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(Journal of Leukocyte Biology. 2001;69:505-512.)
© 2001 by Society for Leukocyte Biology

The endotoxin-binding bactericidal/permeability-increasing protein (BPI): a target antigen of autoantibodies

H. Schultz*, J. Weiss{dagger}, S. F. Carroll{ddagger} and W. L. Gross*

* Department of Rheumatology, University of Lübeck, Rheumaklinik Bad Bramstedt GmbH, Bad Bramstedt, Germany;
{dagger} Deparment of Internal Medicine, Division of Infectious Diseases, University of Iowa, Iowa City, Iowa, and Iowa City VAMC, Iowa City, Iowa; and
{ddagger} XOMA (US) LLC, Preclinical Research, Berkeley, California

Correspondence: H. Schultz, Department of Rheumatology, University of Lübeck, Rheumaklinik Bad Bramstedt GmbH, P.O. Box 1448, D-24572 Bad Bramstedt, Germany. E-mail: HSchultzMD{at}aol.com


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 BPI: STRUCTURE AND FUNCTION
 CLINICAL TRIALS WITH RECOMBINANT...
 ANCA AGAINST BPI (BPI-ANCA)
 FUTURE DIRECTIONS
 REFERENCES
 
The bactericidal/permeability-increasing protein (BPI) is an endotoxin-binding neutrophil leukocyte-granule protein with antibacterial and anti-endotoxin properties. A recombinant form of BPI (rBPI21) has been developed and is being tested as a therapeutic agent to treat Gram-negative bacterial infections and exposure to Gram-negative bacterial endotoxin. BPI is also a target antigen of anti-neutrophil cytoplasmic autoantibodies (ANCA). BPI-ANCA are present in cystic fibrosis, inflammatory bowel disease, vasculitis, and primary sclerosing cholangitis; presence of BPI-ANCA appears associated with a higher inflammatory disease activity and greater organ damage. BPI-ANCA as well as ANCA directed at other neutrophil-granule proteins may exacerbate inflammation by nonspecific effects of extracellular and cell-associated immune complexes. BPI-ANCA may further worsen inflammation by reducing the ability of BPI to promote clearance of Gram-negative bacteria and bacterial-associated endotoxin.

Key Words: anti-neutrophil cytoplasmic autoantibodies • neutrophil granule proteins • Gram-negative bacteria • lipopolysaccharides


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
BPI: STRUCTURE AND FUNCTION
 CLINICAL TRIALS WITH RECOMBINANT...
 ANCA AGAINST BPI (BPI-ANCA)
 FUTURE DIRECTIONS
 REFERENCES
 
Endotoxins of Gram-negative bacteria are structurally unique glycolipids (e.g., lipopolysaccharides, LPS) that can induce potent pathophysiological effects in a wide range of host species including humans [1 , 2 ]. Endotoxins cause a rapid release of proinflammatory cytokines like tumor necrosis factor {alpha} (TNF-{alpha}), interleukin 1 (IL-1), and interferon {gamma} (IFN-{gamma}) and rapidly activate complement, clotting, and fibrinolytic pathways. These effects promote essential host-defence responses to Gram-negative bacterial infections but can also lead to a variety of pathological responses ranging from fever and chills to the fulminant sepsis syndrome with multi-organ failure and high lethality in uncontrolled infections [1 ]. In addition, endotoxins may contribute to the inflammatory sequelae of Gram-negative infections such as reactive arthritis and are thought to trigger flares of vasculitis and collagen vascular diseases [3 , 4 ]. Although there are many antibiotics available for the treatment of infections caused by Gram-negative bacteria, there is not yet a satisfactory therapeutic solution to endotoxin-triggered systemic inflammation. Possible treatment strategies against endotoxin-mediated inflammation that have been investigated are mostly aimed toward blocking crucial pathways of the inflammatory response by clearing endotoxin or by blocking the downstream proinflammatory cytokines such as TNF-{alpha} and IL-1 as the principal mediators of the inflammatory response [2 ].

A promising new approach to solve this problem is offered by innate immunity itself. Proteins of the granules of neutrophil granulocytes play a crucial role in first-line defence against infectious agents and their products. In addition to their well-known, anti-microbial functions, some also possess anti-inflammatory properties [5 6 7 ]. The bactericidal/permeability-increasing protein (BPI) is a neutrophil-granule protein that exhibits strong anti-microbial activity against Gram-negative bacteria and potently neutralizes the endotoxic activity of purified and bacterial envelope-associated LPS [8 ]. These properties and the availability of bioactive recombinant protein derivatives (such as rBPI21, a recombinant product derived from the N-terminal domain of human BPI) have triggered development of BPI for testing in clinical trials. However, other neutrophil proteins like proteinase 3 (PR3) and myeloperoxidase (MPO) are known target antigens of anti-neutrophil cytoplasmatic autoantibodies (ANCA). PR3-ANCA and MPO-ANCA are seromarkers of systemic vasculitides such as Wegener’s granulomatosis, microscopic polyangiitis, or Churg-Strauss syndrome [9 ]. Recently, BPI was identified as another target antigen of ANCA in vasculitis [10 ]. This review article focuses on the prevalence and clinical associations of BPI-ANCA and discusses findings that suggest possible pathophysiological properties of these autoantibodies.


   BPI: STRUCTURE AND FUNCTION
TOP
 ABSTRACT
 INTRODUCTION
 BPI: STRUCTURE AND FUNCTION
CLINICAL TRIALS WITH RECOMBINANT...
 ANCA AGAINST BPI (BPI-ANCA)
 FUTURE DIRECTIONS
 REFERENCES
 
The BPI is a single-chain cationic protein with a molecular weight of ca. 55 kD that is found mainly in the granules of neutrophils and, to a lesser extent, in eosinophils [8 , 11 ]. Additionally, BPI has been found on the surface of monocytes and colon epithelium, possibly secondary to secretion from activated neutrophils [12 , 13 ]. BPI belongs to a family of lipid-transfer proteins that includes the LPS-binding protein (LBP), with which BPI shares a 45% sequence homology [14 15 16 ]. The crystal structure of human BPI revealed a boomerang-like shape and two similar domains with apolar pockets on their concave side where phospholipids (or perhaps LPS) can be bound [17 ]. Initial electrostatic interactions between BPI and endotoxin likely involve multiple cationic residues concentrated at the extreme end of the N-terminal domain.

BPI is the most potent anti-microbial-granule protein identified so far and is especially effective against Gram-negative bacteria [8 , 18 19 20 ]. The antibiotic effect of BPI on Gram-negative bacteria takes place in two stages: a first potentially reversible, sublethal stage, where BPI selectively perturbs the outer membrane, and a second irreversible lethal stage, where BPI-mediated damage extends to the inner cytoplasmic membrane and disrupts energy-generating and -dependent biochemical machinery [21 ]. In addition to these anti-microbial effects, BPI may play a key role in limiting endotoxin-triggered systemic inflammation by binding with high affinity to the lipid A portion of LPS [22 ]. BPI competes with LBP for the binding of endotoxin, but BPI-LPS complexes (in contrast to LBP and LPS) do not activate macrophages and other endotoxin-responsive host cells [23 , 24 ].

BPI can act within neutrophils during phagocytosis and also in cell-free inflammatory fluid of neutrophil-rich exsudates (e.g., in peritonitis), where BPI is found in functionally significant concentrations (>=10 nM) [25 , 26 ]. Whereas LPS and bacterial binding, antibacterial cytotoxicity, and endotoxin neutralization are mediated by the N-terminal domain of BPI, opsonic effects of BPI depend on the C-terminal domain of the protein [18 , 20 , 27 28 29 30 31 ] (see Fig. 1 ). These observations led to the development of rBPI21, which consists of the first 193 N-terminal amino acids of BPI with the cysteine at position 132 replaced by alanine. This recombinant protein has been expressed in Chinese hamster ovary K1 cells and purified by ion-exchange chromatography [22 ].



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  		Figure 1. Correlation of structure and function of BPI. GNB = Gram-negative bacteria.

 

   CLINICAL TRIALS WITH RECOMBINANT BPI
TOP
 ABSTRACT
 INTRODUCTION
 BPI: STRUCTURE AND FUNCTION
 CLINICAL TRIALS WITH RECOMBINANT...
ANCA AGAINST BPI (BPI-ANCA)
 FUTURE DIRECTIONS
 REFERENCES
 
In a variety of animal models, rBPI21 was protective against lethal and sublethal challenges with Gram-negative bacteria or LPS [32 33 34 ]. In a pilot study in eight healthy human volunteers exposed to a single dose of Escherichia coli LPS, rBPI21 not only reduced circulating endotoxin levels but also reduced LPS-triggered mobilization of TNF-{alpha}, IL-6, IL-8, and IL-10 significantly and reduced depletion of circulating neutrophils [35 ]. A randomized, double-blinded, placebo-controlled, multi-center, phase I study in healthy males (n=67) demonstrated safety of rBPI21 administration without development of an antibody response [36 ]. Moreover, reduced mortality in 26 pediatric patients with meningococcal sepsis treated with rBPI21 was observed in an open-labeled, dose-escalating, phase I/II trial when compared with historical standards [37 ]. A subsequent, randomized, placebo-controlled, multi-center, phase I study in 396 patients with meningicoccal sepsis showed in the rBPI21-treated group a reduction in severe amputations and achieved a return to function similar to that before illness. Mortality was also reduced in the rBPI21-treated group (7.4% vs. 9.9% in the placebo-controlled group), but the study was under-powered for detection of statistically significant differences in mortality [38 ]. A controlled, phase I/II, multi-center trial of rBPI21 treatment following hemorrhagic trauma in 401 patients demonstrated significant protection against pulmonary complications and a favorable trend in reducing at least one organ dysfunction, but these findings were not reproduced in a subsequent, truncated, phase III trial [39 ]. In these patients, bacterial translocation from the gastrointestinal system may contribute to infection and organ failure. Recombinant BPI21 appears to be safe in humans and, within appropriate clinical settings, may be highly effective against Gram-negative bacteria and their endotoxins. Thus far, no antibodies have been observed after exposure of humans to rBPI21 [35 36 37 38 39 40 ].


   ANCA AGAINST BPI (BPI-ANCA)
TOP
 ABSTRACT
 INTRODUCTION
 BPI: STRUCTURE AND FUNCTION
 CLINICAL TRIALS WITH RECOMBINANT...
 ANCA AGAINST BPI (BPI-ANCA)
FUTURE DIRECTIONS
 REFERENCES
 
(1) Immunodiagnostic aspects
ANCA are hallmarks in the diagnostic work-up of patients with systemic vasculitides. Indirect immunofluorescence (IIF) is the standard ANCA screening assay. Different fluorescence patterns can be distinguished, including a fine, granular, cytoplasmic (cANCA)-, perinuclear (pANCA)-, or diffuse (aANCA)-staining pattern. At present, the immunodiagnostic significance of ANCA detection has been demonstrated for only a small group of ANCA subspecificities such as cANCA/PR3-ANCA for Wegener’s granulomatosis and pANCA/MPO-ANCA for microscopic polyangiitis [9 ].

Although BPI has been known as a constitutent of polymorphonuclear leukocyte (PMN) granules for many years, it was only recently that BPI was identified as a target antigen of ANCA [10 ]. Normal, healthy donors do not contain detectable BPI autoantibodies [41 ]. The presence of anti-BPI autoantibodies was first detected in patients with the ANCA-associated vasculitides (Wegener’s granulomatosis, microscopic polyarteritis, and Churg-Strauss syndrome), which showed a cANCA or pANCA in IIF but without a defined target antigen (e.g., not PR3 or MPO) when tested by enzyme-linked immunosorbent assay (ELISA). BPI-ANCA was documented by ELISA first in sera of double-negative [PR3-ANCA(-)/MPO-ANCA(-)] vasculitis patients. The frequency of BPI-ANCA-positive sera shown for these patients has varied markedly (7% vs. 45%) in different studies. The basis of these differences remains uncertain [10 , 41 , 42 ]. It is also unknown whether the clinical characteristics (e.g., disease activity) of vasculitis patients with and without BPI-ANCA differ.

BPI-ANCA have also been detected in many other inflammatory disorders without vasculitis (Table 1 ). Most striking is the prevalence of BPI-ANCA in patients with cystic fibrosis (CF). In studies comprising 27–148 patients, BPI-ANCA have been found in up to 91% of the tested patients [44 , 49 50 51 52 ], including in children as early as 5 months of age, in that case preceding signs of clinical disease and indicating that development of BPI-ANCA could be an early event. Other ANCA, such as lactoferrin (LF)-ANCA, cathepsin G (CG)-ANCA, or PR3-ANCA, have also been found in CF patients but much less frequently [44 , 49 50 51 52 ].


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  		Table 1. Prevalence and Clinical Association of ANCA Against the Bactericidal/Permeability-Increasing Protein (BPI)

 
Among the other settings in which BPI-ANCA have been detected, patients with diffuse panbronchiolitis and bronchectasis as a result of chronic airway infection with Gram-negative bacteria [59 , 65 ] also contain BPI-ANCA frequently. However, the number of these patients who have been analyzed is much more limited. Other clinical settings associated with BPI-ANCA include inflammatory glomerular disease [e.g., pauci-immune necrotizing and crescentic glomerulonephritis (NCGN); ref. 43 ], chronic inflammatory bowel diseases (e.g., ulcerative colitis, Crohn’s disease) [41 , 44 45 46 47 ], infectious enteritis [45 ], and primary sclerosing cholangitis [41 , 48 ]. Approximately 20–40% of these patients contain BPI-ANCA, which have also been observed, although maybe less frequently, in rheumatic diseases such as spondylarthropathies, rheumatoid arthritis, and collagen vascular disease [41 , 44 , 54 55 56 ] (Table 1) . There have been case studies of BPI-ANCA in minocycline- and carbimazole-induced autoimmune phenomena and Behcet’s disease as well as in bronchiectasis and Pseudomonas infection in an individual with {alpha}-1-anti-trypsin deficiency [61 62 63 64 ]. It has been suggested that active proteinases within the lung of patients with {alpha}-1-anti-trypsin deficiency could generate antigenic BPI fragments lacking the antibacterial and anti-endotoxic properties of native BPI and thus contribute to increased susceptibility to local infection and inflammation and mobilization of BPI-ANCA. However, results from testing additional individuals with {alpha}-1-anti-trypsin deficiency do not suggest an association of this disorder with BPI-ANCA [44 ]. In patients with sepsis, a possible target population for rBPI21 therapy, BPI-ANCA were detected in only 1 of 15 patients; this patient had acute myeloid leukemia as the underlying disease and, thus, possibly abnormally high levels of extracellular BPI [60 ] that could be available for uptake, proteolysis, and processing by antigen-presenting cells and override normal tolerance.

The extent to which the presence of BPI-ANCA is associated with the appearance of other ANCA with different antigenic specificities has not been studied systematically, but the coincidence of BPI-ANCA with PR3-ANCA, LF-ANCA, CG-ANCA, and elastase (HLE)-ANCA has been demonstrated [50 , 52 , 57 ].

However, in certain clinical settings (e.g., CF), BPI-ANCA appear to be the predominant ANCA generated, whereas in other diseases (e.g., ANCA-associated vasculitides), other ANCA such as PR3- and MPO-directed autoantibodies are more common. In general, the data suggest that BPI-ANCA are found, most likely, in clinical settings in which unusually profuse and/or prolonged exposure to Gram-negative bacteria and endotoxin has occurred, leading to extensive mobilization and activation of PMN, secretion of BPI, and formation of extracellular BPI-endotoxin complexes. The apparent prevalence of BPI-ANCA in patients with autoimmune hepatitis that may have diminished capacity to clear endotoxin and reactive arthritis because of Salmonella and Yersinia infection [53 , 57 , 58 ] (Table 1) , disease settings not typically associated with ANCA, further supports such an association.

In summary, these findings document the presence of BPI-ANCA clearly in a broad array of inflammatory disorders and show a striking prominence of these autoantibodies in patients with CF and perhaps others with chronic airway infection. However, these data do not permit, as yet, a precise assessment of the prevalence of BPI-ANCA in different clinical settings. Controlled prospective studies of larger groups of patients will be needed to better define the extent to which BPI-ANCA are associated with these conditions and whether the prevalence and titers of BPI-ANCA correlate with the duration and/or severity of these diseases.

Typically, routine screening of sera of patients for ANCA has relied on IIF with a detectable pattern of fluorescence required before proceeding with further assays (e.g., ELISA) to determine the antigens recognized by ANCA. However, a high percentage of BPI-ANCA-positive sera has been found in patients with negative results by IIF. In patients with diseases known to be associated with ANCA, up to 43% of BPI-ANCA-positive sera were ANCA-negative when screened by IIF. More dramatically, up to 100% of BPI-ANCA-positive sera were ANCA-negative when screened by IIF in disease settings not previously known to be associated with ANCA [10 , 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 ]. Whether the difference in detection of BPI-ANCA by IIF versus ELISA simply reflects greater sensitivity of the latter assay or more subtle factors is not known. The fact that cells must be permeabilized to assay IIF may cause reduced sensitivity by diffusion of the antigen as suggested by the variable IIF-staining pattern for BPI-ANCA that has been shown [43 ]. It is likely that the BPI-ANCA-binding sites, like the binding sites of PR3, are conformational epitopes. The immunoreactivity of these epitopes is influenced strongly even by minor degradation. If neutrophils are fixated by ethanol, a release of all granule protein occurs simultaneously, because of permeabilization, so that proteolytic enzymes affect BPI epitopes easily. This gives a good explanation for the negative findings of BPI-ANCA-positive sera in IIF [42 , 44 ]. The exclusion of IIF-negative sera from further analysis in many studies undoubtedly has led to an underestimation of the prevalence of BPI-ANCA.

Greater efforts are also needed to ensure that the sensitivity and specificity of assays (e.g., ELISA) used for detection of BPI-ANCA in different laboratories are comparable. Recent evidence of variability in PR3- and MPO-ANCA ELISA kits [67 ] underscores this concern. The common practice of heating (56°C) sera before use to inactivate viruses and complement may need to be avoided, because this manipulation has been shown, in an as yet unexplained way, to yield "false positive" results with sera from healthy donors [66 ]. It is discussed that natural autoantibodies that function as scavenger molecules are responsible for this phenomenon. We believe that a more complete and reliable assessment of BPI-ANCA requires testing sera from patients with ANCA-associated diseases for BPI-ANCA regardless of IIF results and standardization of BPI-ANCA ELISA protocols to minimize procedural differences. A prospective multi-center study to determine prevalence, prognostic, and immunodiagnostic value of BPI-ANCA should be started, as was done for PR3-ANCA and MPO-ANCA [68 ].

In the case of ANCA-associated vasculitides, the presence of cANCA in IIF and PR3-ANCA by ELISA is highly sensitive and specific for the diagnosis of Wegener’s granulomatosis [9 ]. For the reasons described above, it is not yet possible to assess the likely immunodiagnostic significance of BPI-ANCA in most settings in which it has been detected. Perhaps an exception is in inflammatory glomerular diseases where, of nearly 400 patients studied, 20–30% contain BPI-ANCA [43 ]. No association of BPI-ANCA with a particular type of renal injury was apparent. In contrast, in patients with inflammatory bowel disease, primary sclerosing cholangitis, and CF, which are BPI-ANCA-positive, a higher inflammatory activity and greater organ damage are generally seen [44 45 46 47 48 49 50 51 52 , 59 , 65 ]. In addition, in CF, BPI-ANCA titers were related inversely to lung function and chest radiograph score and highest in patients colonized by Pseudomonas [49 , 51 ]. However, all these studies suffer from the small numbers of patients analyzed, making comparison of disease activity, time of testing, or associated conditions (e.g., infection) problematic. Prospective longitudinal studies with defined patient groups are needed for more comprehensive evaluation. In diseases not associated with ANCA (such as leukocytoclastic cutaneous vasculits or bronchectasis with Pseudomonas infection), only single patients with BPI-ANCA have been shown [61 , 64 ]. Yet, there seem to be common features shared by individuals with BPI-ANCA: CF, IBD, PSC, and also in {alpha}-1-anti-trypsin deficiency with bronchiectasis and Pseudomonas infection includes a setting where exposure to Gram-negative bacteria and cell-free LPS is appreciable and sometimes chronic (e.g., CF). In these conditions, a neutrophil-rich inflammatory response can be observed that is likely associated with extracellular mobilization of BPI and subsequent formation of BPI-LPS complexes. Recent observations suggest that BPI-LPS complexes are targeted to monocytes playing an important role in antigen presentation (unpublished results). Thus, it can be hypothesized that BPI-LPS complexes or degraded neutrophils, after being delivered to monocytes [69 ], are processed, and BPI domains—as well as other granule-protein domains—may be presented on the cell surface giving way to the generation of BPI autoantibodies. Given the apparent association with Gram-negative bacterial infections, the possibility that BPI-ANCA represent, at least in part, cross-reactive antibodies induced by bacterial LPS-binding proteins should also be considered [70 , 71 ].

(2) Immunopathological aspects
Because most patients with high levels of ANCA have inflammatory disorders that require immunosuppression, they may be prone particularly to infection. As BPI may be an important endogenous inhibitor of Gram-negative bacteria- and endotoxin-triggered inflammation, BPI-ANCA could exacerbate inflammation and contribute to pathological events leading to organ damage. Possible pathophysiological mechanisms of ANCA can be divided into two categories: those mediated potentially by essentially all ANCA and those that reflect the more specific properties of individual ANCA and the antigen to which a given ANCA is directed (see Table 2 ). One common effect of all ANCA could be activation of PMN. Mobilization of PMN to inflammatory sites is associated with release of some of the granule contents of the cell into the extracellular medium or onto the surface of degranulating and neighboring cells. Reaction of autoantibodies with extracellular granule proteins to form immune complexes or with all surface-associated antigens can lead directly to cell activation [72 ]. Simultaneous binding of an ANCA to surface-associated granule proteins and Fc receptor results in production of reactive oxygen species (ROS) and release of granule content and proinflammatory cytokines such as TNF-{alpha}, IL-1, or IL-6 in blood vessels and tissue and could be shown for anti-BPI mAbs [52 , 73 74 75 76 77 ]. Apoptotic neutrophils may also expose their granule contents on the cell surface where they can react with ANCA. In contrast to the fate of apoptotic cells in the absence of ANCA, phagocytosis of antibody-coated apoptotic neutrophils leads to significant release of TNF-{alpha} from macrophages, as was shown for anti-phospholipid antibodies [78 79 80 81 ]. Thus, in CF, the high levels of apoptotic PMN and BPI-ANCA present in the lung could exacerbate lung inflammation further, leading to more neutrophil influx, activation, and apoptosis as well as BPI secretion and degration and induction of further BPI-ANCA production.


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  		Table 2. Possible Pathophysiological Mechanisms of BPI-ANCA

 
A potentially important additional and specific property of BPI-ANCA could be inhibition of the antibiotic and anti-endotoxin activities of BPI and, as a result, the reduction of normal, host-defense responses to Gram-negative bacteria and endotoxin. Goat-anti-BPI serum and murine monoclonals P1G8 and 4E3 can inhibit the anti-microbial effects and LPS-binding of BPI [25 , 82 , 83 ]. Almost all BPI-ANCA from patients with various diseases recognize epitopes located on the C-terminal part of the BPI molecule in ELISA, with only a small percentage of BPI-ANCA recognizing the N-terminal domain of BPI [41 , 42 , 51 , 87 ]. These properties might suggest that BPI-ANCA are not likely to inhibit BPI binding to Gram-negative bacteria and LPS, antibacterial activity, or endotoxin neutralization, actions mediated by the N-terminal domain of BPI. However, in the holoprotein, sites comprising and surrounding the two lipid-binding clefts of BPI include residues from the N-terminal and C-terminal domains. Thus, it is possible that autoantibodies directed at the C-terminal domain could interfere with functional interactions dependent on the N-terminal domain. Moreover, recent data suggest that BPI-dependent clearance of Gram-negative bacteria and endotoxin depends also on the C-terminal domain of BPI [28 ]. Purified, human BPI-ANCA that recognize the C-terminal domain can inhibit phagocytosis of E. coli by neutrophils in vitro [51 ]. More studies are needed to better characterize the epitopes recognized by human BPI-ANCA and the effects of these antibodies on the antibiotic and anti-endotoxin functions of BPI.


   FUTURE DIRECTIONS
TOP
 ABSTRACT
 INTRODUCTION
 BPI: STRUCTURE AND FUNCTION
 CLINICAL TRIALS WITH RECOMBINANT...
 ANCA AGAINST BPI (BPI-ANCA)
 FUTURE DIRECTIONS
REFERENCES
 
New insights in the structure and molecular mechanisms of the interaction between BPI and Gram-negative bacteria and endotoxin offer a variety of starting points for future research to assess a possible pathophysiological role of BPI-ANCA. Beside conventional epitope-mapping, co-crystallization of recombinant BPI [17 ] with monoclonal BPI-ANCA obtained from animals and humans would not only identify conformational epitopes but might also help to clarify the role of BPI-ANCA binding to these epitopes for BPI function. Furthermore, in vitro models [20 , 85 , 86 ] make it possible to investigate the effects of human BPI-ANCA on BPI function (e.g., outer membrane permeabilization, anti-microbial activity, endotoxin neutralization, etc.). In addition, recent experiments on differences in size and sedimentation rate between BPI/LPS and LBP/LPS complexes [84 ] open the way to examine the impact of BPI-ANCA on modifying the biophysical qualities of BPI/LPS complexes and on availability of LPS to evoke biologic effects. It remains to be determined further how BPI-ANCA may influence the BPI-mediated phagocytosis of different GNB in vitro and in vivo and if they have an effect on the disposal of Gram-negative bacteria and endotoxin by macrophages and thus on inflammation [26 , 51 , 87 ]. Finally, a novel biologic activity of BPI has been demonstrated recently [88 ]: Native BPI inhibits angiogenesis by inducing apoptosis in endothelial cells. It remains to be determined which part of the molecule is responsible for this effect and if BPI-ANCA can influence it. It is important that so far BPI-ANCA does not appear to interfere with the activity of rBPI21, a recombinant derivative of BPI being tested clinically.

In summary, BPI is a granule protein outstanding for its antibiotic and endotoxin-neutralizing effects. It is a target antigen of ANCA, apparently most prevalent in inflammatory disorders associated with Gram-negative bacteria and cell-free LPS. Future studies on the generation and biologic properties of BPI-ANCA and their interaction with BPI during exposure to Gram-negative bacteria and endotoxin might yield insight into how antibodies against mediators of innate immunity may contribute to the development and course of autoimmune disease.


   ACKNOWLEDGEMENTS
 
This work is dedicated to the late C. M. Lockwood, who contributed essentially to the discussion on the pathophysiologic role of BPI-ANCA.

Received August 28, 2000; revised December 27, 2000; accepted January 5, 2001.


   REFERENCES
TOP
 ABSTRACT
 INTRODUCTION
 BPI: STRUCTURE AND FUNCTION
 CLINICAL TRIALS WITH RECOMBINANT...
 ANCA AGAINST BPI (BPI-ANCA)
 FUTURE DIRECTIONS
 REFERENCES
 

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