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Biomedical subjects

K Fehr

Publications and source records attributed to K Fehr.

At least 19 recordsLinked to original sources
PubMed1992

[Polymyositis: disease course and therapy with intravenously administered immunoglobulins].

Corticosteroids and immunosuppressive agents are standard treatment for polymyositis (PM) and dermatomyositis (DM) respectively. Recent reports have emphasized a potentially successful regimen with intravenous immune gammaglobulins (IVIG). The short term success of this treatment in a personally observed case is described. IVIG treatment resulted in normalization of the serum concentrations of the muscle enzymes after continued inflammatory activity under treatment with azathioprine, cyclophosphamide and methotrexate in combination with corticosteroids. The improvement of PM by IVIG was further documented by an increase in muscle strength of up to 367% of the initial value and a regression of the myositic changes in the muscles of the thighs as evidenced by magnetic resonance imaging (MRI). The therapeutic response was paralleled by reversal of peripheral lymphopenia. Experience with IVIG treatment in PM/DM is reviewed and the potential role of this regimen in the management of PM/DM is discussed.

Adrenal Cortex Hormones↗
PubMed1992

Analysis of glycosaminoglycans in human serum after oral administration of chondroitin sulfate.

Chondroitin sulfate was administered orally to six healthy volunteers, six patients with rheumatoid arthritis and six patients with osteoarthritis. Blood was collected at intervals before and after treatment and the glycosaminoglycan concentration was analyzed in serum using a sensitive assay based on the metachromatic reaction with 1,9-dimethylmethylene blue. The glycosaminoglycan concentration in serum before and after ingestion of chondroitin sulfate was statistically unchanged in all of the subjects studied. We suggest that chondroprotection by orally administered chondroitin sulfate is a biologically and pharmacologically unfounded theory. Any possible benefit to osteoarthritic patients after ingestion of chondroitin sulfate should be sought at the gastrointestinal rather than at the plasmatic or articular cartilage level.

Administration, Oral↗
PubMed1979

[Chronic polyarthritis: role of polymorphonuclear leukocytes in the destruction of pannus-free articular cartilage].

The synovial fluid (SF) of RA patients contains large amounts of PMN which are well equipped with neutral enzymes to degrade articular cartilage: elastase and cathepsin G, which both destroy proteoglycans and native collagen, as well as 2 types of collagenoases. Indirect evidence suggests that PMN might be important in the destruction of RA articular cartilage. In 19 SF of RA patients no free elastase or collagenase was found. Using immune histochemical methods, we observed that PMN and macrophages of SF contain both elastase and alpha 1-anti-trypsin and alpha 2-macroglobulin. Peripheral PMN - but not monocytes - contain elastase, however both types of cells lack alpha 1-antitrypsin and alpha 2-macroglobulin. Elastase is demonstratable in the superficial layer of pannus free RA articular cartilage. These findings suggest that neutral proteinases from PMN in RA SF are generally neutralized by physiologic inhibitors and removed by phagocytes. The enzyme-inhibitor interaction might be bypassed during "frustrated phagocytosis" so that enzymes like PMN elastase can damage RA articular cartilage.

Arthritis, Rheumatoid↗
PubMed1977

[Morphology of articular cartilage in fab2-induced arthritis of the knee-joint in the rabbit (author's transl)].

An arthritis closely resembling rheumatoid arthritis in man can be produced by the intra-articular injection of Fab2 into the knee joint of rabbits. This experimental model was used for the examination of ultrastructural alterations in articular cartilage. The lesion starts at the surface and advances gradually to the deeper zones of the cartilage. Morphologically, the lesion is characterized by progressive necrobiosis of the chondrocytes, as well as by a continually increasing thickening of the collagen fibres. It is suggested that the initial damage to the cartilage is not brought about by the pannus tissue, but is caused by a direct reaction to the pathologically-altered synovial fluid in response to inflammation.

Animals↗
PubMed1977

Cathepsin D agglutinators in rheumatoid arthritis. I. Increased CDA titers in serum and synovial fluid of patients with seropositive RA.

The incidence and titer of cathepsin D agglutinators (CDA) were significantly higher in seropositive rheumatoid arthritis (RA) sera than in the sera of healthy blood donors or of patients with other rheumatic diseases, including seronegative RA. A significant elevation was also found in synovial fluid (SF) samples from seropositive RA patients. CDA in the SF tended to be increased when compared with the corresponding serum. The levels of CDA correlated positively with those of rheumatoid factors (RF) when the latter were determined with IgG anti-CD Ripley-coated erythrocytes, but not when they were determined by the Waaler-Rose or latex tests. The increased CDA titers do not seem to be the result of significant amounts of IgM agglutinators or of the presence of IgM-RF. These findings suggest the existence of a link between the formation of RF and CDA, but the nature of this link cannot be fully explained.

Agglutinins↗
PubMed1976

Purification and some properties of a neutral protease from human leukocyte granules and its comparison with pancreatic elastase.

1. A cationic protease has been purified from the granule fraction of blood-donor leukocytes by a preparative method including precipitation by acetone and chromatography on Bio-Gel A 1.5 m, CM-Sephadex C-50 and Sephadex G-G-75. 2. The pH optimum against denatured bovine hemoglobin is 7.4. Gel chromatography indicated a molecular weight close to 23 000. 3. This neutral protease (EC 3.4.-.-) is able to split the synthetic esters Z-Ala-NPh and AcAla3OMe, its activity on the former substrate being 2.2 times greater than that of pancreatic elastase, on the latter the same. It differs crucially from pancreatic elastase in having small elastinolytic activity. 4. In cationic disk electrophoresis, neutral protease resolves into three protein bands with lower mobility than lysozyme: all bands exhibit esterolytic activity against 2-acetoxy-3-naphthoic acid o-toluidide, strongly suggesting that they represent isoenzymes. 5. The enzyme is completely inhibited by iPr2P-F, partially so by soybean trypsin inhibitor and Trasylol. Cysteine, EDTA and TosLysCH2Cl have no effect. 6. During chromatography on CM-Sephadex C-50 a more positively charged enzyme(s) was identified. This had hemoglobinolytic activity at pH 7.4 but only a small esterolytic effect on Z-Ala-NPh; it showed only traces of activity against AcAla3OMe.

Cytoplasmic Granules↗
PubMed1976

Experimental arthritis of rabbits caused by intra-articular injection of autologous Fab2 produced by digestion of IgG with cathepsin D.

Intra-articularly injected autologous Fab2 produced from IgG by homologous cathepsin D induces in animals not given prior immunization acute synovitis after 1 and 3 injections, acute synovitis after 6 injections, and chronic synovitis after 12 injections. Histologically, the chronic synovitis is similar to synovitis in rheumatoid arthritis (RA). In the joint, cathepsin D Fab2 appears to act as a fairly strong antigen. Evidence for this is provided by the infiltration of large numbers of polymorphonuclear leucocytes, the marked phagocytic activity of the exudate leucocytes and tissue phagocytes, and the stimulation of the synthesis of specific antibodies (homoreactants) in the synovial plasma cells. The immediate action of injected Fab2 suggests that it forms biologically active immune complexes with homoreactants already present. These complexes are phagocytosed, the homoreactants being demonstrable immunohistochemically in inclusions of the exudate and tissue phagocytes. In addition, the local synthesis of antigammaglobulins of rheumatoid factor type is also induced. These react with heat-aggregated homologous as well as human IgG and are likewise found in inclusions in the exudate and tissue phagocytes. In the serum of the animals the titre of rheumatoid factor-like antigammaglobulins increases to an extent depending on the number of injections given. These histochemical and serological findings show striking parallels with the findings in human RA.

Acute Disease↗
PubMed1976

Circulating and intra-articular immune complexes in patients with rheumatoid arthritis. Correlation of 125I-Clq binding activity with clinical and biological features of the disease.

The correlation between the incidence and level of immune complexes in serum and synovial fluid and the various clinical and biological manifestations of rheumatoid arthritis has been studied. Immune complexes were quantitated using a sensitive radioimmunoassay, the 125I-Clq binding test, in unheated native sera and synovial fluids from 50 patients with seropositive (RA +) and 45 with seronegative (RA -) rheumatoid arthritis, 17 with other inflammatory arthritis, and 37 with degenerative and post-traumatic joint disease. The following observations were made: (a) when compared to the results from patients with degenerative and post-traumatic joint diseases, the 125I-Clq binding activity (Clq-BA) in synovial fluid was found to be increased (by more than 2 SD) in most of the patients with RA + (80%) and RA - (71%) and in 29% of patients with other inflammatory arthritis; the serum Clq-BA was also frequently increased in both RA + (76%) and RA - (49%) patients, but only exceptionally in patients with other inflammatory arthritis (6%); (b) a significant negative correlation existed between the Clq-BA and the immunochemical C4 level in synovial fluids from patients with RA + and RA -; (c) neither the serum nor the synovial fluid Clq-BA in rheumatoid arthritis significantly correlated with the erythrocyte sedimentation rate, the clinical stage of the disease, or the IgM rheumatoid factor titer; and (d) the serum Clq-BA in patients with rheumatoid arthritis and extra-articular disease manifestations (40 +/- 34% in those with RA +,32 +/- 29% in those with RA -) was significantly increased as compared to the serum Clq-BA in patients with joint disease alone (24 +/- 30% in those with RA +, 10 +/- 13% in those with RA -). Experimental studies were carried out in order to characterize the Clq binding material in rheumatoid arthritis. This material had properties similar to immune complexes: it sedimented in a high molecular weight range on sucrose density gradients (10-30S) and lost the ability to bind Clq after reduction and alkylation, or after acid dissociation at pH 3.8, or after passage through an anti-IgG immunoabsorbant. DNase did not affect the Clq BA. These results support the hypothesis that circulating as well as intra-articular immune complexes may play an important role in some pathogenetic aspects of rheumatoid arthritis. The 125I-Clq binding test may also be of some practical clinical value in detecting patients who have a higher risk of developing vasculitis.

Adult↗
PubMed1976

Ultrastructural studies of rabbit synovitis induced by autologous IgG fragments. I. Proliferation of the lining cells.

The synovial lining cells of rabbits with experimental synovitis induced by intra-articular injection of cathepsin D-digested autologous IgG fragments (Fab2) have been subjected to electronmicroscopic study. From 3 to 50 such injections resulted in hyperplasia of the lining layer with an increase in the numbers of phagocytic and synthetic cells. Morphologically the phagocytes were classified into monocyte-like cells, mature and immature phagocytes, and epitheloid=like cells, indicating that synovial M cells may originate from blood monocytes that differentiate in situ like the monocytes in other tissues. The finding of "undifferentiated" (mesenchymal), transitional and mature synthetic cells in the lining layer suggests that synovial F cells are derived from the undifferentiated mesenchymal cells persisting in the synovial membrane in postnatal life. In the animals with synovitis, the synthetic cells were found to undergo mitosis but not the phagocytic cells. It is concluded that the hyperplasia of the lining layer is due to two distinct processes, namely invasion by precursors of M cells (monocytes) and local proliferation of F cells. As far as immune reactions involved in the synovitis are concerned, the possible roles played by lysosomal substances in these two processes are also discussed.

Animals↗
PubMed1976

Ultrastructural studies of rabbit synovitis induced by autologous IgG fragments. II. Infiltrating cells in the sublining layer.

The synovial sublining layer of rabbits with synovitis induced by intra-articular injection of cathepsin D digested autologous IgG fragments (Fab2) has been examined under the electron microscope. Twelve or more injections of autologous Fab2 led to chronic synovitis with dense mononuclear cell infiltrates containing lymphocytes, blastic cells, plasma cells and macrophages. In the infiltrates there was evidence that the lymphocytes had been activated prior to transformation into mature plasma cells. Indirect evidence suggests that T lymphocyte activation also occurred in these infiltrates. Cellular contacts between macrophages and lymphocytes or plasma cells as well as between M cells and lymphocytes were demonstrated. These contacts are tentatively interpreted as a feature of ongoing immune processes in the synovium.

Animals↗
PubMed1976

Experimental arthritis of rabbits caused by intra-articular injection of autologous Fab2 produced by digestion of IgG with cathepsin D. II. Microscopical and immunohistochemical findings in long-term experiments.

Over 20 successive intra-articular injections of autologous or homologous cathepsin D-Fab2 produce chronic destructive arthritis marked by dense round-cell infiltration, epitheloid hyperplasia of the lining layer, lymph nodules and a few germinal centres. 75% of the animals become Rf-positive and develop high titers of homoreactants to cathepsin D-Fab. Both these antibodies are synthesized in the synovial membrane and phagocytosed. Careful study of control animals makes it possible to exclude the possibility that the effects observed are due to the repeated joint traumata, to endo- or exotoxin-like substances, to chromatographed lysosomal material or to traces of cathepsin D. Autologous and homologous Fab2 have largely identical effects, while those of homologous or autologous IgG are much less marked. These comparisons suggest that the cathepsin D site of IgG acts as a strong antigen when exposed in the joint. The synovitis thereby induced has a pronounced tendency to spread to the left knee joint which was injected with physiological saline.

Animals↗
PubMed1976

Experimental production of rheumatoid factor-like antibodies and antibodies against the cathepsin D site of IgG following the injection of autologous Fab2.

In a very high proportion of rabbits, repeated intra- or extra-articular injections of autolous Fab2 produced by homologous cathepsin D induce the formation of Rf-like antibodies reacting with both homologous and human IgG. Moreover, intra-articular injections of this kind cause a significant rise in the titre of thm of all the animals so far tested. Rf-like antibodies against human IgG appear earlier and have higher serum titres than those reacting with homologous IgG. The reason for this latter observation seems to be the blocking of the anti-rabbit IgG antibodies by the animal's own IgG. The anti-rabbit IgG antibodies can be absorbed only on aggregated rabbit IgG. The anti-human IgG antibodies cross-react to some extent with rabbit IgG. The results of inhibition studies suggest that the formation of anti-Fab2 homoreactants is directly stimulated by the injected Fab2, whereas the Rf-like antibodies owe their appearance to immune complexes formed in vivo by the injected Fab2 and the naturally occuring anti-Fab2 homoreactants. In respect of immunoglobulin class, the two kinds of Rf-like antibody are possibly of both IgM and IgG type.

Animals↗