Biomedical subjects

J Wieslander

Publications and source records attributed to J Wieslander.

At least 19 recordsLinked to original sources

PubMed1996

Integrin-mediated interactions between primary/T-sv40 immortalized human glomerular epithelial cells and type IV collagen.

The use of human glomerular epithelial cells (HGEC) in research has been severely restricted by several obstacles, which have been circumvented by the generation of T-SV40 immortalized human visceral glomerular epithelial cells (Delarue et al, 1991). In this work, we compared the primary and immortalized HGEC for expression of integrin and some nonintegrin surface receptors. We also studied the adhesion of both types of HGEC to glomerular basement membrane (GBM), type IV collagen (tIV), and its major noncollagenous NC1 domain. The integrins mediating adhesion of HGEC to tIV were also examined. Expression of integrin and some nonintegrin cell surface receptors was analyzed by flow cytometry. Adhesion to GBM, tIV, and its major noncollagenous NC1 domain was studied by direct solid phase cell adhesion assays. Identification of integrins mediating adhesion of HGEC to tIV was achieved by inhibition of cell adhesion using monoclonal antibodies to integrin subunits. The primary and immortalized HGEC share phenotypic characteristics, and alpha3beta1 appeared to be the major integrin present on both HGEC types. The kinetics of binding to GBM, tIV, and its noncollagenous NCI domain were similar in both the primary and immortalized HGEC, although the latter displayed a somewhat weaker binding. Both the primary and immortalized HGEC displayed significantly better adhesion to NC1-alpha3 compared with NC1-alpha1, alpha3beta1 appears to be the major integrin mediating the adhesion of HGEC to tIV. Our studies suggest that alpha3beta1 is the major integrin present on HGEC. This has been confirmed by flow cytometric analysis. In addition, we demonstrated a functional role for this integrin in mediating attachment of HGEC to tIV. Our data also demonstrate a preference in binding of HGEC to alpha3 chains of NC1 compared with alpha1 chains of NC1. These findings were seen in both the primary and immortalized HGEC. The T-SV40 immortalized HGEC can therefore serve as a very useful tool to study glomerular visceral cell biology.

Animals↗

PubMed1995

Phosphorylation of the Goodpasture antigen by type A protein kinases.

Collagen IV is the major component of basement membranes. The human alpha 3 chain of collagen IV contains an antigenic domain called the Goodpasture antigen that is the target for the circulating immunopathogenic antibodies present in patients with Goodpasture syndrome. Characteristically, the gene region encoding the Goodpasture antigen generates multiple alternative products that retain the antigen amino-terminal region with a five-residue motif (KRGDS). The serine therein appears to be the major in vitro cAMP-dependent protein kinase phosphorylation site in the isolated antigen and can be phosphorylated in vitro by two protein kinases of approximately 50 and 41 kDa associated with human kidney plasma membrane, suggesting that it can also be phosphorylated in vivo. Consistent with this, the Goodpasture antigen is isolated from human kidney in phosphorylated and non-phosphorylated forms and only the non-phosphorylated form is susceptible to phosphorylation in vitro. Since this motif is exclusive to the human alpha 3(IV) chain and includes the RGD cell adhesion motif, its phosphorylation might play a role in pathogenesis and influence cell attachment to basement membrane.

Amino Acid Sequence↗

PubMed1995

Characterization and expression of multiple alternatively spliced transcripts of the Goodpasture antigen gene region. Goodpasture antibodies recognize recombinant proteins representing the autoantigen and one of its alternative forms.

Collagen IV, the major component of basement membranes, is composed of six distinct alpha chains (alpha 1-alpha 6). Atypically among the collagen IV genes, the exons encoding the carboxyl-terminal region of the human alpha 3(IV) chain undergo alternative splicing. This region has been designated as the Goodpasture antigen because of its reactivity in the kidney and lung with the pathogenic autoantibodies causing Goodpasture syndrome. The data presented in this report demonstrate that, in human kidney, the gene region encompassing the Goodpasture antigen generates at least six alternatively spliced transcripts predicting five distinct proteins that differ in their carboxyl-terminus and retain, except in one case, the exon that harbors the characteristic amino-terminus of the antigen. Goodpasture antibodies specifically recognize recombinant proteins representing the antigen and the alternative form that retains the amino-half of the antigen, suggesting that this moiety could be involved in the in vivo binding of the pathogenic antibodies. Furthermore, the sera of control individuals contain autoantibodies against the antigen that can be differentiated from those causing the syndrome based on their specific reactivities, suggesting that the binding of the pathogenic autoantibodies to a specific determinant likely trigger a distinct and unique cascade of events causing the disease.

Alternative Splicing↗

PubMed1995

The PiZ gene of alpha 1-antitrypsin as a determinant of outcome in PR3-ANCA-positive vasculitis.

We have previously demonstrated that a strong correlation exists between systemic vasculitis with proteinase 3-anti-neutrophil cytoplasm antibodies (PR3-ANCA) and heterozygosity for alpha 1-antitrypsin (alpha 1-AT) deficiency, PiZ. In the present study we characterized the PiZ-positive subgroup by laboratory findings, clinical features and outcome. The series studied consisted of 18 PiZ-positive and 81 PiZ-negative PR3-ANCA patients, comparable in sex ratio, age, C-reactive protein concentrations and renal function at diagnosis, and treatment. PiZ-positive patients had a more disseminated disease as reflected by the number of affected organs (P < 0.01). We found no group differences in relapse tendency. Overall mortality was 39% (7 of 18) in the PiZ-positive and 16% (13 of 81) in the non-PiZ group (P = 0.048). When survival analysis was restricted to 66 patients included in the study at disease onset, the group difference was significant (P = 0.016). The results suggest that the subnormal response of plasma alpha 1-AT seen in PiZ-heterozygotes enhances the risk of dissemination of the vasculitic process and the risk of a fatal outcome. We consider alpha 1-AT phenotyping to be justified in cases of PR3-ANCA-positive vasculitis. Treatments decreasing plasma alpha 1-AT (such as plasmapheresis without plasma replacement) may be deleterious.

Adult↗

PubMed1995

Screening for anti-neutrophil cytoplasmic antibodies (ANCA): is indirect immunofluorescence the method of choice?

Detection of ANCA has become an important tool for the diagnosis and monitoring of disease activity in Wegener's granulomatosis (WG). Unfortunately, a group of sera positive by the standard method for ANCA detection, indirect immunofluorescence (IIF), are negative when more specific tests with purified proteins are used. In order to examine this discrepancy we examined groups of sera selected for being (i) C-ANCA-positive by IIF; (ii) positive in proteinase 3 (PR3)-ANCA ELISA; and (iii) from 24 patients with WG. The following assays were used: IIF, PR3-ANCA ELISA and capture PR3-ANCA ELISA using MoAbs against PR3. Furthermore, since granule enzymes are released during coagulation, we also measured ANCA in complex with PR3. To test if granule enzyme release had any influence on ANCA detection, both serum and EDTA-plasma were collected from a patient with active WG. No difference, however, was found. In the IIF-positive group (n = 60) 68% of the sera were positive in PR3-ANCA ELISA, 86% in capture PR3-ANCA ELISA and 80% were positive for the PR3/IgG-ANCA complex. In the PR3-ANCA ELISA group (n = 105) 88% of the sera were positive by IIF, 98% in capture PR3-ANCA ELISA and 53% in the PR3/IgG-ANCA assay. To evaluate the tests clinically sera from 24 patients with WG were examined. In the remission group (n = 10) two patients were positive by IIF, four in the PR3-ANCA ELISA, and five in the capture PR3-ANCA ELISA. Fourteen had active disease, and in this group 11/14 were positive by IIF, 10/14 in PR3-ANCA ELISA and 12/14 by capture-ELISA. The correlation between IIF and capture PR3-ANCA ELISA titre (r = 0.72, P = 0.0095) was better than between PR3-ANCA ELISA and IIF (r = 0.56, P = 0.043). It is concluded that the capture PR3-ANCA ELISA is more sensitive than PR3-ANCA ELISA, and that the capture ELISA can be used for screening of PR3-ANCA.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed1995

Circulating autoantibodies as serological markers in the differential diagnosis of pulmonary renal syndrome.

OBJECTIVES: Pulmonary renal syndrome (lung haemorrhage and glomerulonephritis) is a fulminant condition that warrants a rapid diagnosis and treatment to prevent mortality and preserve renal functions. However, the patients frequently present with non-specific pulmonary symptoms in the early phase of the syndrome and the diagnosis is often missed. Recently, several autoantibodies have been described in association with various forms of glomerulonephritis. We evaluated the association as well as the diagnostic and the prognostic significance of these antibodies in pulmonary renal syndrome. DESIGN: Retrospective clinical study. SETTING: University Hospital. SUBJECTS: Forty consecutive patients with biopsy verified glomerulonephritis and overt haemoptysis or pulmonary infiltrates compatible with lung haemorrhage. INTERVENTIONS: Analysis of proteinase 3 antineutrophil cytoplasm antibodies (PR3-ANCA), myeloperoxidase (MPO)-ANCA, antiglomerular basement membrane (GBM) and anti-entactin antibodies. RESULTS: Thirty-six (90%) patients possessed one or more autoantibodies. Twenty-seven (70%) patients had ANCA (PR3-ANCA, MPO-ANCA or both). The remaining positive patients (n = 9) had anti-GBM antibodies. Only two patients had anti-entactin antibodies, suggesting a poor association of these antibodies with PRS. The majority of patients with anti-GBM antibodies had a very poor clinical outcome (five irreversible renal failure; three deaths). On the other hand, despite no significant difference in clinical features or renal morphology from patients with anti-GBM antibodies, 19 patients (70%) with ANCA recovered completely following treatment. CONCLUSIONS: Our study demonstrated that the presence of autoantibodies is a predominant feature of PRS and that the type of immunologic injury is of paramount importance in determining the course of illness in this syndrome. Analysis of the aforementioned antibodies can help in an early differential diagnosis and thus, in better management of PRS.

Adult↗

PubMed1995

Anti-neutrophil cytoplasmic antibodies in chronic inflammatory bowel disease. Prevalence and diagnostic role.

BACKGROUND: Anti-neutrophil cytoplasmic antibodies (ANCA), originally found to be associated with vasculitis, have been reported to be present in chronic inflammatory bowel disease. Most often the ANCA staining pattern is of the perinuclear type (p-ANCA), although nuclear and cytoplasmic stainings are seen. Single studies have shown some of the antibodies to react with lactoferrin or cathepsin G; however, most studies have not been able to determine a main antigenic specificity. We studied the prevalence of ANCA in sera from 155 patients with ulcerative colitis, 128 patients with Crohn's disease, and 51 patients with coeliac disease. The presence of ANCA was correlated to disease activity, extent, and age of onset of the diseases. Furthermore, we tried to characterize the antigen specificity by enzyme-linked immunosorbent assay (ELISA), using elastase, lactoferrin, myeloperoxidase, proteinase 3, and cathepsin G as antigens. METHODS: The sera were screened for ANCA by indirect immunofluorescence. Anti-nuclear antibodies (ANA) were analysed on HEp2 cells, and ELISA for specific ANCA was performed using the antigens mentioned. RESULTS: Most of the sera with positive immunofluorescence had the p-ANCA type of pattern. Seventy-eight of 155 (50.3%) of the patients with ulcerative colitis were ANCA-positive, compared with 31 of 128 (24.2%) of patients with Crohn's disease (p < 0.001). However, in the subgroup with Crohn's colitis, 16 of 44 (36.4%) were ANCA-positive. Only 4 of 51 patients (7.7%) with coeliac disease showed positive immunofluorescence (p < 0.001 compared with ulcerative colitis). Less than 10% of the samples were positive in the specific ELISA assays; thus other than the most well known granule proteins can be the target for ANCA in ulcerative colitis. CONCLUSION: ANCA occur significantly more often in ulcerative colitis than in Crohn's disease. However, the prevalence of ANCA is rather high in Crohn's colitis. ANCA are thus of limited value in differentiating Crohn's colitis from ulcerative colitis. ANCA found in inflammatory bowel disease are different from those associated with vasculitis. The antigen(s) responsible remain to be determined.

Adult↗

PubMed1995

Heterogeneity of renal carcinoma.

Monoclonal antibodies were used to study the expression of three recently characterized basement membrane components and two carbohydrate antigens in 11 renal-cell carcinomas, using immunohistological and biochemical techniques. The expression of several site-specific kidney antigens in renal-cell carcinoma were studied to determine the origin of the carcinoma and if it is possible further classify this type of carcinoma. Tubulointerstitial nephritis antigen (TIN) and two alpha-chains of type IV collagen, alpha 1 (IV) and alpha 3 (IV) were studied. In addition the expression of carbohydrate antigens Lex and SLex, which also exhibit site-specific distribution were characterized. Lex and SLex antibodies stained the majority of the tumours. TIN was expressed in 9 of 11 tumours, the alpha 1 (IV) chain was present in all 11, and the alpha 3 (IV) chain in two of the 11 tumours. Interestingly, the two alpha 3 (IV)-positive tumours were the same two that were negative for TIN. In normal tissue alpha 3 (IV) is found in distal tubules while TIN is found in proximal tubules. Our results are consistent with earlier observations that the proximal tubule is the origin of most renal-cell carcinomas, but the results also indicate that renal-cell carcinoma may originate from the distal tubule.

Antibodies, Monoclonal↗

PubMed1994

Measurements of proteinase 3 and its complexes with alpha 1-proteinase inhibitor and anti-neutrophil cytoplasm antibodies (ANCA) in plasma.

Wegener's granulomatosis (WG) is a systemic vasculitis which is diagnosed on clinicopathological findings. The diagnosis may be aided by the presence of anti-neutrophil cytoplasm antibodies (ANCA). In WG, ANCA are primarily directed to proteinase 3 (PR3), a serine protease of the azurophilic granules of the neutrophilic granulocyte. The main plasma inhibitor of PR3 is alpha 1-proteinase inhibitor (PI). To study if free PR3 or complexes between the enzyme and PI or PR3 and ANCA could be found in the plasma from patients with WG we have developed three ELISA systems for the detection of these complexes and free PR3. In all three assays monoclonal antibodies against PR3 were used as capture antibodies. After incubation with plasma, free PR3 was detected by affinity purified rabbit anti-PR3 followed by alkaline phosphatase-labelled swine anti-rabbit IgG. Serial dilutions of purified PR3 was used as standard. The detection limit was 3 ng/ml. PR3 complexed with PI was measured by rabbit anti-PI antibodies and alkaline phosphatase-labelled swine anti-rabbit IgG. Pre-formed in vitro complexes of PR3/PI in serial dilutions were used as standard. The detection limit of this assay was 1 ng/ml. PR3/IgG-ANCA complexes were detected by alkaline phosphatase labelled goat anti-human IgG. A positive plasma sample in serial dilutions was used as standard. Plasma samples from nine patients with WG, eight patients with fever of infectious origin without evidence of vasculitis and ten healthy donors were examined by these methods. Free PR3 could not be found in any of the plasma samples. PR3/PI complexes were detected in healthy donors at levels between 41-85 ng/ml. All WG patients, both active and inactive, had PR3/PI concentrations above this level, and so had all patients with fever. PR3/IgG-ANCA was found in three of the patients with WG, two being ANCA negative with inactive disease and one was ANCA positive with active disease. Thus, the developed methods can be useful for future studies of the clinical relevance of these complexes in patients with WG and possibly other vasculitides.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed1994

A rapid and semi-quantitative method for the detection of autoantibodies by multiple spot immunoassay.

A method for rapid simultaneous determination of multiple autoantibodies in sera has been developed. 42 different antigens were coated onto a nitrocellulose membrane in a miniblotter apparatus with 42 lanes. The membrane was also coated with different concentrations of human IgG to create a standard curve. The blotting apparatus after coating, blocking and washing was turned 90 degrees so that all lanes crossed the antigen coated lanes. Thereafter, 42 sera were incubated with the antigens. After this stage the membrane was treated as in the usual dot-blot procedure. After incubation with alkaline phosphatase labelled anti-human IgG, staining and drying of the membrane, the staining intensity of individual lanes was scanned into a data file and analyzed by computer. By this method it was possible in 4 h to examine 42 sera for autoantibodies against 42 antigens, i.e., more than 1600 tests. Furthermore, the amount of antibody could be semi-quantified, using the IgG standards. The method should be useful for rapid screening of autoantibodies in a routine laboratory.

Antigens↗

PubMed1994

The phylogeny of proteinase 3/myeloblastin, the autoantigen in Wegener's granulomatosis, and myeloperoxidase as shown by immunohistochemical studies on human leukemic cell lines.

Proteinase 3/myeloblastin (Pr3/MBN) is a serine protease found in primary granules of neutrophilic granulocytes and monocytes in man. This enzyme has been identified as the main autoantigen in Wegener's granulomatosis. Pr3/MBN was earlier identified in the promyelocytic cell line HL-60 and was assumed to be at least partly responsible for controlling proliferation and differentiation within the granulocytic-monocytic system. We have investigated 98 leukemic cell lines representing all lineages of the hemopoietic system. Pr3/MBN was found to appear in mature myeloblastic precursors and in CD34+ immature monoblastic cells and was restricted to the granulocytic and monocytic lineage. Myeloperoxidase (MPO) was found to be expressed earlier in development in the granulocytic lineage, but appeared later than Pr3/MBN in the monocytic lineage. The identification of cell lines which contained Pr3 only or MPO only may make them useful for demonstration of anti-neutrophil cytoplasmic antibodies in primary vasculitides.

Autoantigens↗

PubMed1994

Immunoreactivity of the JK-132 monoclonal antibody directed against basement membrane collagen in normal and diabetic glomeruli.

The possible involvement of basement membrane-associated collagen (recognized by the monoclonal antibody JK-132) in the evolution of diabetic nephropathy was studied in kidney specimens from seven patients with noninsulin-dependent diabetes mellitus, and its distribution was compared with those of antibodies against alpha 1 to alpha 4 chains of type IV collagen. JK-132, a monoclonal antibody against basement membrane-associated collagen, reacted immunohistochemically exclusively with the mesangial matrix of the glomerular capillary. In contrast, antibodies to the alpha 1 and alpha 2 chains (IV) reacted strongly with mesangial matrix, and less strongly with the glomerular basement membrane (GBM). Antibodies to the alpha 3 and alpha 4 chains (IV) reacted mainly with GBM. In diabetes, JK-132 reacted most extensively with the expanded mesangial matrix, its staining intensity increasing with progression of the diabetic glomerulosclerosis. Antibodies to the alpha 1 and alpha 2 chains (IV) reacted prominently with the expanded mesangial matrix but less strongly with the GBM. Antibodies to the alpha 3 and alpha 4 chains reacted intensely with the thickened GBM. These results suggest that basement membrane-associated collagen differs from alpha 1 to alpha 4 chains of type IV collagen and that basement membrane-associated collagen is a good marker of mesangial expansion in diabetic nephropathy.

Aged↗

PubMed1994

Expression of glomerular extracellular matrix components in human diabetic nephropathy: decrease of heparan sulphate in the glomerular basement membrane.

Diabetic nephropathy is characterized by albuminuria which proceeds to overt proteinuria. The highly negatively stained HS side chain of heparan sulphate proteoglycan (HSPG) is a major determinant of the charge-dependent permeability of the GBM. We set out to study the presence of HS and HSPG in the GBM of patients with diabetic nephropathy using newly developed monoclonal antibodies, and to compare HSPG expression to the expression of other previously investigated glomerular extracellular matrix compounds. Immunohistochemically, glomerular extracellular matrix components were analysed in 14 renal biopsies of patients with diabetic nephropathy and compared with those of normal control subjects. Monoclonal antibodies used were: JM403 against the HS side chain of GBM HSPG and JM72 against the HSPG-core protein. Also, a polyclonal antiserum (B31) against human GBM-HSPG-core protein was used. Additionally, antibodies were used against collagen types I, III, IV and against alpha 1 (IV)NC, alpha 3(IV)NC and fibronectin. Staining was scored for intensity and for staining pattern by four independent observers who had no previous knowledge of the sample origin. No glomerular staining was seen for collagen type I. Collagen type III was present in some diabetic nodules. Anti-collagen type IV showed a decreased GBM staining in patients with diabetic nephropathy (p = 0.04). With anti-alpha 1 (IV)NC no changes in GBM staining intensity were observed; with anti-alpha 3 (IV)NC brilliant GBM staining was seen in both groups. Increased mesangial staining (p = 0.003) was seen with anti-collagen type IV in biopsies with nodular lesions.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1994

Characterization of anti-GBM antibodies involved in Goodpasture's syndrome.

Goodpasture's syndrome is a life threatening autoimmune kidney disease. The patients have autoantibodies to the glomerular basement membrane, which are specific for the C-terminal domain of type IV collagen (NC1). The major antigen has been localized to the alpha 3 (IV)-chain. We have investigated sera from 44 patients with anti-NC1 antibodies. The quantity of antibodies to four different alpha(IV)-chains of type IV collagen was measured with direct ELISA. We used affinity chromatography to separate the antibodies and their specificities were studied with ELISA. The results show that about 1% of the patients total IgG are anti-NC1 antibodies and that 90% of these antibodies are specific for the alpha 3(IV)-chain. Antibodies to the other alpha(IV)-chains were found in 80% of the patients. Furthermore, affinity purified anti-alpha 3(IV) antibodies from one patient were inhibited by antibodies from the other patients, from 4 to 72%. The antibodies, from 39 of the patients, were inhibited by a monoclonal antibody against the alpha 3(IV)-chain. The results indicate that patients with Goodpasture's syndrome can have antibodies to most of the alpha(IV)-chains, while the majority of anti-NC1 antibodies are restricted to the alpha 3(IV)-chain. Moreover the number of epitopes seems to be limited and the majority of the antibodies from most patients are against one single epitope on the alpha 3(IV)-chain.

Anti-Glomerular Basement Membrane Disease↗

PubMed1994

Some patients with anti-myeloperoxidase autoantibodies have a C-ANCA pattern.

Rapidly progressive glomerulonephritis with or without other signs of systemic vasculitis is often accompanied by antibodies to myeloperoxidase. Such antibodies normally produce a perinuclear pattern on ethanol-fixed neutrophils (perinuclear anti-neutrophil cytoplasm antibodies (P-ANCA)) at indirect immunofluorescence. We report here sera from three patients that are anti-myeloperoxidase-positive in ELISA that instead produce a cytoplasmic pattern (classical anti-neutrophil cytoplasmic antibodies (C-ANCA)), a pattern normally seen in conjunction with antibodies to proteinase 3. These sera did not react with proteinase 3. For two of the sera the specificity of the anti-myeloperoxidase reaction was confirmed with inhibition-ELISA experiments and with immunoblotting. A mouse anti-myeloperoxidase MoAb that produces a cytoplasmic pattern is also described. Competition ELISA experiments show that this antibody and anti-myeloperoxidase sera with cytoplasmic pattern recognize epitopes that are separate from epitopes recognized by another perinuclear pattern producing anti-myeloperoxidase MoAb. 'Cytoplasmic pattern' epitopes as well as 'perinuclear pattern' epitopes can be found on all three major myeloperoxidase isoforms, after separation by ion exchange chromatography. Affinity chromatography, using the cytoplasmic pattern producing anti-myeloperoxidase monoclonal antibody, shows that the epitope recognized by this MoAb is present on all myeloperoxidase molecules. This epitope is not confined to any special subpopulation. These findings indicate that all myeloperoxidase do not relocate after ethanol fixation, and that C-ANCA and P-ANCA epitopes exist simultaneously on the same myeloperoxidase molecule. We propose that the two immunofluorescence patterns arise due to different availabilities of the epitopes in the microenvironment where myeloperoxidase is present.

Aged↗

PubMed1994

Strong link between the alpha 1-antitrypsin PiZ allele and Wegener's granulomatosis.

OBJECTIVES: To ascertain whether a relationship exists between the PiZ alpha 1-antitrypsin (alpha 1AT) variant and antineutrophil cytoplasm antibodies (ANCA)-positive vasculitis in a large group of Swedish patients, and whether analysis for the presence of the PiZ variant might be useful for diagnostic or prognostic purposes. DESIGN: Retrospective cross-sectional study. SETTING: The Department of Internal Medicine, Malmö General Hospital, and the Department of Nephrology, University of Lund, Sweden. SUBJECTS AND MAIN OUTCOME MEASURES: Serum samples from 105 proteinase 3-ANCA-positive patients were analysed using an ELISA with a monoclonal antibody specific for the PiZ-gene product. Complete clinical data were retrieved for 84% (88/105) of the patients, for diagnosis and survival analysis. RESULTS: We identified 17 heterozygotes and one homozygote (P < 0.0001). All 88 patients with available clinical data were considered to have some form of microscopic vasculitis including 66 (75%) diagnosed as having Wegener's granulomatosis (WG), of whom 15 (23%) were PiZ heterozygotes (odds ratio 6.0, 95% confidence interval 3-10). There were no significant differences between PiZ carriers and noncarriers in sex distribution, mean age at onset of disease, interval between onset and inclusion in the study, or in median duration of follow-up (P > 0.2 for all comparisons). During follow-up, 38% (6/16) of the PiZ heterozygotes died, compared with 17% (11/66) of noncarriers of the variant (P= 0.02), which suggests that PiZ heterozygosity may be a marker of poor prognosis. PiZ heterozygotes with systemic vasculitis would not appear to be identifiable by their pretreatment plasma alpha 1AT concentrations, as all such patients in the present study had concentrations within or above the normal range. CONCLUSION: We conclude that heterozygotes for the PiZ variant of the alpha 1AT gene are at greater risk of than the general population of developing WG. Knowledge of such a genetic factor may not only aid our understanding of the mechanism involved in this illness but may also serve as significant prognostic factor in following the course of the disease.

Adolescent↗

PubMed1994

Localization of fibril/microfibril and basement membrane collagens in diabetic glomerulosclerosis in type 2 diabetes.

Collagen is one of the major components of the extracellular matrices of the kidney. Basement membrane collagen, type IV collagen, is the major component in normal glomeruli. Fibril and interstitial collagen such as type III collagen, type V collagen, and type VI collagen are minor components of glomerular extracellular matrices and are localized mainly in the interstitium. Diabetic glomerulosclerosis is characterized by the expansion of the glomerular mesangial matrix as well as by thickening of the glomerular basement membrane. In order to clarify the roles of these various types of collagen in the development of diabetic glomerulosclerosis, immunohistochemical studies were performed in kidney specimens from patients with Type 2 diabetes. Early glomerulosclerosis is characterized by expansion of mesangial matrix with basement membrane collagen. However, in later stages glomerulosclerosis is characterized by an increase in the minor collagen components, such as type V and type VI collagen or collagens not normally present, such as type III collagen. Mesangial cells are known to synthesize all these types of collagen. In diabetes, phenotypic change in mesangial cells might produce excess amounts of fibril and interstitial collagen such as type III, type V, and type VI collagen, thus, leading to glomerulosclerosis.

Aged↗

PubMed1994

Significance of anti-entactin antibodies in patients with systemic lupus erythematosus and related disorders.

OBJECTIVES: To further evaluate the association of anti-entactin antibodies with clinical manifestations in patients with systemic lupus erythematosus (SLE) and related disorders. METHODS: Sera were analysed for anti-entactin antibodies from 79 patients with SLE, 38 patients with rheumatoid arthritis, 20 patients with progressive systemic sclerosis and five with Behçet's syndrome. Sera from 150 healthy blood donors and 20 patients with pneumonia were analysed as controls. To study the association of anti-entactin antibodies with severity and activity in SLE, 30 patients were assigned into three groups with 10 patients in each: (1) with mild manifestations; (2) severe disease without renal involvement and (3) frank lupus nephritis. Two blood samples from each patient were analysed, one from the active and the other from the inactive phase of the disease. Additionally, serial sera from 12 patients with SLE were also analysed. RESULTS: Thirty one patients with SLE (39%) had IgG, IgM or both anti-entactin antibodies. Twenty three of these patients (29%) had biopsy verified glomerulonephritis and 12 (50%) were positive for anti-entactin antibodies. Of the remaining 56 patients without apparent renal involvement, 18 (36%) were positive for anti-entactin antibodies. (chi squared = 2.77, p > 0.05). With the exception of rheumatoid arthritis where six patients (24%) had IgM anti-entactin antibodies, the antibodies were present much less frequently in other diseases (two patients with systemic vasculitis whilst none of the patients with PSS or Behçet's syndrome). Only one patient with pneumonia and none of the 150 sera from healthy blood donors had anti-entactin antibodies. Among Group 1, three (30%) were positive for IgG or IgM anti-entactin antibodies. Six (60%) patients in group 2, and five patients (50%) in group 3 were positive for anti-entactin antibodies. However, the difference between the presence of anti-entactin antibodies between group 1 and 2 or between group 1 and 3 was not significant (p = 0.15 and 0.19 respectively). There was no significant correlation between the titres of anti-entactin antibodies and total serum concentration of IgG (r = 0.141, p > 0.10) and IgM. (r = 0.130, p > 0.10). Furthermore, no significant correlation was observed between SLE disease activity index (SLEDAI) scores and the titres of IgG (r = 0.067, p > 0.10) or IgM (r = -0.033, p > 0.10) anti-entactin antibodies. CONCLUSION: The study demonstrates that anti-entactin antibodies are present in a significant number of patients with SLE and tend to be more common in those with severe disease, with or without nephritis, than in patients with mild disease manifestations. There is no correlation between the titre of anti-entactin antibodies and severity or activity of SLE.

Adult↗