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L van den Bersselaar

Publications and source records attributed to L van den Bersselaar.

16 recordsLinked to original sources
PubMed2001

IL-1-independent role of IL-17 in synovial inflammation and joint destruction during collagen-induced arthritis.

T cell IL-17 displays proinflammatory properties and is expressed in the synovium of patients with rheumatoid arthritis. Its contribution to the arthritic process has not been identified. Here, we show that blocking of endogenous IL-17 in the autoimmune collagen-induced arthritis model results in suppression of arthritis. Also, joint damage was significantly reduced. In contrast, overexpression of IL-17 enhanced collagen arthritis. Moreover, adenoviral IL-17 injected in the knee joint of type II collagen-immunized mice accelerated the onset and aggravated the synovial inflammation at the site. Radiographic and histologic analysis showed markedly increased joint destruction. Elevated levels of IL-1beta protein were found in synovial tissue. Intriguingly, blocking of IL-1alphabeta with neutralizing Abs had no effect on the IL-17-induced inflammation and joint damage in the knee joint, implying an IL-1 independent pathway. This direct potency of IL-17 was underscored in the unabated IL-17-induced exaggeration of bacterial cell wall-induced arthritis in IL-1beta(-/-) mice. In conclusion, this data shows that IL-17 contributes to joint destruction and identifies an IL-1-independent role of IL-17. These findings suggest IL-17 to be a novel target for the treatment of destructive arthritis and may have implications for tissue destruction in other autoimmune diseases.

Adenoviridae↗
PubMed1993

Reversible depletion of synovial lining cells after intra-articular treatment with liposome-encapsulated dichloromethylene diphosphonate.

We studied the depletion and repopulation of synovial lining cells in mice. A single intra-articular injection of liposomes encapsulating the drug dichloromethylene diphosphonate (CL2MDP) in the mouse knee joint caused selective elimination of synovial lining cells. Depletion of cells occurred within a few days as evidenced by light microscopic, electronmicroscopic and immunohistochemical studies. Maximal depletion was seen on day 7. Repopulation was observed in the following weeks, starting at the bone side of the joint. Until day 30, full recovery (60% recovery) was not observed in the lining lying adjacent to the dermis. Side effects on cartilage metabolism, such as inhibition of proteoglycan synthesis or degradation of proteoglycans from the matrix was minor but significant, 1 and 2 days after liposome treatment but thereafter full recovery was observed. Selective elimination of lining cells from the joint enabled us to study the in vivo role of these cells in the onset and subsequent pathology of experimental arthritis. An immune-complex-mediated experimental arthritis elicited in lining cell depleted joints that had received CL2MDP-liposomes 7 days earlier prevented inflammation as compared to controls.

Animals↗
PubMed1993

Role of phagocytic synovial lining cells in experimental arthritis.

We investigated the in vivo role of phagocytic synovial lining cells (SLC) in the onset of experimental arthritis by depleting phagocytic SLC prior to arthritis induction. Phagocytic SLC were depleted by a single intra-articular injection of liposomes encapsulating the drug dichloromethylene diphosphonate (CL2MDP). Seven days after injection optimal depletion was observed and this time point was chosen for induction of arthritis in SLC depleted joints. Joint swelling was highly reduced after elicitation with either zymosan, immune complexes or antigen, as compared to observations in normal non-depleted joints. In addition cellular infiltration was markedly reduced. Further study in the immune complex mediated arthritis revealed that reduced cell influx in SLC depleted knee joints was correlated to lowered chemotactic activity and IL-1 levels as measured in washouts of joint tissues. This indicates that IL-1 driven chemotactic factors might be involved. Furthermore reduced cell influx was also correlated to significantly diminished loss of 35S-prelabeled PG from the cartilage. Out data indicate that SLC are directly involved in the onset of joint inflammation.

Animals↗
PubMed1991

Chondrocyte nonresponsiveness of arthritic articular cartilage caused by short term immobilization.

We studied the effect of short term immobilization on chondrocyte synthetic function. Arthritis from intraarticular injection of either glucose oxidase or interleukin 1 (IL-1) led to suppression of proteoglycan synthesis. Extension casting of arthritic knees prevented inhibition of proteoglycan synthesis, whereas later casting restored synthesis to normal. During chronic antigen induced arthritis casting protected chondrocyte synthesis for a period of 5 days. The chondrocyte nonresponsiveness was not from altered penetration of suppressing substances. Radiolabelled biologically active IL-1 showed no difference in retention or localization in articular cartilage of either mobile or immobile knees. Flexion casting did not induce unresponsiveness of chondrocytes and suppression of synthesis was similar to that in mobile arthritic knees, indicating the importance of loading. The nonresponsiveness occurred only during immobilization and rapidly disappeared after removal of the cast, provided that suppressing agents were still present. Thus, during short term immobilization chondrocytes are protected from inhibition of proteoglycan synthesis by suppressing agents. This protection may benefit repair of the depleted cartilage matrix with waning inflammation.

Animals↗
PubMed1990

Immobilization aggravates cartilage damage during antigen-induced arthritis in mice. Attachment of polymorphonuclear leukocytes to articular cartilage.

The early and late effects of short-term immobilization on arthritic joints have been studied. Knee joints of mice in which an antigen-induced unilateral arthritis was elicited were immobilized in extension for 3, 5, and 7 days. After 5 and 7 days' immobilization, arthritis was significantly more severe. More leukocytes infiltrated the periarticular tissues and more cellular exudate was found in the joint space. A striking observation was that large numbers of polymorphonuclear leukocytes (PMN) attached to the surface of the cartilage, a phenomenon not found in mobile arthritic joints. Electron-microscopy confirmed PMN adhesion and showed severe ruffling of the cartilage surface under immobilized conditions. Further examination of factors determining PMN sticking revealed that attachment is rapid when the cartilage surface is already damaged, and that retained immune complexes and complement play a pivotal role. The late effects of immobilization were studied after a remobilization period of 2 weeks. Enhanced matrix depletion and chondrocyte death persisted in arthritic joints that were previously immobilized for 5 and 7 days, and the latter also showed significantly increased osteophyte formation. Although these results are speculative for the human situation, this study indicates that treatment of arthritic joints by complete rest should be applied with caution.

Animals↗
PubMed1989

Allergic arthritis induced by cationic proteins: role of molecular weight.

Previous studies have shown that chronic murine allergic arthritis can only be induced with cationized BSA, related to excellent retention of the cationic antigen in the joint. We now investigate the impact of size of cationic proteins on their potential to induce this form of arthritis. After intra-articular injection, antigen retention is much enhanced with high molecular weight cationized proteins, like albumin or immunoglobulin, compared to small-sized proteins like myoglobulin and lysozyme. Consequently, severe chronic arthritis was only found with the former ones. The role of size is further substantiated with poly-L-lysine-coupled lysozyme. This derivative shows excellent retention in vivo and causes a chronic destructive arthritis in preimmunized mice, in contrast to the poor arthritis seen with native cationic lysozyme. Control experiments made it clear that antigen retention is the most important denominator and that differences in chronicity are not related to gross variations in T-cell reactivity. Retention studies in vitro revealed that the potential to bind to joint structures is similar for the various proteins, suggesting that in vivo conditions determine size-related differences in antigen clearance. Our data indicate that cationicity per se does not make a protein a proper arthritogen.

Animals↗
PubMed1989

Fate of antigen after intravenous and intraarticular injection into mice. Role of molecular weight and charge.

The role of the charge of differently sized proteins in their penetration, persistence and localization in murine joint tissues was studied. Radiolabeled proteins of variable molecular weight (14-150 kDa) and charge (isoelectric point (pI) 4.5-10) were administered by intravenous and intraarticular routes, and localization studies in the first 2 and at 24 h were done with autoradiography. Small cationic proteins rapidly penetrated joint tissues after intravenous injection and persisted in larger amounts compared to anionic proteins of corresponding size. Small cationic proteins easily penetrated the matrices of both epiphysial and articular cartilage. In contrast larger cationic proteins (cBSA, cIgG) persisted for the greater part in the tissues just around the vessels and cartilage association was less striking. After intraarticular injection it was found that low molecular weight proteins (14 to 47 kDa) are rapidly cleared from the joint. Small cationic proteins persisted somewhat better than anionic ones, but impressive retention was only found with cationic proteins with higher molecular weight (67 to 150 kDa). Our data help to define prerequisite properties of proteins for penetration and interaction with joint structures after systemic supply or local production.

Animals↗
PubMed1988

Electrical charge of a protein determines penetration and localization in hyaline articular cartilage. Quantitative and autoradiographic studies on cartilage of different species, including man.

Sufficient antigen retention in joint structures is a prerequisite for sustained antigen-induced arthritis. In this in vitro study we investigated the retention of native and charge-modified bovine serum albumin (BSA) with patellar cartilage of different species (mouse, rat, rabbit, and man). Association of BSA with cartilage due to charge of the protein with that due to immune complex formation was compared. Using radiolabeled proteins we showed quantitatively that the retention of highly positively charged BSA is considerably higher (200-500 times) than retention of the anionic BSA in all cartilage species examined. Mouse, rat, and human cartilage bind more protein per mg dry weight, compared to rabbit cartilage. No clear-cut relation was found with the glycosaminoglycans (GAG) contents. Retention of native BSA by anti-BSA antibodies was low in the dense hyaline patellar cartilage in all species. Enhanced immune-complex formation was found in marginal regions of rabbit patellar cartilage, consisting of fibrous-like cartilage. Localization studies by autoradiography showed that cationic BSA penetrates deeply into the cartilage matrix. Even in a thick cartilage specimen, such as rabbit cartilage, very deep penetration into the calcified zone was demonstrated. This study indicates that binding and deep penetration of cationized protein in cartilage is not restricted to mouse specimen, as had been found previously, but is a general phenomenon.

Animals↗
PubMed1987

The impact of protein size and charge on its retention in articular cartilage.

The interaction of several globular proteins with intact murine hyaline articular cartilage was studied in vitro. Proteins with molecular weights from 12 to 440 kDa and isoelectric points (pI) from 4.5 to 10 were tested for the ability to penetrate and persist in cartilage. Native proteins were modified for a range of pI. Using radiolabeled proteins we showed that retention of proteins in cartilage is a function of their pI. At pI 8.5-9 all proteins showed a sharp increase in cartilage when incubated at physiologic pH. The molecular weight of a protein and its charge is a determining factor for penetration of cartilage. By autoradiography highly cationic proteins up to 150 kDa (IgG) readily penetrated cartilage. Immunofluorescence confirmed these findings. Cationic catalase (240 kDa) showed superficial penetration, but penetration of cationic ferritin (440 kDa) was not demonstrated, suggesting that 240 to 440 kDa represents the upper range for penetration. Small anionic proteins (cytochrome-c; pI less than 4.5; 12 kDa) penetrate in small quantities but do not persist, whereas larger anionic proteins (IgG; pI less than 4.5; 150 kDa) cannot penetrate at all. Our data help define the properties of proteins that are able to interact with cartilage matrix and chondrocytes.

Animals↗
PubMed1987

Allergic arthritis induced by cationic antigens: relationship of chronicity with antigen retention and T-cell reactivity.

In order to define the antigenic properties necessary for sustained allergic arthritis, we prepared a range of differently charged bovine serum albumin (BSA) species with increasing isoelectric points (4.5, 4.5-7.4, 7-8, 8.5-9 and greater than 9). The highly cationic BSA greater than 9 appeared to be in a polymeric form. We investigated three properties of these proteins: (i) antigen retention, (ii) T-cell reactivity, and (iii) arthritis induction. Injection of the respective radiolabelled antigens in the knee-joints of immunized mice showed that antigen retention increased with cationicity of the proteins, with the best retention found for BSA with pI greater than 9. However, sustained joint inflammation was only found with BSA8.5-9, and not with a level BSA of lower or even higher pI. T-cell reactivity in vivo as measured by delayed-type hypersensitivity (skin testing) was similar for the tested antigens, with the exception of polymeric BSA (greater than 9). The latter appeared to be a poor antigen. In vitro, T-cell reactivity ([3H]-thymidine incorporation) against the cationized BSA species was slightly higher as compared to native BSA. The combination of excellent antigen retention and adequate T-cell reactivity appears to be optimal for the induction of chronic arthritis.

Animals↗
PubMed1985

Cationization of catalase, peroxidase, and superoxide dismutase. Effect of improved intraarticular retention on experimental arthritis in mice.

Several enzymes and other proteins were made cationic either by coupling to polylysine or by shielding of anionic sites. These cationic proteins, all having an isoelectric point greater than 8.5 exhibited excellent retention in articular structures when injected in mouse knee joints. Autoradiography and histochemistry showed that cationic forms of catalase, superoxide dismutase, and horseradish peroxidase were firmly retained by synovial and cartilaginous tissues. The half-life of these enzymes in the joint is thus significantly extended compared with native enzymes. The native enzymes and their cationic derivatives were tested for antiinflammatory properties in mice, using antigen-induced arthritis and zymosan-induced arthritis. It was found that injection of cationic catalase or peroxidase induced a marked suppression of some parameters of the inflammatory response in both types of arthritis, as measured by 99m technetium pertechnetate uptake and leakage of 125I-labeled albumin. Native catalase and peroxidase were less, or not at all effective. Cationic superoxide dismutase or cationic nonenzyme proteins did not suppress inflammation. The observed suppression of two different types of inflammation (an immune and a nonimmune arthritis) by catalase and peroxidase suggests that elimination of peroxides contributes to the suppression of an inflammatory response. We would hypothesize that cationic enzymes offer the possibility for investigating the mechanisms of inflammation and, in addition, might be interesting from a therapeutical point of view.

Animals↗
PubMed1984

Flare-up of antigen-induced arthritis in mice after challenge with oral antigen.

Mice with unilateral chronic mBSA-induced arthritis were orally challenged with mBSA. Three hours after antigen challenge clear flare-up of the chronic arthritis was demonstrable as detected by an increase in the 99mTc uptake of the knee joint and the reaction continued for at least 2 days. The contralateral non-arthritic knee joint was not affected. The dose of mBSA needed to induce a flare-up in nearly all mice within a group was in the order of 20 mg. After oral challenge with 10 or 5 mg of mBSA the incidence was lower and flare-up reactions were only rarely observed after challenge with 2.5 or 1.25 mg mBSA. Histology of knee joints taken at 24 h after oral challenge of 20 mg mBSA revealed an increase in the number of cells in the infiltrate in the synovial tissue and exudate in the joint space, the most conspicuous sign being the increase of PMN. Passage of macromolecules through the gastrointestinal mucosa may be an important principle in the perpetuation of human chronic arthritis.

Administration, Oral↗