Bactericidal/permeability-increasing protein (BPI) and BPI homologs at mucosal sites

Canny, Gerard J.; Levy, Ofer

doi:10.1016/j.it.2008.07.012

Cited by 74 publications

(69 citation statements)

References 97 publications

(111 reference statements)

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“…34 Thus, one role of PF4 might also be to protect from endotoxic shock, as has been shown for ␤ 2 -glycoprotein I. 35 Lipid A also binds antimicrobial peptides, such as the bactericidal/permeability-increasing protein (BPI) 36,37 and the cyclic lipopeptide polymyxin B, which interacts with the phosphate groups of lipid A. [38][39][40][41][42] In line with our other findings, BPI and polymyxin B inhibited PF4 binding to isolated lipid A ( Figure 3B), further confirming that PF4 interacts with lipid A.…”

Section: Discussionmentioning

confidence: 97%

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Krauel

Weber

Brandt

et al. 2012

Blood

100

105

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The positively charged chemokine platelet factor 4 (PF4) forms immunogenic complexes with heparin and other polyanions. Resulting antibodies can induce the adverse drug effect heparin-induced thrombocytopenia. PF4 also binds to bacteria, thereby exposing the same neoantigen(s) as with heparin. In this study, we identified the negatively charged lipopolysaccharide (LPS) as the PF4 binding structure on Gram-negative bacteria. IntroductionBesides their pivotal role in hemostasis, platelets are involved in host defense against pathogens and in modulation of immune reactions. This function of platelets occurs either indirectly through their interaction with endothelial cells and leukocytes 1,2 or directly by secretion of antimicrobial substances from platelet storage granules and lysosomes. 3,4 Recently, we have shown that the chemokine platelet factor 4 (PF4), which is stored within platelet ␣-granules, plays a role in bacterial host defense by inducing a humoral immune response to PF4-coated bacteria. 5 During bacterial infections, platelets are activated 6,7 and release positively charged PF4, which can bind in a charge-dependent manner to the bacterial surface, thereby inducing neoepitopes. The formation of antigenic PF4 clusters is probably the result of neutralization of the positive charge of PF4 by polyanions, 8 which allows narrowing of the distance between single PF4 tetramers down to 3 to 5 nm. This creates linear, ridge-like complexes and exposes new antigenic epitopes on PF4. 9 Antibodies to PF4/polyanion complexes bind to PF4 on the bacterial surface, leading to opsonization and increased phagocytosis of PF4-coated bacteria. 5 As PF4 is capable of binding to a large variety of bacteria, the antibody response to PF4/polyanion complexes constitutes a very broad reactive defense mechanism and could represent an evolutionary interface between innate and specific immunity. Antibodies induced by PF4 clusters would be an example of antibodies with a limited target antigen repertoire that nevertheless could result in binding to a large variety of bacteria when these bacteria are coated with PF4. 5 In medicine, research on the immune reaction to PF4/polyanion complexes to date has primarily focused on its role in causing an adverse reaction to the anticoagulant heparin as PF4 forms immunogenic complexes with heparin on platelet surfaces. Anti-PF4/polyanion antibodies bind to these PF4/heparin complexcoated platelets and induce Fc-receptor-dependent platelet activation, 10,11 leading to intravascular consumption of platelets, associated potentiation of in vivo thrombin generation, and the prothrombotic syndrome, heparin-induced thrombocytopenia (HIT).We and others have recently demonstrated the prevalence of anti-PF4/heparin antibodies of the IgM class in up to 20% and of the IgG class in up to 6% of the general population and in a slightly lower number of normal blood donors. 5,12 These antibodies are highly significantly associated with periodontitis, one of the most prevalent human infections, often associate...

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Section: Discussionmentioning

confidence: 97%

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Krauel

Weber

Brandt

et al. 2012

Blood

100

105

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“…94,95 Although quite little is known about the function of the PLUNC proteins, it appears that they can bind to bacteria and LPS but do not exert direct killing. 96 Using an air-liquid interface culture system of human primary bronchial epithelial cells it was found that SPLUNC1 may be important in controlling Mycoplasma pneumoniae infection.…”

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confidence: 99%

Antimicrobial peptides: The ancient arm of the human immune system

Wiesner¹,

Vilcinskas²

2010

Virulence

599

559

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The production of peptides and small proteins with microbicidal activity collectively called antimicrobial peptides (AMPs) is commonly considered to be a primitive mechanism of immunity and has been extensively studied in insects and other non-vertebrate organisms. In addition, a variety of AMPs present in amphibian skin secretion has been well characterised. There is now increasing evidence that AMPs play a crucial role in human immunity as well. Virtually all human tissues and cells typically exposed to microbes are able to produce AMPs. Important AMPs belonging to two structurally distinct classes, known as the defensins and the cathelicidins, are mainly produced by epithelial cells and neutrophils. AMPs significantly contributing to the chemical skin barrier are represented by dermcidin, psoriasin and RNase 7. The antimicrobial activity of saliva largely depends on histidine-rich AMPs known as histatins. Many more, in part less well-known AMPs and AMP-like proteins exist that exhibit various additional functions, apart from their antimicrobial properties. Among them, the neutrophil granule proteins azurocidin and cathepsin G are members of a family of serine-protease homologues called serprocidins and play a role in the regulation of the immune response and degradation of extracellular matrix proteins respectively. As another AMP-like protein of the neutrophil granule content, bactericidal/permeability increasing protein (BPI) is both able to permeabilise bacterial membranes and to function as an opsonin. The whey acidic protein (WAP) domain containing class of AMPs, including secretory leukocyte protease inhibitor (SLPI), elafin and trappin-2, is equally important in inhibition of neutrophil serine proteases and killing of microbes. Certain CC or CXC chemokines are known to possess antimicrobial properties and therefore are called kinocidins. Several kinocidins, including thrombocidin-1 and -2, are contained in the ?-granules of platelets. A cytoplasmic AMP described as ubiquicidin turned out to be identical with the strongly basic ribosomal protein S30. Proteolytic cleavage of the histone protein H2A in the stomach gives rise to an AMP initially described as buforin I. Adrenomedullin is a hormone-like AMP exhibiting vasodilatory and hypotensive effects. Lysozyme is mainly known for its cell wall degrading activity, but is also capable of non-enzymatic killing of bacteria. An iron-binding protein present in milk and other secretions named lactoferrin was shown to possess antimicrobial and antiviral activity and has been implicated in protection against cancer. Clinical studies on the treatment of infectious diseases have been performed with artificial peptides derived from human lactoferrin, histatins and BPI in addition to porcine protegrins, frog magains and bovine indolicidin. Omiganan, representing an indolicidin derivative, has been demonstrated to be effective in the treatment of acne and catheter-related local infections and is currently considered to be the most promising AMP-based drug candidate

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“…BPI is primarily released from granules of neutrophils at inflammatory sites. The protein is highly antimicrobial against Gram-negative bacteria and acts antiinflammatorily by binding to lipopolysaccharide to neutralize it [154]. When SPLUNC1 was shown to bind lipopolysaccharide, its involvement in innate immunity was strengthened [155][156].…”

Section: Splunc1mentioning

confidence: 99%

Upper Airway Mucosal Inflammation : Proteomic Studies after Exposure to Irritants and Microbial Agents

Fornander¹

2015

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People are, in their daily lives, exposed to a number of airborne foreign compounds that do not normally affect the body. However, depending on the nature of these compounds, dose and duration of exposure, various airway symptoms may arise. Early symptoms are often manifested as upper airway mucosal inflammation which generates changes in protein composition in the airway lining fluid.This thesis aims at identifying, understanding mechanisms and characterizing protein alterations in the upper airway mucosa that can be used as potential new biomarkers for inflammation in the mucosa. The protein composition in the mucosa was studied by sampling of nasal lavage fluid that was further analyzed with a proteomic approach using two-dimensional gel electrophoresis and mass spectrometry. Additionally, by studying factors on site through environmental examination, health questionnaires and biological analyses, we have tried to understand the background to these protein alterations and their impact on health.Respiratory symptoms from the upper airways are common among people who are exposed to irritative and microbial agents. This thesis have focused on personnel in swimming pool facilities exposed to trichloramine, metal industry workers exposed to metalworking fluids, employees working in damp and moldy buildings and infants diagnosed with respiratory syncytial virus infection. The common denominator in these four studies is that the subjects experience upper airway mucosal inflammation, which is manifested as cough, rhinitis, phlegm etc. In the three occupational studies, the symptoms were work related. Notably, a high prevalence of perceived mucosal symptoms was shown despite the relatively low levels of airborne irritants revealed by the environmental examination. Protein profiling verified an ongoing inflammatory response by identification of several proteins that displayed altered levels. Interestingly, innate immune proteins dominated and four protein alterations occurred in most of the studies; SPLUNC1, protein S100A8 and S100A9 and alpha-1-antitrypsin. Similarly, these proteins were also found in nasal fluid from children with virus infection and in addition a truncated form of SPLUNC1 and two other S100 proteins (S100A7-like 2 and S100A16), not previously found in nasal secretion, were identified.Altogether, the results indicate the potential use of a proteomic approach for identifying new biomarkers for the upper respiratory tract at an early stage in the disease process after exposure to irritant and microbial agents. The results indicate an effect on the innate immunity system and the proteins; SPLUNC1, protein S100A8 and S100A9 and alpha-1-antitrypsin are especially promising new biomarkers. Moreover, further studies of these proteins may help us to understand the molecular mechanisms involved in irritant-induced airway inflammation. POPULÄRVETENSKAPLIG SAMMANFATTNING FÖRÄNDRAD PROTEINSAMMANSÄTTNING I DE ÖVRE LUFTVÄGARNA EFTER EXPONERING FÖR SLEMHINNEIRRITERANDE ÄMNENVarje dag utsätts vi för partikla...

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Bactericidal/permeability-increasing protein (BPI) and BPI homologs at mucosal sites

Cited by 74 publications

References 97 publications

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Platelet factor 4 binding to lipid A of Gram-negative bacteria exposes PF4/heparin-like epitopes

Antimicrobial peptides: The ancient arm of the human immune system

Upper Airway Mucosal Inflammation : Proteomic Studies after Exposure to Irritants and Microbial Agents

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