic Changes in Neutrophil Defensins during Endotoxemia

Bacterial endotoxin or lipopolysaccharide (LPS) is an important causative agent of sepsis. This study determines the expression of defensins NP-2 and NP-5 and the function of polymorphonuclear leukocytes (PMN) in rabbits treated with LPS. PMN functional activity was assessed by measuring CD18 expression and H(2)O(2) production and by examining the lungs. NP-2 and, to a minor extent, NP-5 of circulating PMN increase during endotoxemia. This early increase is concomitant with neutrophilia and elevated CD18 expression and H(2)O(2) production, as well as with enhanced NP-2 immunoreactivity in pulmonary microvessels. A decline in defensins, shortly after the last LPS treatment, is associated with a decrease in the circulating activated PMN and enhanced immunoreactivity in the inflammatory cells, as well as with lung tissue damage. This study shows that LPS-induced changes in the defensins of circulating PMN correlate with the number and activated condition of these cells and suggests that PMN-derived products implement the inflammatory reaction that leads to lung injury and sepsis.     

人中性粒细胞防御素的分离纯化

从人中性粒细胞分离胞浆颗粒,以5%乙酸从中提取酸溶性组分,经SephadexG100及Bio-gel P10凝胶过滤层析后获得纯化的人中性粒细胞防御素(HNP)。纯化的HNP经AU-PAGE分析不含杂质蛋白区带,SDS—PAGE分析为一条分子量约3 000的带。氨基酸组成分析表明,在被检测的17种氨基酸中,HNP含12种,各种氨基酸残基的推算数与文献报道氨基酸序列分析结果一致。HNP在体外实验中表现较强杀白色念珠菌活性,在浓度为100μg/ml时,白色珠菌死亡率近90%。     

Defensins in saliva and the salivary glands

Saliva contains several types of antimicrobial peptides that play a role in innate immunity. Peptides that were recently added to this list are the defensins. The purpose of this review is to summarize what is known about the production and role of defensins in the salivary glands and to discuss their therapeutic potential. The -defensins, human neutrophil defensins (HNP)-1, -2, and -3, have been detected in saliva and may be derived from neutrophils. The -defensins, human -defensins (HBD)-1 and -2, have also been detected in saliva. Although it has been speculated that salivary HBDs are derived from keratinocytes that line the oral mucosa rather than from the salivary glands, the HBD-1 peptide was recently found to be specifically expressed in salivary ductal cells, although not in acini. Defensins may be useful for the treatment of periodontal disease and for the prevention of caries and periodontitis.     

Transmembrane T-cell receptor peptides inhibit B- and natural killer-cell function

A synthetic hydrophobic peptide (core peptide; CP) containing two positively charged amino acids, lysine and arginine was derived from the transmembrane sequence of the T-cell receptor (TCR) alpha chain and has been shown to inhibit T-cell-mediated inflammation. In this study, we investigated the specificity of CP (10 microm) on lymphocyte function and found that it significantly inhibited interleukin-2 production in T cells and natural killer cytotoxicity by 46-58% compared to positive control. CP had no effects on B-cell proliferative responses when used at these concentrations; however, it suppressed B-cell proliferation at higher concentrations (50 microm). Inhibition by CP was not the result of membrane pore formation or cytotoxicity when examined by trypan blue, propidium iodide staining or transmission electron microscopy. CP analogues, with both lysine and arginine replaced by neutral or negatively charged amino acids, or by randomly distributing charges in the peptide sequence, had no effect on lymphocyte function. These results suggest that peptide inhibition is affected by its structure and charge interactions, and may involve common signalling molecules in T, B and natural killer cells. The potential of the immuno-inhibitory effects of CP as a novel anti-inflammatory peptide in therapy should be further explored.     

Defensins impair phagocytic killing by neutrophils in biomaterial-related infection

The implantation of foreign material carries a risk of infection which frequently is resistant to all treatment short of removing the implant. We have previously shown that these materials activate neutrophils by contact, leading to production of oxygen free radicals accompanied by release of granule products. Such activation further results in depletion of local host defenses, including the capacity of biomaterial-activated neutrophils to kill bacteria. Among the granule products released from neutrophils are small cationic antibacterial peptides (human neutrophil peptides [HNP]) known as defensins. Here we tested the hypothesis that defensins, released from activated neutrophils onto the surface of biomaterials, might play a role in the deactivation of subsequent neutrophil populations. Incubation of neutrophils with purified HNP resulted in a dose-related impairment of stimulus-induced oxygen radical production and of phagocytic killing. Furthermore, fresh neutrophils added to biomaterial-associated neutrophils exhibited impaired phagocytic killing. This impairment could be abrogated by antibody to HNP but not by an irrelevant antibody. Taken together, these observations support the idea that neutrophils activated at a material surface can create, by means of HNP release, an environment hostile to their microbicidal function and that of their infiltrating brethren.