Hendrik Schultz

Publications of Hendrik Schultz

• The bactericidal/permeability-increasing protein (BPI) in infection and inflammatory disease.

  Authors: Hendrik Schultz, Jerrold P Weiss

  Clinica chimica acta; international journal of clinical chemistry. 10/2007; 384(1-2):12-23.

  Gram-negative bacteria (GNB) and their endotoxin present a constant environmental challenge. Endotoxins can potently signal mobilization of host defenses against invading GNB but also potentiallyGram-negative bacteria (GNB) and their endotoxin present a constant environmental challenge. Endotoxins can potently signal mobilization of host defenses against invading GNB but also potentially induce severe pathophysiology, necessitating controlled initiation and resolution of endotoxin-induced inflammation to maintain host integrity. The bactericidal/permeability-increasing protein (BPI) is a pluripotent protein expressed, in humans, mainly neutrophils. BPI exhibits strong antimicrobial activity against GNB and potent endotoxin-neutralizing activity. BPI mobilized with neutrophils in response to invading GNB can promote intracellular and extracellular bacterial killing, endotoxin neutralization and clearance, and delivery of GNB outer membrane antigens to dendritic cells. Tissue expression by dermal fibroblasts and epithelia could further amplify local levels of BPI and local interaction with GNB and endotoxin, helping to constrain local tissue infection and inflammation and prevent systemic infection and systemic inflammation. This review article focuses on the structural and functional properties of BPI with respect to its contribution to host defense during GNB infections and endotoxin-induced inflammation and the genesis of autoantibodies against BPI that can blunt BPI activity and potentially contribute to chronic inflammatory disease.

• A novel role for the bactericidal/permeability increasing protein in interactions of gram-negative bacterial outer membrane blebs with dendritic cells.

  Authors: Hendrik Schultz, Janet Hume, De Sheng Zhang, Theresa L Gioannini, Jerrold P Weiss

  Journal of immunology (Baltimore, Md. : 1950). 09/2007; 179(4):2477-84.

  The bactericidal/permeability-increasing protein (BPI) is thought to play an important role in killing and clearance of Gram-negative bacteria and the neutralization of endotoxin. A possible role forThe bactericidal/permeability-increasing protein (BPI) is thought to play an important role in killing and clearance of Gram-negative bacteria and the neutralization of endotoxin. A possible role for BPI in clearance of cell-free endotoxin has also been suggested based on studies with purified endotoxin aggregates and blood monocytes. Because the interaction of BPI with cell-free endotoxin, during infection, occurs mainly in tissue and most likely in the form of shed bacterial outer membrane vesicles ("blebs"), we examined the effect of BPI on interactions of metabolically labeled ([(14)C]-acetate) blebs purified from Neisseria meningitidis serogroup B with either human monocyte-derived macrophages or monocyte-derived dendritic cells (MDDC). BPI produced a dose-dependent increase (up to 3-fold) in delivery of (14)C-labeled blebs to MDDC, but not to monocyte-derived macrophages in the presence or absence of serum. Both, fluorescently labeled blebs and BPI were internalized by MDDC under these conditions. The closely related LPS-binding protein, in contrast to BPI, did not increase association of the blebs with MDDC. BPI-enhanced delivery of the blebs to MDDC did not increase cell activation but permitted CD14-dependent signaling by the blebs as measured by changes in MDDC morphology, surface expression of CD80, CD83, CD86, and MHC class II and secretion of IL-8, RANTES, and IP-10. These findings suggest a novel role of BPI in the interaction of bacterial outer membrane vesicles with dendritic cells that may help link innate immune recognition of endotoxin to Ag delivery and presentation.

• From infection to autoimmunity: a new model for induction of ANCA against the bactericidal/permeability increasing protein (BPI).

  Authors: Hendrik Schultz

  Autoimmunity reviews. 04/2007; 6(4):223-7.

  Antineutrophil cytoplasmic autoantibodies against the neutrophil granule bactericidal/permeability increasing protein (BPI-ANCA) have been found in diseases of different etiologies, such as cysticAntineutrophil cytoplasmic autoantibodies against the neutrophil granule bactericidal/permeability increasing protein (BPI-ANCA) have been found in diseases of different etiologies, such as cystic fibrosis, TAP deficiency or inflammatory bowel diseases. A common feature of these conditions is the chronic or profuse exposure of the host to Gram-negative bacteria and their endotoxin. BPI plays an important role in killing Gram-negative bacteria as well as neutralization and disposal of their endotoxin. During this interaction BPI can direct the delivery of complexes which contain endotoxin and bacterial outer membrane proteins to antigen presenting cells. Based on recent findings on how complexes of endotoxin and protein antigens need to be processed by dendritic cells in order to become presented on MHC class II molecules, a model can be proposed how Gram-negative bacterial infections can be linked to the generation of autoantibodies against BPI.

• [Somatoform vertigo: a guide for the general practitioner].

  Authors: Hendrik Schultz, Christoph Helmchen

  MMW Fortschritte der Medizin. 05/2006; Spec no. 2:42, 44-6, 48.

  The symptoms associated with somatoform vertigos take on many forms and often appear to be organic in origin. Only a complete medical history in connection with a clinical neurootological examinationThe symptoms associated with somatoform vertigos take on many forms and often appear to be organic in origin. Only a complete medical history in connection with a clinical neurootological examination and psychiatric/psychosomatic exploration can differentiate between organic (e.g., vestibular) and somatoform vertigos. The patients must be informed about this disorder so that the symptoms are taken seriously. Even though they cannot be ascribed to an organic impairment, the symptoms are still clinically significant. Somatoform vertigo is primarily treated with behavior therapy (if necessary, combined with supportive psychopharmacotherapy). Many patients have good prognosis, particularly when therapy is initiated early.

• Autoantibodies against the bactericidal/permeability-increasing protein from inflammatory bowel disease patients can impair the antibiotic activity of bactericidal/permeability-increasing protein.

  Authors: Susanne Schinke, Klaus Fellermann, Karen Herlyn, Philipp H Reichel, Rilana Fundke, Eduard F Stange, Wolfgang L Gross, Hendrik Schultz

  Inflammatory bowel diseases. 12/2004; 10(6):763-70.

  Bactericidal/permeability-increasing protein (BPI) is an antineutrophil cytoplasmic autoantibody (ANCA) target antigen in inflammatory bowel disease (IBD). The aim of this study was to characterizeBactericidal/permeability-increasing protein (BPI) is an antineutrophil cytoplasmic autoantibody (ANCA) target antigen in inflammatory bowel disease (IBD). The aim of this study was to characterize binding regions of BPI-autoantibodies and to analyze their ability to block the antibiotic effect of BPI. Sera of 24 ulcerative colitis and Crohn's disease patients were examined in indirect immuno-fluorescence, ANCA enzyme-linked immunosorbent assay (ELISA), and by epitope mapping with 13mer peptides and Western blot for presence of BPI-autoantibodies. IgG preparations were used to determine inhibition of BPI's antimicrobial function by BPI-autoantibodies in a bacterial growth inhibition assay. BPI-autoantibodies were detected by ELISA in 18/24 patients. Epitope mapping and western blotting revealed an additional 3 patients with BPI-autoantibodies. IgG preparations of all patients with Crohn's disease and 9 of 12 ulcerative colitis patients could inhibit the antibiotic function of BPI in vitro as compared with healthy control subjects. Inhibiting BPI-autoantibodies correlated with extraintestinal manifestations, peripheral blood leukocyte counts, and anemia. BPI-autoantibodies recognizing the N-terminal portion were associated with greater mucosal damage and intestinal extent of disease. BPI is a frequent target antigen of autoantibodies in ulcerative colitis and Crohn's disease. Inhibition of the antibiotic function mediated by the N-terminal region of BPI by these autoantibodies may contribute to a proinflammatory environment in IBD patients.

• BPI-ANCA of pediatric cystic fibrosis patients can impair BPI-mediated killing of E. coli DH5alpha in vitro.

  Authors: Hendrik Schultz, Susanne Schinke, Katharina Mosler, Karen Herlyn, Antje Schuster, Wolfgang L Gross

  Pediatric pulmonology. 03/2004; 37(2):158-64.

  Gram-negative bacterial lung infections and chronic bacterial colonization are major threats for pediatric cystic fibrosis (CF) patients. Besides impeded mucociliary clearance, other mechanisms thatGram-negative bacterial lung infections and chronic bacterial colonization are major threats for pediatric cystic fibrosis (CF) patients. Besides impeded mucociliary clearance, other mechanisms that contribute to increased susceptibility to infections are presumed. The bactericidal/permeability-increasing protein (BPI), which is delivered by neutrophil granulocytes and mucosal epithelial cells, is one of the most potent innate antibiotics against Gram-negative bacteria and endotoxin. Antineutrophil cytoplasmic autoantibodies against BPI (BPI-ANCA) have been found in up to 90% of CF patients, and titers correlated inversely with lung function parameters. As major pulmonary damage is mediated by Gram-negative bacteria and their products, the question was raised as to whether BPI-ANCA can inhibit the antibiotic function of BPI in these patients. Sera of 23 pediatric CF patients were analyzed for the presence of BPI-ANCA by indirect immunofluorescence, ELISA, epitope mapping, and Western blotting. Patients' IgG were tested in a bacterial growth inhibition assay with recombinant BPI (rBPI) and an amino-terminal fragment of BPI (rBPI(21)) that retains antibiotic activity for inhibition of the antibiotic function of BPI against E. coli DH5alpha in vitro. BPI was recognized by 21 of 23 patients' sera in our detection assays. Thirteen of 23 patients' BPI-ANCA (56%) could inhibit the antibiotic function in vitro. Moreover, epitope mapping over the whole BPI sequence revealed that more patients' BPI-ANCA recognize the amino-terminal part of BPI than can be detected by ELISA. Thus, in pediatric CF patients, BPI-ANCA may contribute to diminished bacterial clearance by inhibiting the antibiotic function of BPI.

• Bactericidal/permeability-increasing protein is expressed by human dermal fibroblasts and upregulated by interleukin 4.

  Authors: Philipp H Reichel, Christine Seemann, Elena Csernok, Jens-M Schröder, Antje Müller, Wolfgang L Gross, Hendrik Schultz

  Clinical and diagnostic laboratory immunology. 06/2003; 10(3):473-5.

  The bactericidal/permeability-increasing protein (BPI) is an antibiotic- and endotoxin-neutralizing protein of granulocytes and epithelial cells. Constitutive expression of BPI, which increases uponThe bactericidal/permeability-increasing protein (BPI) is an antibiotic- and endotoxin-neutralizing protein of granulocytes and epithelial cells. Constitutive expression of BPI, which increases upon interleukin 4 stimulation, by human dermal fibroblast was demonstrated, suggesting an important role of BPI in gram-negative bacterial clearance and a dampened response to endotoxin in the skin.

• From infection to autoimmunity: A new model for induction of ANCA against the bactericidal/permeability increasing protein (BPI)

  Authors: Hendrik Schultz

  Autoimmunity Reviews.

  Antineutrophil cytoplasmic autoantibodies against the neutrophil granule bactericidal/permeability increasing protein (BPI-ANCA) have been found in diseases of different etiologies, such as cysticAntineutrophil cytoplasmic autoantibodies against the neutrophil granule bactericidal/permeability increasing protein (BPI-ANCA) have been found in diseases of different etiologies, such as cystic fibrosis, TAP deficiency or inflammatory bowel diseases. A common feature of these conditions is the chronic or profuse exposure of the host to Gram-negative bacteria and their endotoxin. BPI plays an important role in killing Gram-negative bacteria as well as neutralization and disposal of their endotoxin. During this interaction BPI can direct the delivery of complexes which contain endotoxin and bacterial outer membrane proteins to antigen presenting cells. Based on recent findings on how complexes of endotoxin and protein antigens need to be processed by dendritic cells in order to become presented on MHC class II molecules, a model can be proposed how Gram-negative bacterial infections can be linked to the generation of autoantibodies against BPI.

• Use of native and recombinant bactericidal/permeability-increasing proteins (BPI) as antigens for detection of BPI-ANCA

  Authors: Hendrik Schultz, Elena Csernok, Thomas W Johnston, Christopher M Lockwood, Wolfgang L Gross

  Journal of Immunological Methods.

  Anti-neutrophil cytoplasmic antibodies (ANCA) against native bactericidal/permeability-increasing protein (nBPI) have gained increasing diagnostic significance in inflammatory bowel disease andAnti-neutrophil cytoplasmic antibodies (ANCA) against native bactericidal/permeability-increasing protein (nBPI) have gained increasing diagnostic significance in inflammatory bowel disease and cystic fibrosis. However, routine detection of BPI-ANCA requires pure antigen in large quantities. As nBPI is difficult to isolate and is very susceptible to proteolytic cleavage with subsequent epitope loss, it was the aim of this study to determine whether recombinant BPI (rBPI) can be used as an alternative to nBPI as target antigen for ANCA in diagnostic procedures. Therefore, 93 BPI-ELISA-positive sera and controls were compared in different ELISAs using nBPI, rBPI, unglycosylated rBPI and a 21-kDa amino-terminal fragment of rBPI. ELISA results were confirmed by immunoblotting and all sera were tested in indirect immunofluorescence (IFT). There was an 88% (82/93) agreement in recognition of nBPI and rBPI by ANCA in both ELISA systems, yet the quantitation of BPI-ANCA in relative units showed a less optimal result and correlated only by 45% (p<0.01). Most sera recognized nBPI, rBPI and unglycosylated rBPI equally suggesting that glycosylation has no influence on antigen recognition. Only two sera were positive for the 21-kDa nBPI indicating that the binding sites for ANCA are either conformational epitopes and/or are located mainly on the carboxy-terminal part of the BPI molecule. Most BPI-ELISA-positive sera were negative in IFT (43%), but a perinuclear (pANCA, 30%), a cytoplasmic (cANCA,10%) or an atypical ANCA (aANCA, 2%) staining pattern, as well as a cytoplasmic pattern only on formaldehyde-fixed granulocytes (13%) were also observed. Overall, no characteristic pattern was seen for BPI-ELISA-positive sera in IFT. Taken together, these data suggest that rBPI offers an excellent alternative to nBPI for broad-based BPI-ANCA ELISA and will be of great value in further investigations of BPI-ANCA interactions.