[What opportunities are afforded by enzyme replacement therapy].
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Enzymes↗
Biomedical subjects
H I Huppertz
Publications and source records attributed to H I Huppertz.
The German etanercept registry for treatment of juvenile idiopathic arthritis.
OBJECTIVE: To describe a registry set up to monitor children treated with etanercept in Germany and Austria. METHODS: Giannini's criteria, duration of morning stiffness, number of swollen, tender and contracted joints, adverse events, and reasons for discontinuation were assessed. RESULTS: 322 patients with juvenile idiopathic arthritis (JIA) and 12 additional patients with non-JIA rheumatic diagnoses were included. Therapeutic efficacy was observed from one month after treatment was started. The number of patients with significant improvement and the degree of improvement increased during the first year. The mean (SD) number of tender and swollen joints decreased from 9 (9) and 8.4 (9) to 3.0 (6.5) and 4.5 (7) after one month, and to 2.2 (5.5) and 3.3 (5.5) after three months; morning stiffness decreased from 45 (65) minutes to 12 (30) and 7 (19) after one and three months (p<0.001 for all). Using Gianinni's criteria of 30%, 50%, and 70% improvement, a therapeutic response in JIA patients was achieved in, respectively, 66%, 54%, and 30% after one month, 78%, 61%, and 38% after three months, and 83%, 72%, and 52% after six months. Therapeutic efficacy was lower in patients with systemic onset arthritis. Overall tolerability was good: in 592 patient treatment-years there were 69 reports of adverse events in 56 patients, including one CNS demyelination. There were no opportunistic infections or lupus-like reactions. Treatment was discontinued in 53 JIA patients, in 25 because of lack of efficacy. CONCLUSION: Etanercept treatment was safe and led to a significant improvement in most JIA patients resistant to conventional treatment.
Adrenal Cortex Hormones↗
Differential stimulation of helper and cytotoxic T cells by dendritic cells after infection by Yersinia enterocolitica in vitro.
Dendritic cells (DC) are antigen-presenting cells crucial for initiating immune responses like sensitization of T cells to foreign antigens. We have previously shown that infection of DC by enteropathogenic Yersinia enterocolitica in vitro leads to a transient suppression in the immunostimulatory capacity for autologous enriched total T cells. In this study, we found that killed Yersinia could replace live bacteria in this aspect, and that yersinial lipopolysaccharide (LPS)-antigen could be detected intracellularly over a time course of 8 days. A suppressive effect on T cell proliferation after stimulation with Yersinia-infected compared to uninfected DC was seen for CD4+ T cells isolated by immunomagnetic separation techniques over the whole time course of 8 days, whereas CD8+ T cells followed to exhibit a suppressed proliferation rate starting on day 5 post infection till the end of the time course. In contrast, enriched total T cells stimulated by Yersinia-infected DC showed weaker proliferation till day 6 post infection compared to stimulation by uninfected DC, but not thereafter. Mixing of purified CD4+ and CD8+ T cells at day 8 post infection could reconstitute the effect seen for enriched total T cells. Thus, helper in concert with cytotoxic T cells might contribute to the immune responses, that are necessary for control of Yersinia-infections.
Antigen Presentation↗
Lyme disease in children.
Lyme borreliosis is a multisystem disorder caused by Borrelia burgdorferi and transmitted by ticks in the northern hemisphere. The disease is common in children. In addition to frequently recognized manifestations such as erythema migrans, neuroborreliosis, and Lyme arthritis, rarer manifestations, including eye and ear disease, are increasingly understood. Clinical diagnosis is supported by serologic confirmation. Improvement of laboratory methodology, especially polymerase chain reaction-based tests, is continuing. Actual treatment recommendations based on controlled studies reflect expanding scientific knowledge. In the United States, license of a vaccine to prevent infection in children is awaited. Lyme borreliosis is an intriguing human example of bacterial persistence in the presence of the host immune system. Chronic Lyme arthritis is a model of chronic arthritis resembling forms of arthritis of unknown cause, such as rheumatoid arthritis and juvenile idiopathic arthritis.
Adolescent↗
Infection of synovial fibroblasts in culture by Yersinia enterocolitica and Salmonella enterica serovar Enteritidis: ultrastructural investigation with respect to the pathogenesis of reactive arthritis.
Synovial fibroblasts were infected with Yersinia enterocolitica or Salmonella enterica serovar Enteritidis and analyzed by electron microscopy and fluorescence in situ hybridization. Intracellular bacterial replication was followed by degradation leading to "ghosts" possessing lipopolysaccharides but not DNA. However, single bacteria survived for more than 2 weeks. Therefore, transient intra-articular infection might be the missing link between initial intestinal infection and late synovial inflammation in the pathogenesis of reactive arthritis.
Arthritis, Reactive↗
[Arsenal against juvenile rheumatoid arthritis. Preventing permanent damage].
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Anti-Inflammatory Agents↗
Infection of dendritic cells by enterobacteriaceae.
Dendritic cells (DC) are potent antigen-presenting cells that play a crucial role in initiation and modulation of specific immune responses. Various pathogens like viruses or bacteria are able to persist inside DC. In this study we investigated the ability of the Gram-negative bacteria Salmonella typhimurium and Escherichia coli to infect DC. DC isolated from peripheral blood of healthy donors were infected with wild-type S. typhimurium and a nonpathogenic E. coli stool isolate. Association of bacteria with DC was assessed by labeling of the bacteria with green fluorescent protein. Both Gram-negative bacteria were associated with DC as evidenced by microscopy and flow cytometry. The intracellular location could be confirmed by lysis of DC and subsequent determination of colony-forming units on agar plates, which showed a rapid decline in viable Gram-negative bacteria 6 h after infection, being by far more pronounced for E. coli than for S. typhimurium. Testing the stimulation of T cells by infected versus uninfected but otherwise identically treated human immature DC in a mitogen-dependent T cell proliferation assay, we found that S. typhimurium. but not E. coli exhibited a suppressive effect on T cell stimulation, being most significant on days 3-5 after infection. Thus, suppression of dendritic cell function was associated with an enteropathogenic bacterium, S. typhimurium, which can cause severe forms of enteritis. The bacteria with normally mild or no gastric symptoms, E. coli, had no influence on stimulation of T cells by DC.
Cell Division↗
Human decidua contains potent immunostimulatory CD83(+) dendritic cells.
Dendritic cells (DCs) are sentinel cells of the immune system important in initiating antigen-specific T-cell responses to microbial and transplantation antigens. DCs are particularly found in surface tissues such as skin and mucosa, where the organism is threatened by infectious agents. The human decidua, despite its proposed immunosuppressive function, hosts a variety of immunocompetent CD45 cells such as natural killer cells, macrophages, and T cells. Here we describe the detection, isolation, and characterization of CD45(+), CD40(+), HLA-DR(++), and CD83(+) cells from human early pregnancy decidua with typical DC morphology. CD83(+) as well as CD1a(+) cells were found in close vicinity to endometrial glands, with preference to the basal layer of the decidua. In vitro, decidual CD83(+) cells could be enriched to approximately 30%, with the remainder of cells encompassing DC-bound CD3(+) T cells. Stimulation of allogeneic T cells in a mixed leukocyte reaction by the decidual cell fraction enriched for CD83(+) cells, was similar to that obtained with blood monocyte-derived DCs, demonstrating the potent immunostimulatory capacity of these cells. Decidual DCs with morphological, phenotypic, and functional characteristics of immunostimulatory DCs might be important mediators in the regulation of immunological balance between maternal and fetal tissue, leading to successful pregnancy.
Antigens, CD↗
Dendritic cell function is perturbed by Yersinia enterocolitica infection in vitro.
Infection with Yersinia enterocolitica is the cause of intestinal or extraintestinal diseases. We investigated the role of dendritic cells (DC), the most potent antigen-presenting cell (APC), in the course of infection with Y. enterocolitica in vitro. For these studies, DC were isolated from human peripheral blood and infected with green fluorescent protein (GFP)-labelled Y. enterocolitica. Bacteria were found within DC by FACS analysis and viable bacteria could be cultured from lysed cells. Within 24 h after infection, DC upregulated CD83 and CD86 followed at day 3, indicating maturation of DC. In contrast, for MHC class II, a marked but transient downregulation was observed at day 3 after infection, and downregulation to a lesser extent for CD80 at day 5. To assess the immunostimulatory capacity of DC, viable infected and uninfected DC were incubated with autologous T cells in the presence of phytohemagglutinin A (PHA). T cell proliferation was significantly reduced at days 4-6 after infection but not thereafter, whereas nonpathogenic Escherichia coli was not able to mimick this suppressive effect of Y. enterocolitica. The same suppression could be observed when infected DC were used in a mixed leucocyte reaction with allogeneic T cells. Thus Y. enterocolitica is able to invade DC, does not induce necrosis or apoptosis, but affects maturation of DC. However, MHC class II-molecules are downregulated initially, which coincides with a diminished immunostimulatory capacity of DC infected with Y. enterocolitica. The diminished immunostimulatory capacity of DC following infection with Y. enterocolitica in vitro might impair or delay elimination of bacteria thereby contributing to pathogenesis of bacterial enteritis or extraintestinal manifestations such as reactive arthritis.
Antigens, CD↗
Lyme arthritis in children and adolescents: outcome 12 months after initiation of antibiotic therapy.
OBJECTIVE: Lyme arthritis in children and adolescents due to infection with Borrelia burgdorferi responds well to intravenous and oral antibiotics, but nonresponders have been described with all antibiotic regimens tested and a standard therapy has not yet been established. We examined causes of the failure of antibiotic treatment in the presence of persistent organisms and autoimmune mechanisms. METHODS: A prospective multicenter study was carried out in 55 children and adolescents with Lyme arthritis. RESULTS: There were significant differences between younger and older patients with pediatric Lyme arthritis. Younger patients were more likely to have fever at the onset of arthritis and to have acute or episodic arthritis. Older patients were more likely to have chronic arthritis, higher levels of IgG antibodies to B. burgdorferi (by ELISA and immunoblot), and a longer interval between antibiotic treatment and the disappearance of arthritis. Of 51 patients followed for at least 12 months after initiation of antibiotic treatment, 24% retained manifestations of the disease including arthritis (8 patients) and arthralgias (4 patients). These patients were predominantly female (9/12) and were significantly older than patients without residual symptoms. Patients who had received intraarticular steroids prior to antibiotic treatment required significantly more courses of antibiotic treatment and the time required for disappearance of the arthritis was longer. CONCLUSION: Pediatric Lyme arthritis is more benign in younger children. Lyme arthritis should be excluded as a possible cause of arthritis prior to the administration of intraarticular steroids.
Acute Disease↗
Effect of cytokines on invasion and survival of Yersinia in primary human fibroblasts.
Bacteria or bacterial antigen triggering reactive arthritis have been detected in inflamed joint tissue and fluid of patients. Although live yersiniae have not yet been found in joints of patients with Yersinia arthritis, early dissemination and propagation has been proposed. In this study, we investigated the influence of the proinflammatory cytokines interleukin- (IL-) 1beta, tumor necrosis factor-(TNF-) alpha, the Th1 lymphokine interferon- (IFN-) gamma, and the Th2 lymphokine IL-4 on the intracellular survival of Yersinia enterocolitica O.3 in primary human fibroblast cell monolayers as a model for joint tissue. Bacterial titers in infected cells decreased significantly and in a dose-dependent manner following treatment with IL-1beta, TNF-alpha, or IFN-gamma. The bactericidal effects of IL-1beta and TNF-alpha were synergistic. In contrast, IL-4 significantly supported bacterial survival. In addition, IL-4 antagonized in part the bactericidal effect of TNF-alpha and IFN-gamma. Although IL-1beta, TNF-alpha, and IFN-gamma accelerated killing of intracellular yersiniae the ratio of cells containing bacterial antigen did not differ from that in untreated cells. The differential effects of the investigated cytokines on intracellular survival of yersiniae may be of relevance for the development of Yersinia arthritis: enhanced production of IL-4 by synovial tissue may prolong the survival of yersiniae and persistence of antigen, and thus potentiate immune complex formation and inflammation. In conclusion these results show (1) that fibroblasts can take up virulent yersiniae as non-professional phagocytes and (2) that cytokines, found in the joints of patients with Yersinia arthritis, are able to affect the intracellular survival of yersiniae differentially.
Arthritis, Reactive↗
Incidence of Lyme borreliosis in the Würzburg region of Germany.
To assess the incidence of Lyme borreliosis in Central Europe, a 12-month, prospective, population-based surveillance study of Lyme borreliosis was conducted in the Wurzburg region of central Germany, following an aggressive awareness campaign. The diagnosis of Lyme borreliosis required the presence of (i) erythema migrans (diameter > or =5 cm); (ii) lymphocytoma; or (iii) another specific manifestation including Lyme arthritis, neuroborreliosis, carditis or acrodermatitis chronica atrophicans in conjunction with serological confirmation. A total of 313 cases of Lyme borreliosis was diagnosed, giving an incidence of 111 cases/100000 inhabitants, the highest rates occurring in children and elderly adults living in wooded as opposed to agricultural areas. The incidence in city dwellers and inhabitants of rural areas was not significantly different. Erythema migrans was the only manifestation in 279 (89%) patients. Of the 34 patients with manifestations other than erythema migrans alone, 15 had arthritis, nine neuroborreliosis, six lymphocytoma, four acrodermatitis chronica atrophicans and one carditis. Children were more likely than adults to have manifestations other than erythema migrans alone. Lyme borreliosis was very common in central Germany, and one of the most frequent bacterial infections. The observation of more cases of arthritis than neuroborreliosis was similar to that in the USA. These results may be representative for many parts of central Europe and suggest the need for development of a vaccine against borreliosis caused by European strains of Borrelia species.
Adolescent↗
Chronic recurrent multifocal osteomyelitis in children: diagnostic value of histopathology and microbial testing.
Chronic recurrent, unifocal or multifocal osteomyelitis (CRMO), an inflammatory disorder of unknown origin, involves different osseous sites and may be associated with palmoplantar pustulosis. Bacterial cultures of affected tissue were reported negative in nearly all cases. Radiological and magnetic resonance imaging features of CRMO have been described, but differential diagnosis remains difficult, including rheumatic diseases, bacterial osteomyelitis, and malignancy. Although definite diagnosis relies on histopathologic confirmation by biopsy, histopathologic criteria have not been defined. Because CRMO may be treated with nonsteroidal antiinflammatory drugs, but not antibiotics, distinguishing CRMO from bacterial osteomyelitis is of major importance. Histopathologic analysis of 12 patients with CRMO indicated a wide variation of reparative changes of bone, but chronic inflammation could not be found at all sites in the same biopsy. The inflammatory infiltrate was mostly scattered, consisting mainly of lymphocytes, plasma cells, histiocytes, and also few neutrophil granulocytes. Immunohistochemistry showed a predominance of CD3(+), CD45RO(+) T-cells, which were mainly CD8(+). In addition, CD20(+) B cells and CD68(+) macrophages were abundant in each biopsy specimen. Mild lymphocytic and granulocytic infiltrates were also detected in three synovial biopsy specimens obtained from adjacent joints. All bacterial and fungal cultures from native biopsy tissues were negative. Amplification of partial-length 16S ribosomal DNA by polymerase chain reaction (PCR) using broad-range eubacterial primers was below the detection limit in all patients. Because histopathologic features alone may not provide conclusive evidence, CRMO should be included in the differential diagnosis of chronic inflammatory bone lesions in children, and the definite diagnosis should be made by the clinical picture, x-ray studies, bone scan, bacterial culture, and histopathologic analysis in a multidisciplinary approach.
Acquired Hyperostosis Syndrome↗
Bone metabolism and bone mineral density in childhood hypophosphatasia.
Childhood hypophosphatasia (HP) is an inborn error of bone metabolism, characterized by a reduced tissue-nonspecific isoenzyme of alkaline phosphatase (TNSALP). Bone mineral density (BMD) in childhood HP has not been reported so far. We measured BMD, in addition to markers of bone metabolism, in 6 boys with childhood HP (age 2-13 years) and in 10 parents and one sibling, each carrying the autosomal-recessive trait. BMD, measured by peripheral quantitative computed tomography (pQCT) and by dual-energy X-ray absorptiometry (DXA), was expressed as standard deviation from the normal mean (Z scores) and compared with bone mineralization by standard X-rays of the same locations. HP was confirmed by low TNSALP and its elevated substrates. In patients, BMD of the total body or spine, measured by DXA, was in the lower normal range. Total BMD of the distal metaphyses of the radius, measured by pQCT, was normal (Z score: mean +1.5). However, trabecular BMD of both radius (Z score: mean +4) and femur was grossly elevated. In parallel, X-rays showed reduced transradiancy of the radial and femoral metaphyses in all patients. In parents of patients with HP, BMD was in the lower normal range. Only one father had a decreased lumbar BMD. The discrepancy in BMD between cortical and trabecular bone of the metaphyses in patients was not present in their relatives. TNSALP levels in all first degree relatives were just below or in the lower normal range. The markers of bone turnover hydroxyproline and free deoxypyridinoline in urine were normal in patients and relatives. Hypermineralization/sclerosis of trabecular bone might serve as a compensation for a mechanically incompetent bony structure due to an impaired mineralization of cartilage caused by the genetic deficiency of alkaline phosphatase.
Absorptiometry, Photon↗
Treatment of childhood hypophosphatasia with nonsteroidal antiinflammatory drugs.
Hypophosphatasia (HP) is an inborn error of metabolism that is characterized by reduced bone mineralization. The aim of this investigation was to evaluate treatment of incapacitating lower limb pain in patients with childhood HP using nonsteroidal antiinflammatory drugs (NSAID). All patients (seven boys; age 32 months to 16 years) presented with delayed walking, the typical waddling gait, muscular weakness of the lower limbs, and a limited walking distance. Six patients had severe diffuse lower limb pain following physical activity and were therefore treated with NSAID. The benefit of this treatment was evaluated clinically and by measurement of renally (PGE2) and systemically (PGE-M) derived prostaglandins (PG) in urine before and during therapy. After treatment with NSAID all six patients showed marked clinical improvement with reduced pain, increased muscle strength, and a normalized walking distance. Levels of PGE-M, which had been elevated in four patients prior to therapy, returned to normal. The use of NSAID in childhood HP should be considered as a possible therapeutic approach because the quality of life in these patients is markedly impaired by pain of the limbs. Elevated PG might play a role in the bone metabolism of HP patients.
Anti-Inflammatory Agents, Non-Steroidal↗
Bovine colostrum ameliorates diarrhea in infection with diarrheagenic Escherichia coli, shiga toxin-producing E. Coli, and E. coli expressing intimin and hemolysin.
BACKGROUND: Diarrheagenic Escherichia coli may cause serious extraintestinal complications, but there is no specific treatment. METHODS: Patients with diarrhea caused by diarrheagenic E. coli, specifically Shiga toxin-producing E. coli and E. coli-expressing intimin and enterohemorrhagic E. coli-hemolysin were treated by administration of pooled bovine colostrum, rich in antibodies to Shiga toxin and enterohemorrhagic E. coli-hemolysin, in a placebo-controlled, double-blind study. Symptom resolution and fecal excretion of infecting strains were assessed. RESULTS: No side effects were attributable to colostrum. Stool frequencies in the group treated with bovine colostrum were significantly reduced compared with those in the placebo group. No effect of therapy on the carriage of the pathogens or on complications of the infection could be demonstrated. CONCLUSIONS: Bovine colostrum is well tolerated and diminishes frequency of loose stools in children with E. coli-associated diarrhea. A prospective study should be conducted among a larger number of children with Shiga toxin-producing E. coli identified early in illness, to determine the effectiveness of colostrum therapy.
Adhesins, Bacterial↗
Escherichia coli O157:H7 and O157:H(-) strains that do not produce Shiga toxin: phenotypic and genetic characterization of isolates associated with diarrhea and hemolytic-uremic syndrome.
We have isolated one sorbitol-nonfermenting (SNF) Escherichia coli O157:H7 isolate and five sorbitol-fermenting (SF) E. coli O157:H(-) isolates that do not contain Shiga toxin (Stx) genes (stx). Isolates originated from patients with diarrhea (n = 4) and hemolytic-uremic syndrome (HUS) (n = 2). All isolates harbored a chromosomal eae gene encoding gamma-intimin as well as the plasmid genes E-hly and etp. The E. coli O157:H7 isolate was katP and espP positive. Respective sera obtained from the patient with HUS contained antibodies to the O157 lipopolysaccharide antigen. The stx-negative E. coli O157:H7 isolate is genetically related to stx-positive SNF E. coli O157:H7. All stx-negative SF E. coli O157:H(-) isolates belong to the same genetic cluster and are closely related to stx-positive SF E. coli O157:H(-) isolates. Our data indicate that stx-negative E. coli O157:H7/H(-) variants may occur at a low frequency and cannot be recognized by diagnostic methods that target Stx.
Antibodies, Bacterial↗