Enthesitis and ankylosis in spondyloarthropathy: what is the target of the immune response?
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Ankylosis↗
Biomedical subjects
J Braun
Publications and source records attributed to J Braun.
Quantitative analyses of sacroiliac biopsies in spondyloarthropathies: T cells and macrophages predominate in early and active sacroiliitis- cellularity correlates with the degree of enhancement detected by magnetic resonance imaging.
OBJECTIVE: Sacroiliitis is a hallmark of the spondyloarthropathies (SpA). The degree of inflammation can be quantified by magnetic resonance imaging (MRI). The aim of this study was to further elucidate the pathogenesis of SpA by quantitative cellular analysis of immunostained sacroiliac biopsy specimens and to compare these findings with the degree of enhancement in the sacroiliac joints (SJ) as detected by dynamic MRI. METHODS: The degree of acute sacroiliitis detected by MRI after intravenous administration of gadolinium-DTPA was quantitatively assessed by calculating the enhancement observed in the SJ and chronic changes were graded as described in 32 patients with ankylosing spondylitis (n=18), undifferentiated SpA (n=12) and psoriatic arthritis (n=2). Back pain was graded on a visual analogue scale (VAS, 0-10) and disease duration (DD) was assessed. Shortly after MRI, SJ of patients with VAS > 5 were biopsied guided by computed tomography. Immunohistological examination was performed using the APAAP technique; only whole sections > 3 mm were counted. RESULTS: By MRI, chronic changes </= grade II were detected in nine patients (group I, DD 2.5 (SD 2.9) years) and > II in 13 patients (group II, DD 7.3 (SD 4.8) years), while enhancement < 70% was found in eight (group A, DD 5.6 (SD 3.3) years) and > 70% in 12 patients (group B, DD 4.7 (SD 5.8) years). The relative percentage of cartilage (78-93%), bone (7-18%) and proliferating connective tissue (1-4%) was comparable between the groups (range). There were more inflammatory cells in group I compared with group II (mean (SD) 26.7(20.1) versus 5.3 (5. 2), p=0.04) and group A compared with B (21.8 (17.3) versus 6.0 (5. 6), p=0.05) cells/10 mm(2)), T cells (10.9 (8.5)) being slightly more frequent than macrophages (9.6 (16.8/10 mm(2))). Clusters of proliferating fibroblasts were seen in three and new vessel formation in seven cases. CONCLUSION: This study shows that T cells and macrophages are the most frequent cells in early and active sacroiliitis in SpA. The correlation of cellularity and MRI enhancement provides further evidence for the role of dynamic MRI to detect early sacroiliitis.
Acute Disease↗
Response to methotrexate in early rheumatoid arthritis is associated with a decrease of T cell derived tumour necrosis factor alpha, increase of interleukin 10, and predicted by the initial concentration of interleukin 4.
OBJECTIVE: This study was performed to assess whether there is any change in the T cell cytokine pattern in early rheumatoid arthritis (RA) patients treated with methotrexate (MTX) and whether the lymphocytic cytokine pattern correlates with disease activity. METHODS: Eight patients with RA (disease duration < six months) were studied serially before, after three, and after six to nine months of treatment with MTX for the cytokines tumour necrosis factor alpha (TNFalpha), interferon gamma (IFNgamma), interleukin 4 (IL4) and interleukin 10 (IL10) by intracellular staining of T cells derived from peripheral blood. Response to treatment was assessed by the modified disease activitiy score. RESULTS: The clincial response was accompanied by a significant decrease of TNFalpha positive CD4(+) T cells from a median of 8.53% (interquartile range 5.83-10.91%) before treatment to 6.17% (2.15-6.81%) after six to nine months of treatment (p=0.021). Inversely, IL10 positive T cells increased from a median of 0.65% (interquartile range 0.6-0.93%) to a median of 1. 3% (1.22%-1.58%) after six to nine months of treatment (p=0.009). No significant change in the percentage of INFgamma positive T cells and a small decrease of IL4 positive T cells during treatment were observed. The percentage of IL4 positive CD4(+) T cells before treatment correlated with disease activity after six to nine months (r= -0.7066; p=0.05). CONCLUSIONS: During treatment of RA with MTX the percentage of TNFalpha producing T cells decreases whereas that of IL10 producing T cells increases. This may affect macrophage activation and, therefore, may represent a regulatory mechanism relevant to disease remission. Furthermore, the percentage of IL4 positive CD4(+) T cells at disease onset may be a useful prognostic marker.
Antirheumatic Agents↗
Anti-TNFalpha: a new dimension in the pharmacotherapy of the spondyloarthropathies !?
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Acute Disease↗
Treatment of spondyloarthropathies with antibodies against tumour necrosis factor alpha: first clinical and laboratory experiences.
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Antibodies, Monoclonal↗
Familial expression of anti-Saccharomyces cerevisiae mannan antibodies in affected and unaffected relatives of patients with Crohn's disease.
BACKGROUND: Crohn's disease is a familial disorder, and antiglycan antibodies to the cell wall mannan of Saccharomyces cerevisiae (ASCA) are highly correlated with Crohn's disease. AIMS: To determine whether there is a familial pattern for expression of serum levels of anti-mannan Ig, and whether this trait is expressed in clinically unaffected Crohn's disease family members. METHODS: 349 patients with Crohn's disease, 87 Crohn's disease affected relatives, 333 inflammatory bowel disease (IBD) free relatives, 58 spouses, and 190 healthy control patients were studied. Serum IgG and IgA binding activity to S cerevisiae cell wall mannan was quantitated by ELISA. RESULTS: A high percentage of patients with Crohn's disease (51.9%) and affected family members (56.3%) were seropositive for anti-mannan Ig, compared with the normal control population (3.7%). Seropositive and seronegative phenotypes of Crohn's disease probands were correlated among all affected relatives, and this association was stronger in affected first degree relatives. Statistical intraclass correlations of quantitative anti-mannan Ig levels revealed significantly less variation within, rather than between families. A significant familial aggregation was observed for affected relatives; this was even stronger for unaffected relatives. While a significant familial aggregation was observed among unaffected siblings pairs, there was no significant correlation among marital pairs. CONCLUSION: Results show that anti-mannan Ig in family members affected and unaffected with Crohn's disease is a familial trait for both affected and unaffected relatives. The lack of concordance in marital pairs indicates that familiality is due in part to a genetic factor or childhood environmental exposure.
Adult↗
Neutrophil inflammation and activation in bronchiectasis: comparison with pneumonia and idiopathic pulmonary fibrosis.
BACKGROUND: Pulmonary inflammation in bronchiectasis, pneumonia and idiopathic pulmonary fibrosis (IPF) is dominated by neutrophils. Pathophysiologic differences are seen in the degree of airway and tissue destruction. Neutrophil activation and neutrophil proteolytic activity might differ between bronchiectasis, pneumonia and IPF. OBJECTIVE: The aim of this study was to determine whether levels of inflammatory and protective markers in bronchoalveolar lavage (BAL) differed among cases of bronchiectasis, pneumonia and IPF. METHODS: We studied 11 bronchiectasis patients (group 1), 30 pneumonia patients (group 2), 15 IPF patients (group 3) and 12 healthy volunteers (group 4). In the bronchoalveolar lavage fluid, concentrations of alpha(1)-proteinase inhibitor, myeloperoxidase (MPO) and elastase-alpha(1)PI complex were determined using immunoluminometric assays. Elastase inhibition capacity (EIC) and elastase activity were determined using a colorimetric assay. RESULTS: No EIC, but free elastase activity, was found in 82% of group 1, 20% of group 2, 20% of group 3 and 0% of group 4. Median MPO concentration was highest in group 1: 7,951 ng/ml (16th-84th percentile [16-84%]: 256-36,342) vs. 692 ng/ml (106-2,279; group 2), 332 ng/ml (98-1,657; group 3), and 0.12 ng/ml (0.08-0.26; group 4). Bronchiectasis patients with bronchial Pseudomonas infection showed higher amounts of neutrophils (p < 0.01) and higher elastase activity (p < 0.05) than patients with sterile lavage. CONCLUSION: Bronchiectasis patients show a severe imbalance between neutrophil activity and protective molecules leading to possible lung destruction. Chronic Pseudomonas infection might trigger neutrophil activation. Future research and treatment strategies should focus on increased bacterial clearance and inhibition of neutrophil toxicity.
Adult↗
Activation of neutrophils, eosinophils, and lymphocytes in the lower respiratory tract in Wegener's granulomatosis.
Levels of cell products released by neutrophils, eosinophils and lymphocytes were measured in the bronchoalveolar lavage fluid (BALF) of 19 patients with pulmonary active Wegener's granulomatosis (WG) to assess in vivo the magnitude of cellular activation at sites of active disease. Measurements included the BAL cell profile and BALF levels of myeloperoxidase (MPO), free proteinase 3 (fPR3), complexes of PR3 and alpha1-antitrypsin (PR3/alpha1-AT), eosinophil cationic protein (ECP), peroxidase activity (PEROX), and soluble interleukin-2 receptor (sIL-2R). Six patients also underwent a repeat examination after immunosuppressive treatment. Pulmonary active WG was found to be associated with elevated MPO, PEROX, ECP, and sIL-2R levels in BALF. Only trace amounts of fPR3 were detected, the bulk of PR3 being found in PR3/alpha1-AT complexes. Clinically effective treatment depressed BAL neutrophil counts and reversed elevated levels of MPO and PEROX but had an inconsistent effect on the BAL lymphocyte count and the sIL-2R level. In conclusion, the elevated levels of extracellular MPO and PEROX at a site of active disease and the correlation between these and clinical disease activity support the view that neutrophils are indeed an important effector cell population in WG lung disease. The present data also suggest that oxidative injury is an important aspect of neutrophil-mediated lung injury, whereas it remains unresolved whether the low levels of fPR3 in the BALF adequately reflect the situation at inflammatory tissue sites.
Adult↗
Revisiting spatial vision: toward a unifying model.
We report contrast detection, contrast increment, contrast masking, orientation discrimination, and spatial frequency discrimination thresholds for spatially localized stimuli at 4 degrees of eccentricity. Our stimulus geometry emphasizes interactions among overlapping visual filters and differs from that used in previous threshold measurements, which also admits interactions among distant filters. We quantitatively account for all measurements by simulating a small population of overlapping visual filters interacting through divisive inhibition. We depart from previous models of this kind in the parameters of divisive inhibition and in using a statistically efficient decision stage based on Fisher information. The success of this unified account suggests that, contrary to Bowne [Vision Res. 30, 449 (1990)], spatial vision thresholds reflect a single level of processing, perhaps as early as primary visual cortex.
Computer Simulation↗
Decreased apoptosis and increased activation of alveolar neutrophils in bacterial pneumonia.
STUDY OBJECTIVES: The central role of apoptosis in the regulation of lung inflammation is increasingly recognized. The aim of this study was to determine the parameters of cell activation and apoptosis on neutrophils from the circulation and the pulmonary compartment in patients with community-acquired pneumonia (CAP), and to assess the role of the Fas system and of complement-regulating molecules in this context. DESIGN AND METHODS: The study population consisted of nine patients with CAP (group 1) and six age-matched control patients without evidence of bronchopulmonary inflammation (group 2). Apoptosis rate and expression of CD11b, CD16, CD55, CD59, CD95, and CD114 surface molecules on systemic and bronchoalveolar neutrophils were assessed ex vivo using fluorescence-activated cell sorter analysis. RESULTS: In patients with CAP, we found a significant decrease of the mean apoptosis rate in pulmonary neutrophils compared to systemic neutrophils, without concomitant changes in Fas expression. In contrast, cell activation markers were significantly increased on pulmonary cells (CD11b, 288 +/- 98.2 relative mean fluorescence intensity [rMFI] vs 53.8 +/- 10.8 rMFI on peripheral cells), and similar changes were observed with respect to the expression of complement-regulating molecules. Pulmonary polymorphonuclear neutrophils of the control group showed analogous changes, compared to systemic neutrophils, but a significantly higher rate of apoptosis and a lower increase of activation-marker expression were found, compared to pulmonary neutrophils of patients with pneumonia. CONCLUSIONS: Pulmonary neutrophils from patients with CAP show a decreased rate of apoptosis and increased activation status in the alveolar compartment, which may be important for effective control of pulmonary inflammation.
Adaptor Proteins, Signal Transducing↗
Vitamin D receptor allele combinations influence genetic susceptibility to type 1 diabetes in Germans.
Vitamin D has been shown to exert manifold immunomodulatory effects. Because type 1 diabetes is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse, we investigated the role of the vitamin D receptor (VDR) gene as a candidate for type 1 diabetes susceptibility. A total of 152 Caucasian families with at least one affected offspring were genotyped for four VDR restriction-site polymorphisms (FokI, BsmI, ApaI, and TaqI). Whereas the BsmI, ApaI, and TaqI polymorphisms are in strong linkage disequilibrium with each other, no significant linkage disequilibrium with the FokI site was observed. Extended transmission disequilibrium testing (ETDT) was used to detect preferential transmission of allelic combinations to affected offspring. We found significant haplotype-wise ETDT results for the BsmI/ApaI/TaqI (chi2 = 18.886, df = 7, P = 0.0086), the BsmI/TaqI (chi2 = 8.373, df = 3, P = 0.0389), and theApaI/TaqI (chi2 = 17.182, df = 3, P = 0.0006) haplotypes. The "At" and "Bt" alleles confer an increased risk, whereas "AT" and "at" are protective. The combination with the strongest susceptibility was the "BAt" haplotype (64% transmitted, P = 0.0106). Analysis of the FokI site does not provide more information on susceptibility (FokI/BsmI/ApaI/TaqI [chi2 = 24.702, df = 15, P = 0.0541]). These findings suggest a linkage of VDR itself or a nearby gene with type 1 diabetes susceptibility in Germans, confirming respective observations previously made in Indian Asians.
Adolescent↗
Disability and handicap in rheumatoid arthritis and ankylosing spondylitis--results from the German rheumatological database. German Collaborative Arthritis Centers.
OBJECTIVE: To describe indicators of disability and handicap in the 2 major inflammatory rheumatic diseases rheumatoid arthritis (RA) and ankylosing spondylitis (AS) and to estimate the burden of illness in terms of functional status, pain, and global well being, as well as with regard to unemployment and early retirement. METHODS: Data from the German rheumatological database on 52,444 patients with RA and 8,776 patients with AS seen at 21 collaborative arthritis centers in Germany between 1993 and 1997 were analyzed. To estimate the burden of the 2 diseases at different biographical phases, age and sex matched groups of patients were compared for functional disability, pain, global assessment of health status, education level, and employment status. RESULTS: For comparable ages, disability in female patients with AS or RA was rated similarly by the physicians (e.g., 61-70 years: 42% severe disability in RA and 44% in AS), whereas men with AS were rated more disabled than men with RA (61-70 years: 35% in RA and 48% in AS). Patients' self-ratings of disability were generally worse for women than for men (age 61-70: women 37% severe disability in RA and 35% in AS, men: 24% in RA and 19% in AS). Pain intensity was rated similarly by women and men with RA and AS at ages < 51 years (33% severe pain at ages 41-50 in men and 34% in women in both diseases). It increased with age in women (> 70 years: 41% severe pain in RA and 44% in AS) and remained stable in men (27% RA and 29% AS > 70 years). At 71.3% the employment rate in AS was clearly higher than in RA (49.5%). There was significant influence of the education level (men 51-60 years with AS: low education 56% employment rate, high education 79%) and the labor market (men 51-55 years with AS: 80% employment rate under good, 59% under bad overall labor market conditions). CONCLUSION: Age and sex matched groups of patients with RA and AS in tertiary rheumatological care show similar amounts of disability, pain, and reduction in well being. Therefore, the offer of comprehensive care and pain management to both groups should be comparable.
Activities of Daily Living↗
Clinicians' discussion: trends in HIV care.
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Anti-HIV Agents↗
On the difficulties of establishing a consensus on the definition of and diagnostic investigations for reactive arthritis. Results and discussion of a questionnaire prepared for the 4th International Workshop on Reactive Arthritis, Berlin, Germany, July 3-6, 1999.
OBJECTIVE: There is no agreement on how to classify and diagnose reactive arthritis (ReA) and it is also unclear what kind of specific clinical and laboratory investigations are appropriate. We define relevant points of agreement and identify points of disagreement among an international group of experts in the field. METHODS: Prior to the 4th International Workshop on Reactive Arthritis, Berlin, July 1999, we sent questionnaires to 42 experts identified by personal knowledge and recent publications. RESULTS: The response rate was 81% (n = 34). There was agreement on the nomenclature and recommendation to use the term "reactive arthritis" only if the clinical picture and the microbes involved are HLA-B27 and spondyloarthropathy (SpA) associated, whereas the term "infection related arthritis" is used for all other arthritides related to or associated with infections. A differentiation between acute and chronic ReA with a cutoff of 6 months is recommended. The history of a preceding symptomatic infection is thought to be most relevant for a diagnosis of ReA. The minimal interval between preceding symptoms and arthritis is proposed to be 1-7 days, maximally 4 weeks. The joint pattern in ReA is asymmetrical, with predominance of the lower limbs. SpA related symptoms may contribute to the diagnosis. A search for chlamydia in urine/urethra/cervix is recommended, while in the case of diarrhea enterobacteria should be searched for in stool and antibodies against them in serum. There were also areas of disagreement, such as: Is arthritis essential for the diagnosis of ReA?, Is it oligoarthritis or any arthritis?, What are the role and value of polymerase chain reaction investigation?, The role and value of serology?, Is the diagnostic sensitivity of microbiological tests for ReA increased by HLA-B27 determination? CONCLUSION: The points of agreement will support better communication in this area, and clarification of the disagreements will lead to further studies and discussion.
Arthritis, Reactive↗
The anatomic relationship between the second genu of the facial nerve and the incus: a high-resolution computed tomography study.
OBJECTIVE: This study defines the three-dimensional location of the posterior-most point of the tympanic segment of the facial nerve (TSFN) relative to the posterior-most point of the short process of the incus, using ultrahigh-resolution computed tomography (CT) of the temporal bone. STUDY DESIGN, SETTING, AND PATIENTS: Included were patients who had been referred for CT of the temporal bone for various reasons other than suspected pathologic conditions of the middle ear. The decision whether to include a patient in the study was based on the referring physician's referral note for the examination. INTERVENTION: All of the patients underwent axial CT of the temporal bone, with consecutive slices of 1.1 mm width and 0.5-mm increments. MAIN OUTCOME MEASURES: The posterior-most point of the short process of the incus was identified on axial CT and was superimposed onto a lower axial slice in which the posterior-most point of the TSFN was identified. Its shortest distance to the TSFN was measured. Afterward, the length of the TSFN that remained posterior to the perpendicular of the posterior-most point of the short process of the incus was measured by measuring the length of TSFN that could be seen posterior to the point of bisection of the line marking the shortest distance between the posterior-most point of the short process of the incus and the FN in the previous measurement. The measurements were performed on 30 normal temporal bones. RESULTS: The shortest distance measured between the posterior-most point of the short process of the incus and the TSFN was, on average, 3.31 mm for all 30 ears (range 2-4.8 mm). The length of TSFN that could be seen posterior to the perpendicular of the most posterior point of the short process of the incus was, on average, 2.70 mm (range 1.80-3.90 mm). CONCLUSIONS: In addition to defining the spatial location of the posterior-most point of the TSFN, this study also offers a practical method by which the surgeon can evaluate, preoperatively, how far medial to the incus and how much posterior to the posterior-most point of the short process of the incus the facial nerve is located.
Adult↗
Enhanced HIV infectivity and changes in GP120 conformation associated with viral incorporation of human leucocyte antigen class I molecules.
BACKGROUND: Assembly of human immunodeficiency virus type 1 (HIV-1) occurs at the level of the plasma membrane of the host cell. During this process HIV incorporates significant quantities of cell surface-derived molecules into its lipid bilayer including human leucocyte antigen (HLA) class I and II, intercellular adhesion molecule-1 and lymphocyte function antigen-1. Several studies indicate that virion-bound host-cell-derived molecules are functional and affect the biological properties of HIV-1. Virion-associated HLA class II and intercellular adhesion molecule-1 enhance the infectivity of T-cell line-adapted (TCLA) viruses. No role for virion-associated HLA class I molecules has yet been identified. OBJECTIVE: To investigate the role of HLA class I molecules in HIV replication and infectivity. METHODS: HLA class I negative human cells lines transfected with the HLA Cw4 gene were infected with different TCLA viruses as well as primary X4 isolates. The infectivity of HLA Cw4 positive and negative viruses was determined on indicator cell lines and on phytohaemagglutinin-activated peripheral blood mononuclear cells. An entry polymerase chain reaction assay was used to determine differences in entry-competence of Cw4 positive and negative viruses. The expression of selected gp120 epitopes on native Env molecules derived from Cw4 positive and negative viruses was determined by a monoclonal antibody-based enzyme-linked immunosorbent assay. Immunoprecipitation experiments were performed to investigate the presence of gp120/HLA Cw4 complexes. Neutralization assays determined the differences in susceptibility to neutralization between HLA Cw4 negative and positive viruses. RESULTS AND CONCLUSIONS: The infectivity of primary HIV-1 X4 isolates and of TCLA viruses is increased upon viral incorporation of HLA Cw4 molecules. This effect is associated with changes in viral envelope proteins conformation including an enhanced expression of the V3 loop of gp120, and of epitopes that are exposed upon CD4 binding. The gp120 conformational changes are consistent with the formation of a multimolecular complex between HLA class I and gp120/160. HLA Cw4 incorporation is also associated to a lower susceptibility to antibody neutralization. These findings have important implications for understanding the immune response to cryptic and conformational epitopes of the viral envelope.
Cell Line↗
[Abdominal actinomycosis after stomach surgery in a patient with long-term rheumatoid arthritis treated with methotrexate].
HISTORY AND ADMISSION FINDINGS: A 78-year-old woman had a 30-year history of rheumatoid arthritis, of late treated with prednisolone and methotrexate. A week before admission she had first noticed a mass about 3 cm in diameter, at the lower end of a scar from a Billroth II gastric resection for gastric ulcer, performed 4 months before. She reported to have lost 6.5 kg in weight. On admission a moderately mobile, hard mass was palpated on the abdomen. INVESTIGATIONS: Ultrasound and computed tomography revealed a superficial, inhomogenous space-occupying lesion with poorly circumscribed margins. TREATMENT AND COURSE: After two days the skin over the mass became reddened and a laparotomy was performed because an incarcerated herniation was suspected. An abscess and inflammatory adhesions were found in the area of the transverse colon, histologically shown to be a chronic purulent abscess with granular clusters of pathogens indicating actinomycosis. After 3 weeks' treatment with imipenem i.v. the patient became free of symptoms, oral doxycyclin was continued for a further 6 months. CONCLUSION: Actinomycosis should be considered in the differential diagnosis of a tumour of undetermined benignity in the region of the head, chest or abdomen in immunosuppressed patients. This bacterial infection should be thought of especially if the gastrointestinal mucosa has been penetrated by invasive procedures.
Abdominal Abscess↗