Search PubMed⌕ Search

Biomedical subjects

C G Kallenberg

Publications and source records attributed to C G Kallenberg.

At least 19 recordsLinked to original sources
PubMed1999

Patients with systemic lupus erythematosus with high plasma levels of sFas risk relapse.

OBJECTIVE: We related soluble Fas (sFas) levels to the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) in a longitudinal series of plasma samples of patients with SLE to evaluate the relation between excessive production of sFas and disease activity. METHODS: We generated 21 monoclonal antibodies against Fas. Two of these were used to develop and validate a sensitive sandwich ELISA for the longitudinal analysis of sFas levels in plasma of 30 patients and 25 controls. RESULTS: At the start of followup, a significant elevation (p<0.0001) was found in sFas levels in SLE (1167+/-347 pg/ml sFas) compared to controls (618+/-98 pg/ml sFas). Also, at the start of the followup a significant difference (p = 0.0028) existed between patients who were going to have a relapse (1236+/-402 pg/ml sFas) during followup and patients who were not (809+/-276 pg/ml sFas). While sFas did not fluctuate with disease activity in individual patients, we found a strong correlation (r = 0.75, p<0.0001) between sFas and SLEDAI, but only at the time of relapse, when we analyzed the patients as a group. CONCLUSION: In individual patients with SLE, sFas does not fluctuate with disease activity. However, patients with high plasma levels of sFas are at risk of relapse.

Biomarkers↗
PubMed1998

[Immunology in clinical practice IX. Systemic vasculitis].

A diagnosis of vasculitis generally requires histopathological proof of vasculitis, particularly because many other disease entities may mimic vasculitis ('vasculitis-look-alikes'). Vasculitis can be primary (idiopathic) or secondary to other diseases, especially infectious diseases. The primary vasculitides are classified according to the size of the vessels involved and the nature of the inflammation, in combination with clinical symptoms. The detection of autoantibodies, particularly the antineutrophil cytoplasmic antibodies (ANCA), in some of the primary vasculitides, has facilitated the diagnosis of those diseases and has given more insight into their pathophysiology. Treatment of primary vasculitis still consists of corticosteroids whether or not in combination with immunosuppression. New insights in pathophysiology may provide more specific and less toxic treatment modalities.

Adrenal Cortex Hormones↗
PubMed1998

The Fc gammaRIIIA-158F allele is a risk factor for systemic lupus erythematosus.

OBJECTIVE: To study whether the Fc gammaRIIIA-158V/F polymorphism, which affects IgG binding affinity, is a risk factor for systemic lupus erythematosus (SLE). METHODS: We genotyped a group of 70 Caucasian SLE patients for all known Fc gammaR polymorphisms. Of this group, 45 patients (64%) had nephritis. In 35 patients, this diagnosis was confirmed by renal biopsy. RESULTS: In the total group of 70 SLE patients, the frequency of the Fc gammaRIIIA-158F allele was 0.74, versus 0.57 in healthy controls (P = 0.003). The genotype distribution of the Fc gammaRIIIA-158V/F polymorphism was also significantly different from that of the control population (P = 0.004). The distribution of the other Fc gammaR polymorphisms--Fc gammaRIIA-131R/H, Fc gammaRIIIB-NA(1,2), and Fc gammaRIIIA-48L/R/H--was similar in SLE patients and controls. CONCLUSION: In our group of SLE patients, only the distribution of the alleles of the Fc gammaRIIIA-158V/F polymorphism was significantly different from that in the control group. This might indicate that macrophage expression of the Fc gammaRIIIA-158F isoform is involved in the disturbed clearance of immune complexes in patients with SLE.

Alleles↗
PubMed1998

Prevalence and clinical significance of anti-lactoferrin autoantibodies in inflammatory bowel diseases and primary sclerosing cholangitis.

Anti-neutrophil cytoplasmic antibodies (ANCA) are autoantibodies directed against cytoplasmic constituents of neutrophil granulocytes. Antibodies with specificity for proteinase 3 and myeloperoxidase are seromarkers for systemic vasculitides. ANCA with specificity for lactoferrin were described in patients with several idiopathic inflammatory diseases, such as the inflammatory bowel diseases and rheumatoid arthritis. However, the clinical significance of anti-lactoferrin autoantibodies is still unclear. In this study, we determined the clinical significance of anti-lactoferrin autoantibodies in sera from large groups of patients with ulcerative colitis (UC), Crohn's disease (CD), and primary sclerosing cholangitis (PSC). Antibodies to human lactoferrin were detected by ELISA and by immunoblotting, using an extract of sonicated neutrophils as antigen source. Autoantibodies to lactoferrin were found in 29% of patients with UC, 13% of patients with CD, and 22% of patients with PSC. In inflammatory bowel diseases, the presence of anti-lactoferrin antibodies was not related to treatment, disease activity, duration of disease, or disease extent. In PSC, the presence of autoantibodies to lactoferrin did not correlate with duration of disease or the presence of cirrhosis. However, patients with PSC and coexistent UC had significantly more frequently antibodies to lactoferrin than PSC patients without IBD. In conclusion, autoantibodies to lactoferrin are a common feature of inflammatory bowel diseases and PSC. However, the clinical significance of those autoantibodies is limited as they lack sensitivity and specificity for those disorders. Future research should address the pathophysiological role of anti-lactoferrin ANCA and the influence of anti-lactoferrin ANCA binding on the functional properties of the lactoferrin molecule.

Autoantibodies↗
PubMed1998

Autoantibodies to myeloperoxidase: clinical and pathophysiological significance.

Autoantibodies to MPO are associated with various forms of systemic vasculitis, including the renal limited form described as idiopathic crescentic glomerulonephritis. In vitro the antibodies are able to further activate primed neutrophils to the production of reactive oxygen species and the release of lysosomal enzymes. In vivo experimental studies in which an autoimmune response to MPO was induced in rats have demonstrated the in vivo potential of the autoantibodies to aggravate subclinical inflammatory lesions. In the right context, vasculitis and glomerulonephritis can ensue. Further studies are being directed to the precise characterization of autoimmune responses in order to obtain clues for the etiopathogenesis of the associated diseases.

Animals↗
PubMed1998

Antineutrophil cytoplasmic antibodies in primary sclerosing cholangitis: defined specificities may be associated with distinct clinical features.

PURPOSE: The clinical significance of antineutrophil cytoplasmic autoantibodies (ANCA) in primary sclerosing cholangitis has not been established. We investigated whether analysis of the antigenic specificities of ANCA is useful for delineating clinical subsets of the disease. METHODS: Sixty-nine patients with primary sclerosing cholangitis were studied. The presence of ANCA was analyzed by indirect immunofluorescence. Antibodies directed against specific antigens--proteinase 3, myeloperoxidase, elastase, bactericidal/permeability-increasing protein, cathepsin G, and lactoferrin--were identified by enzyme-linked immunosorbent assay. RESULTS: ANCA were detected by indirect immunofluorescence in 46 (67%) patients. In antigen-specific enzyme-linked immunosorbent assays, 37 (55%) of the 69 patients had antibodies to one or more antigens: 32 (46%) had antibodies to bactericidal/permeability-increasing protein, 16 (23%) had antibodies to cathepsin G, and 15 (22%) had antibodies to lactoferrin. Only 3 patients had antibodies to proteinase 3. Antibodies to myeloperoxidase or elastase were not detected. Twenty (29%) patients had antibodies to different antigens simultaneously. ANCA as detected by indirect immunofluorescence were not significantly associated with the presence of cirrhosis nor with the coexistence of inflammatory bowel disease. However, antibodies to bactericidal/permeability-increasing protein and cathepsin G were both associated with the presence of cirrhosis, and antibodies to lactoferrin were more frequently detected in patients with primary sclerosing cholangitis in conjunction with ulcerative colitis than in those without inflammatory bowel disease. CONCLUSION: Defined specificities of ANCA in primary sclerosing cholangitis may be related to particular clinical features of the disease.

Adult↗
PubMed1998

Catalase and alpha-enolase: two novel granulocyte autoantigens in inflammatory bowel disease (IBD).

In IBD, the target antigens of anti-neutrophil cytoplasmic autoantibodies (ANCA) have not been fully identified, which limits the analysis of the diagnostic significance as well as of the possible pathophysiological role of these antibodies. In this study, we identify the target antigens of ANCA in large groups of patients with ulcerative colitis (UC) and Crohn's disease (CD). Apart from antibodies against lactoferrin and bactericidal/permeability-increasing protein (BPI), which have been reported before, antibodies against two novel granulocyte antigens were identified: antibodies against a 57/56-kD doublet were found in 38% of samples from UC patients and in 26% of samples from CD patients, whereas antibodies against a 47-kD protein were found in 10% of samples from UC patients and in 18% of samples from CD patients. Partial purification and amino acid sequence analysis identified the 57-kD protein as catalase and the 47-kD protein as alpha-enolase. This study is the first to report catalase and alpha-enolase as granulocyte antigens for autoantibodies in IBD.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1998

Levels of soluble Fc gammaRIII correlate with disease severity in sepsis.

Neutrophil activation is thought to play a crucial role in the pathogenesis of sepsis. During activation, neutrophils adhere to and migrate through the endothelium. Therefore, the amount of circulating neutrophils does not adequately reflect the total amount of neutrophils that are involved in the pathophysiologic process of this condition. In this study we test the hypothesis that the severity of sepsis is associated with the total body mass of neutrophils as reflected in the plasma concentration of soluble Fc gamma receptor type III (sFc gammaRIII). Nineteen patients with sepsis (12 male, seven female, median age of 69 years, range 29-87 years) were included in this study. Ten healthy volunteers served as controls. Plasma sFc gammaRIII concentrations were measured by ELISA. Other parameters that were studied were leucocyte count, plasma concentrations of lactoferrin and soluble L-selectin, and surface expression of CD11b and CD66b on circulating neutrophils. Disease activity was measured using the Acute Physiology and Chronic Health Evaluation (APACHE) II score. Soluble Fc gammaRIII levels were elevated in sepsis patients whereas soluble L-selectin levels were moderately decreased compared with healthy controls. Markers of cell activation were significantly increased in sepsis patients. Soluble Fc gammaRIII correlated with disease severity as measured by the APACHE score (P<0.05, r=0.53), whereas the other parameters did not correlate with the APACHE score. In conclusion, this study demonstrates that soluble Fc gammaRIII is a useful marker for disease severity in patients with sepsis.

Adult↗
PubMed1998

Are circulating neutrophils intravascularly activated in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides?

Vascular injury in vasculitis may be due to activation of circulating neutrophils resulting in their increased adhesiveness to locally activated endothelium (Shwartzman phenomenon). Previously, we demonstrated up-regulation of endothelial intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in biopsies from patients with ANCA-associated vasculitis. In the present study, we investigated the expression of adhesion molecules (CD11b, ICAM-1, VLA-4, L-selectin) and activation markers (CD66b, CD64, CD63) on circulating neutrophils from patients with ANCA-associated vasculitis in comparison with their expression on cells from healthy volunteers and patients with sepsis. We related these findings to parameters of disease activity. Surface marker expression was determined by using a non-activating whole blood flow cytometric assay. The expression of activation markers, but not the expression of adhesion molecules, was increased on neutrophils from patients with active vasculitis. The expression of CD63 and CD66b on neutrophils correlated with disease activity as determined by the Birmingham Vasculitis Activity Score (BVAS). In contrast to patients with active vasculitis, patients with sepsis showed up-regulation of all markers, including adhesion molecules, suggesting that circulating neutrophils are fully activated in sepsis. We conclude that in ANCA-associated vasculitis, circulating neutrophils are not fully activated, since they do not express increased levels of adhesion molecules as sepsis or in the Shwartzman reaction. These findings are compatible with the concept that in vivo vascular damage in ANCA-associated vasculitides does not occur due to a Shwarzman-like reaction but only after ANCA-induced neutrophil activation at the endothelial cell surface.

Adult↗
PubMed1998

Expression of iNOS, eNOS, and peroxynitrite-modified proteins in experimental anti-myeloperoxidase associated crescentic glomerulonephritis.

Nitric oxide radicals are recognized as important mediators in various physiological and pathophysiological processes. During inflammation, increased amounts of nitric oxide (NO) are produced, but it is unclear whether NO radicals are either protective or harmful. To obtain more insight into the role of NO in glomerular inflammation, we studied the temporal expression of endothelial NO synthase (eNOS) and inducible NOS (iNOS) in conjunction with platelet aggregation, inflammatory cell influx, superoxide anion production cells, and nitrotyrosine formation in an experimental model of anti-myeloperoxidase (MPO) associated necrotizing crescentic glomerulonephritis (NCGN). Brown Norway rats were immunized with MPO in complete Freund's adjuvant (CFA) or CFA alone. After two weeks, the left kidney was perfused with a neutrophil lysosomal extract and H2O2. Rats were sacrificed at 24 hours, four days, and 10 days after perfusion. Kidney sections were stained by immunohistochemistry for eNOS, iNOS, platelets, nitrotyrosines, polymorphonuclear cells (PMN), monocytes, and T-cells. Superoxide anion producing cells were identified by enzyme cytochemistry using diaminobenzidine. Strong staining for eNOS was found in glomerular capillaries and interstitial tubular capillaries and larger vessels from non-perfused kidneys. At 24 hours after perfusion, glomerular and interstitial eNOS staining was greatly reduced, which was associated with massive platelet aggregation. At later time points, eNOS expression was absent in severely damaged glomeruli. Inducible NOS expression was found at all time points in infiltrating inflammatory cells, which by double labeling studies were identified as PMNs and monocytes. The peak in iNOS expression was observed at four days after perfusion but declined thereafter. Superoxide anion and nitrotyrosine generating cells were also found at all time points, but were most abundantly present at four days after perfusion, coinciding with the peak in iNOS expression. Double labeling experiments revealed that most nitrotyrosine generating cells also produced superoxide anions and expressed iNOS. In conclusion, these studies suggest that during the course of anti-MPO associated NCGN, loss of NO production by eNOS in conjunction with NO radical production by iNOS contribute to tissue injury. This is compatible with a protective role for eNOS contrasting with the possibly harmful effects of iNOS in anti-MPO associated NCGN.

Animals↗
PubMed1998

Leucocyte membrane expression of proteinase 3 correlates with disease activity in patients with Wegener's granulomatosis.

Wegener's granulomatosis (WG) is an inflammatory disorder characterized by granulomatous inflammation and vasculitis, and is strongly associated with antineutrophil cytoplasmic antibodies (ANCA). ANCA in patients with WG are directed against proteinase 3 (Pr3) in most of the cases. In vitro, upon neutrophil priming, ANCA antigens are expressed on the cell surface, thereby becoming available for interaction with ANCA. Subsequently, these neutrophils become activated. Since ANCA can only interact with leucocytes when the ANCA antigens are present on the cell surface, we questioned whether Pr3 is already expressed on the membranes of circulating granulocytes and monocytes of patients with WG, and whether Pr3 expression is related to disease activity, so explaining the systemic nature and severity of the disease. The expression of Pr3, and other ANCA antigens, i.e. myeloperoxidase (MPO) and human leucocyte elastase (HLE), was analysed on circulating granulocytes and monocytes by flow cytometry, using a non-activating whole-blood method. Disease activity was quantitated using the Birmingham Vasculitis Activity Score (BVAS). Seventeen patients with active WG and anti-Pr3 antibodies were included in this study. Nine of these patients were also analysed at the time of remission. Twelve patients with sepsis served as positive controls, and 10 healthy volunteers as negative controls for granulocyte/monocyte activation. Pr3 expression on neutrophils was increased in patients with active WG compared to patients with quiescent disease and healthy controls. On monocytes, no differences in Pr3 expression were found between those groups. Furthermore, the expression of MPO and HLE did not differ between patient groups and healthy controls. Upon follow-up, the expression of Pr3 on neutrophils from patients with active WG decreased when patients went into remission. Pr3 expression on neutrophils correlated with the BVAS score (r = 0.40, P < 0.05). In conclusion, circulating neutrophils from patients with active WG have increased expression of Pr3. In addition, the expression of Pr3 correlates with disease activity, suggesting that the availability of Pr3 for interaction with ANCA plays a central role in the disease process.

Adult↗
PubMed1998

Silicon exposure and vasculitis.

A combination of risk factors are involved in susceptibility to a primary or secondary form of vasculitis. Most forms of vasculitis are probably genetically based but environmentally triggered. This review discusses currently available evidence for a pathophysiologic role of one possible environmental trigger, silica. Since 1960, several patients with pulmonary silicosis have been described that developed pauci-immune necrotizing crescentic glomerulonephritis, i.e., with either completely negative immunofluorescence findings or nonspecific granular IgM or C3 deposits along the capillary wall. Recently it was reported that these patients have antineutrophil cytoplasmic antibodies (ANCAs) that are in most cases directed to myeloperoxidase. Further, patients with pulmonary silicosis may develop microscopic polyangiitis, the syndrome of lung hemorrhage and nephritis, or Wegener's granulomatosis. To further substantiate the relation between silicon exposure and renal failure or vasculitis, several case-control studies have been reported. Exposure to silicon-containing compounds was found to be related to chronic renal failure (odds ratio, 1.7:2.5) or vasculitis (odds ratio, 6.5:14.0). The mechanisms by which silica may induce ANCA-associated glomerulonephritis or vasculitis are not well known. Silicon-containing compounds have a pronounced adjuvant effect on immune responses, and silica particles are potent stimulators of lymphocytes and monocytes or macrophages. Further, silica may induce apoptosis of monocytes or macrophages and possibly neutrophils. In conclusion, at present there is ample evidence that occupational exposure to silicon-containing compounds is related to the development of ANCA-associated glomerulonephritis and vasculitis, and silica is one of the first well-documented environmental triggers in these diseases.

Adult↗
PubMed1998

Pathogenesis of vasculitis.

This review discusses current thoughts on the pathogenesis of vasculitis. Secondary vasculitides, frequently associated with infections or systemic autoimmune diseases, are, in most cases, characterized by immune deposits in the vessel wall, which probably underlies the development of lesions. In the primary vasculitides, immune deposits are generally absent. A group of primary vasculitides is, however, strongly associated with anti-neutrophil cytoplasmic autoantibodies (ANCA). Various in vitro and in vivo experimental data suggest that those ANCA are involved in the pathogenesis of lesions in the associated disorders.

Antibodies, Antineutrophil Cytoplasmic↗
PubMed1998

Determinants of renal outcome in anti-myeloperoxidase-associated necrotizing crescentic glomerulonephritis.

Patients with anti-myeloperoxidase (MPO)-associated necrotizing crescentic glomerulonephritis (NCGN) may develop chronic renal failure (CRF) leading to end-stage renal disease despite an initially favorable response to treatment. The aim of this study was to determine the prognostic value of clinical, laboratory, and histopathologic features at the time of presentation and during follow-up for the development of CRF in 21 consecutive anti-MPO-positive patients with NCGN. Renal function did not recover in two of five patients who were dialysis-dependent at presentation. The remaining 19 patients all went into remission and were off dialysis at 3 mo after diagnosis. At long-term follow-up, nine of these patients had stable renal function and did not relapse (group A), five patients developed CRF without signs of relapse (group B), and five patients relapsed (group C). At diagnosis, serum creatinine, C-reactive protein, and anti-MPO levels did not differ between groups A, B, and C. Microscopic erythrocyturia resolved in all patients within 4 mo of treatment. BP at presentation and during follow-up did not differ between groups A, B, and C. Proteinuria at diagnosis and in the first 6 mo after diagnosis was higher in patients who developed CRF than in patients with a stable renal function. Anti-MPO levels at 3 mo had decreased compared with anti-MPO levels at diagnosis in groups A and C, whereas anti-MPO levels did not fall significantly in patients who developed CRF. The predictive value of a renal biopsy at diagnosis on long-term renal outcome was limited. In conclusion, a higher degree of proteinuria at diagnosis and during follow-up as well as persistently elevated anti-MPO levels after induction of remission are associated with the development of CRF and are predictive of poor renal outcome in anti-MPO-associated NCGN.

Adrenal Cortex Hormones↗