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T W Kuijpers

Publications and source records attributed to T W Kuijpers.

At least 37 records · Page 2Linked to original sources
PubMed2001

CD18 activation epitopes induced by leukocyte activation.

The cell surface adhesion molecule LFA-1 coordinates leukocyte trafficking and is a costimulatory molecule for T cell activation. We developed a panel of mAbs that recognize activation epitopes on the CD18 subunit, and show that stimulation of T lymphocytes appears to be accompanied by a conformational change in a subpopulation of LFA-1 that does not require ligand binding. Activation epitope up-regulation requires divalent cations, is sensitive to cellular signal transduction events, and correlates with cell adhesion. In addition, the stimulated appearance of these activation epitopes is absent in cell lines from patients with leukocyte adhesion deficiency-1/variant that has previously been shown to be defective in LFA-1 activation. Thus, these activation epitope Abs can be used to dissect signal transmission to CD18. Evidence suggests that these CD18 activation epitopes are induced early in cellular activation and are independent of actin rearrangement necessary for avid adhesion. We have also determined that function-blocking CD18 Abs inhibit the induction of activation epitopes. One activation epitope Ab binds to a site on CD18 distinct from that of the blocking Abs, indicating that the blocking Abs suppress a conformational change in LFA-1. We also find that these neoepitopes are present on rLFA-1 with high affinity for ICAM-1 and their binding is modulated in parallel with the affinity of LFA-1 for ICAM-1. Collectively, these neoepitope Abs identify a subpopulation of LFA-1 most likely with high affinity for ICAM-1 and necessary for LFA-1 function.

Adjuvants, Immunologic↗
PubMed2001

Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia.

The clinical benefit of intravenous immunoglobulin (IVIG) preparations in the treatment of immune thrombocytopenic purpura (ITP) is supposed to be mediated by blockade of Fc gamma receptor--bearing phagocytes. In 2 experimental models for ITP, it is shown that the therapeutic efficacy of IVIG preparations is related to the IgG dimer content present in these preparations. A rat monoclonal antibody (mAb; MWReg30) directed to the murine platelet-specific integrin alpha(IIb)beta(3) (gpIIb/IIIa) was administered intraperitoneally either as bolus injection or continuous infusion. With bolus injection, the circulating platelet count dropped to almost zero within 3 hours. Pretreatment with cobra venom factor did not affect platelet depletion, whereas pretreatment with anti-Fc gamma RII/III mAb 2.4G2 or IVIG greatly reduced platelet clearance. With continuous infusion, platelet numbers reached a steady state after 4 days, at approximately 25% of control. This reduction in platelets was, however, not observed in mice deficient for the FcR gamma-chain, lacking Fc gamma RI, Fc gamma RIII, and Fc gamma RIII(-/-) mice. Infusion of a single dose of IVIG with a high IgG dimer content on the 4th day--ie, mimicking therapeutic administration--resulted in a platelet increase for several days. IVIG predominantly consisting of monomeric IgG had no effect on platelet numbers. In conclusion, continuous infusion of MWReg30 induces thrombocytopenia in mice by enhancing Fc gamma receptor--mediated clearance of platelets. In this model, it is shown that IgG dimers present in IVIG preparations are responsible for the increase in platelet counts. (Blood. 2001;98:1095-1099)

Animals↗
PubMed2001

Beta1 integrin activation on human neutrophils promotes beta2 integrin-mediated adhesion to fibronectin.

Although the importance of beta1 integrin-mediated binding to adhesion molecules and extracellular matrix (ECM) molecules is well established for most types of leukocytes, the expression patterns and functional importance of beta1 integrins on neutrophils have remained controversial. Using flow cytometry, we found that human neutrophils express the alpha4, alpha5, alpha9 and beta1 integrin subunits. To examine whether the integrins VLA-4 (alpha4/beta1) and VLA-5 (alpha5/beta1) have a functional role on neutrophils, we studied adhesion to their ligand fibronectin. Treatment of neutrophils with antibody 8A2, which specifically binds and activates beta1 integrins, resulted in increased binding to fibronectin. However, addition of blocking mAb revealed that 8A2-induced adhesion did not depend on beta1 integrins, but on the beta2 integrin CD11b/CD18. Similarly, activation of beta1 integrins by 8A2 resulted in CD11b-dependent binding of neutrophils to fibrinogen. 8A2 treatment increased expression of an activation epitope of CD11b/CD18, which depended on phosphoinositide 3-OH kinase activity and an adequate concentration of intracellular free Ca2+. These data suggest that engagement of beta1 integrins on neutrophils results in a cross-talk signal that leads to activation of the beta2 integrin CD11b/CD18, followed by CD11b-mediated adhesion. As transmigrated neutrophils are surrounded by both beta1 and beta2 ligands in the ECM, this integrin cross-talk could play a role in modifying migration and cellular activation in inflamed tissues.

Androstadienes↗
PubMed2001

Flow cytometric immunophenotyping in the diagnosis and follow-up of immunodeficient children.

From time to time, paediatricians are confronted with children who might suffer from a primary immunodeficiency disease. For practical purposes, these children can be divided into four main clinical categories: (1) a relatively large group of children with recurrent ear-nose and throat and lower respiratory tract infections, in some cases caused by deficiencies of antibodies or complement; (2) children with failure to thrive, intractable diarrhoea or an opportunistic infection which can be caused by a T-lymphocyte or combined immunodeficiency; (3) children with infections with pyogenic bacteria or fungi as seen in case of granulocyte/monocyte function deficiency; and (4) a small heterogeneous group of children with recurrence of particular infections. Also, acquired immunodeficiency becomes a more common problem in paediatric practice. Flow cytometric immunophenotyping of leucocytes appears to be an efficient and rapid tool in the diagnosis and follow-up of immunodeficient patients, supporting early recognition, before serious infections have compromised the child's general condition. This technique can now be performed in many hospitals. In this review, we give directions for the use of flow cytometric immunophenotyping of leucocytes in the diagnosis and follow-up of immunodeficient children according to the four main clinical categories.

Child↗
PubMed2001

Intravenous immunoglobulin preparations induce mild activation of neutrophils in vivo via triggering of macrophages--studies in a rat model.

Despite widespread use in various immune disorders, the in vivo mechanisms of action of intravenous immunoglobulin (IVIG) preparations are not well known. We previously reported that human neutrophils degranulate after incubation with IVIG in vitro as a result of interaction with FcgammaRII. The purpose of this study was to determine whether IVIG might stimulate neutrophils in vivo. Anaesthetized rats received a bolus intravenous injection of IVIG preparations, containing either high (aged IVIG) or low (fresh IVIG) amounts or IgG dimers at a dose of 250 mg/kg. Administration of aged IVIG induced neutrophil activation in vivo, whereas no effect was observed after infusion of fresh IVIG. Histological examination of lung tissue demonstrated mild influx of neutrophils into the pulmonary tissue after aged IVIG administration, though gross damage did not occur. Macrophage-depleted rats no longer showed activation of neutrophils after infusion of aged IVIG, suggesting that neutrophils become activated via an indirect macrophage dependent way. We conclude that IVIG induces a mild activation of neutrophils in vivo via triggering of macrophages depending on the amount of IgG dimers. For this reason, IVIG preparations with a high content of dimers may not always be as harmless as generally believed and may be responsible for some of the side-effects observed during IVIG infusions.

Analysis of Variance↗
PubMed2001

The impact of platelet-activating factor (PAF)-like mediators on the functional activity of neutrophils: anti-inflammatory effects of human PAF-acetylhydrolase.

Platelet-activating factor (PAF) is a proinflammatory agent in infectious and inflammatory diseases, partly due to the activation of infiltrating phagocytes. PAF exerts its actions after binding to a monospecific PAF receptor (PAFR). The potent bioactivity is reflected by its ability to activate neutrophils at picomolar concentrations, as defined by changes in levels of intracellular Ca(2+) ([Ca(2+)](i)), and induction of chemotaxis and actin polymerization at nanomolar concentration. The role of PAF in neutrophil survival is, however, less well appreciated. In this study, the inhibitory effects of synthetic PAFR-antagonists on various neutrophil functions were compared with the effect of recombinant human plasma-derived PAF-acetylhydrolase (rPAF-AH), as an important enzyme for PAF degradation in blood and extracellular fluids. We found that endogenously produced PAF (-like) substances were involved in the spontaneous apoptosis of neutrophils. At concentrations of 8 microg/ml or higher than normal plasma levels, rPAF-AH prevented spontaneous neutrophil apoptosis (21 +/- 4% of surviving cells (mean +/- SD; control) versus 62 +/- 12% of surviving cells (mean +/- SD; rPAF-AH 20 microg/ml); P < 0.01), during overnight cultures of 15 h. This effect depended on intact enzymatic activity of rPAF-AH and was not due to the resulting product lyso-PAF. The anti-inflammatory activity of rPAF-AH toward neutrophils was substantiated by its inhibition of PAF-induced chemotaxis and changes in [Ca(2+)](i). In conclusion, the efficient and stable enzymatic activity of rPAF-AH over so many hours of coculture with neutrophils demonstrates the potential for its use in the many inflammatory processes in which PAF (-like) substances are believed to be involved.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2001

Clinical and molecular variability in childhood periodic fever with hyperimmunoglobulinaemia D.

OBJECTIVES: The hyperimmunoglobulinaemia D and periodic fever syndrome (HIDS) was found recently to be caused by a deficiency of mevalonate kinase (MK). The aim of this study was to examine whether a relationship exists between the clinical expression of HIDS and the extent of MK deficiency. METHODS: The medical records of children diagnosed with HIDS were reviewed for clinical features and serum immunoglobulin values. The mevalonic acid excretion in urine and MK enzyme activity in patients' cells were measured and the cDNA of the MVK gene was sequenced. RESULTS: Fifteen patients with recurrent fever and raised serum immunoglobulin (Ig) D were included. Their clinical features varied. Eleven patients had a deficiency of MK, caused by mutations in the MVK gene. One mutation (V377I) was common to all 11 patients. Nine patients were compound heterozygotes for V377I and various other MVK mutations. There was no apparent relationship between the observed mutations and the clinical features. Surprisingly, four boys had normal MK activity and no MVK mutations. CONCLUSIONS: Most HIDS patients have mutations in the MVK gene. The clinical variability observed cannot be explained by genotypic differences. Periodic fever and elevated IgD can result from other, still unknown, causes. Hence, testing for MK deficiency is necessary in patients with unexplained periodic fever.

Child↗
PubMed2001

Divergent effects of tumor necrosis factor alpha on apoptosis of human neutrophils.

Apoptosis of neutrophils is a key mechanism to control the intensity of the acute inflammatory response. Previously, the cytokine tumor necrosis factor alpha (TNF-alpha) was reported by some to have pro-apoptotic and by others to have antiapoptotic effects on neutrophils. The aim of this study was to explain these contradictory results. We found that TNF-alpha at low concentrations strongly decreased apoptosis of neutrophils. However, at higher concentrations, TNF-alpha lost its protective effects, and also reversed the protective effects of interferon-gamma (IFN-gamma) and granulocyte-macrophage colony-stimulating factor (GM-CSF). This pro-apoptotic effect of TNF-alpha was blocked by anti-CD11b and was absent in neutrophils from patients with chronic granulomatous disease, which cannot produce toxic oxygen metabolites. Under these circumstances, we found that TNF-alpha retained its anti-apoptotic effects even at high concentrations. In conclusion, the protective effects against apoptosis of IFN-gamma, GM-CSF, and TNF-alpha itself are overruled when the concentration of TNF-alpha is high enough to produce a respiratory burst. These dual, concentration-dependent effects of TNF-alpha provide an explanation for previous controversial reports and support a dominant role for TNF-alpha in neutrophil apoptosis.

Apoptosis↗
PubMed2000

[Immunology in medical practice. XXXIV. Screening for suspected immunodeficiency: Introduction].

A multistage laboratory protocol for the diagnosis of immunodeficiency is useful for the efficient identification of immunodeficient patients. The protocol presented in this article starts with the patient's clinical presentation. In the initial stages a low threshold for the performance of simple screening is applied, thus allowing early exclusion of potential immunodeficiencies, as well as identification of patients before serious infections have compromised their general condition. In the later stages, more elaborate tests leading to diagnosis and definitive classification are reserved for those few patients in whom the presence of an immunodeficiency is more probable. This definitive classification is important for the identification of carriers and for the genetic counselling of the family. The protocol described has been developed in cooperation with the Dutch national working parties of clinical immunologists (paediatric as well as internal medicine) and laboratory immunologists who are involved in diagnosing or treating patients with immunodeficiency.

Clinical Protocols↗
PubMed2000

[Immunology in medical practice. XXXV. Screening of suspected immunodeficiency: diagnostic protocols for patients with opportunistic or recurrent severe infections, wasting and failure to thrive].

With a multistage laboratory protocol immunodeficiencies can be efficiently identified. The article presents a diagnostic protocol that consists of three schemes. Scheme 1 describes the diagnostic protocol for the large group of patients with recurrent pulmonary and ENT-infections, where an antibody deficiency can occasionally be found. Scheme 2 presents the diagnostic protocol for the much smaller group of patients with opportunistic infections, wasting or failure to thrive. Several of these patients suffer from a severe T-lymphocyte disorder. Early diagnosis and treatment is important for the prognosis in these patients. Scheme 3 shows the diagnostic protocol for patients with recurrent infections of surface areas and deeper organs; these patients may suffer from a phagocyte disorder.

Algorithms↗
PubMed2000

[Immunology in the medical practice. XXXIII. Hereditary immune deficiencies: from genotype to phenotype].

The advances of molecular biological techniques of the last decade have made possible identification of a rapidly increasing number of congenital (or primary) immune deficiencies at the genetic level. As soon as an immune deficiency is becoming a likely conclusion from a series of diagnostic laboratory tests, these recent developments in molecular techniques allow us in principle to make a conclusive diagnosis on the basis of a well-defined genetic defect. The hereditary immune deficiencies can be divided in 4 groups according to the functional immune aberration: antigen recognition, communication between immune cells, adhesion and directional motility, and killing as an effector mechanism.

Autoimmune Diseases↗
PubMed2000

Cytolytic mechanisms and expression of activation-regulating receptors on effector-type CD8+CD45RA+CD27- human T cells.

Circulating CD8+ T cells with a CD45RA+CD27- phenotype resemble cytolytic effector cells because they express various cytolytic mediators and are able to execute cytotoxicity without prior stimulation in vitro. We here demonstrate that CD8+CD45RA+CD27- T cells can use both granule exocytosis and Fas/Fas ligand pathways to induce apoptosis in target cells. The availability of these cytolytic mechanisms in circulating T cells suggests that the activity of these cells must be carefully controlled to prevent unwanted tissue damage. For this reason, we analyzed the expression of surface receptors that either enhance or inhibit T cell function. Compared with memory-type cells, effector cells were found to express normal levels of CD3epsilon and TCRzeta and relatively high levels of CD8. CTLA-4 was absent from freshly isolated effector cells, whereas a limited number of unstimulated memory cells expressed this molecule. In line with recent findings on CD8+CD28- T cells, CD45RA+CD27- T cells were unique in the abundant expression of NK cell-inhibitory receptors, both of Ig superfamily and C-type lectin classes. Binding of NK cell-inhibitory receptors to classical and nonclassical MHC class I molecules may inhibit the activation of the cytolytic machinery induced by either Ag receptor-specific or nonspecific signals in CD8+CD45RA+CD27- T cells.

Abatacept↗
PubMed2000

[Immunology in the medical practice. XXXI. Hereditary immune deficiencies: relationship between clinical symptoms and abnormalities of the immune system].

Severe congenital immunodeficiency diseases occur in approximately 1:10,000 newborns, in Western Europe and North America. They are characterised by recurrent infections, mostly caused by opportunistic micro-organisms, and autoimmune phenomena. In many patients the immune deficiency occurs as part of a syndrome. An immunological dysfunction may be caused by total absence, strong reduction or dysfunction of one or more cellular elements or of cell-associated or cellular secretion products. It is convenient to divide the immune system into a cellular compartment (with specific T and B cells, and non-specific natural killer cells and myelomonocytes), a compartment for cellular interactions (adhesion, costimulation and communication through cytokines) and an aspecific opsonization compartment. In cases of deficient humoral immunity treatment options are antimicrobial drugs and substitution therapy with immunoglobulins, in cases of phagocytic dysfunction the application of intracellularly active antibiotics and in cases of disturbances of cellular immunity allogeneic transplantation of haematopoietic stem cells and in the future perhaps the repair of the genetic defect by somatic gene therapy.

Anti-Bacterial Agents↗
PubMed2000

Vasoactive side effects of intravenous immunoglobulin preparations in a rat model and their treatment with recombinant platelet-activating factor acetylhydrolase.

Previously, we observed in a rat model that intravenous administration of intramuscular immunoglobulin preparations induced a long-lasting hypotension, which appeared to be associated with the presence of IgG polymers and dimers in the preparations, but unrelated to complement activation. We found evidence that this hypotensive response is mediated by platelet-activating factor (PAF) produced by macrophages. In this study, we compared the vasoactive effects of 16 intravenous immunoglobulin (IVIG) products from 10 different manufacturers, in anesthetized rats. Eight of the IVIG preparations showed no hypotensive effects (less than 15% decrease), whereas the other 8 had relatively strong effects (15%-50% decrease). The hypotensive effects correlated with the IgG dimer content of the preparations. Pretreatment of the rats with recombinant PAF acetylhydrolase completely prevented the hypotensive reaction on IVIG infusion, and administration after the onset of hypotension resulted in normalization of the blood pressure. We also observed PAF production on in vitro incubation of human neutrophils with IVIG, which could be blocked by anti-Fcgamma receptor antibodies. This indicates that induction of PAF generation may also occur in a human system. Our findings support the hypothesis that the clinical side effects of IVIG in patients may be caused by macrophage and neutrophil activation through interaction of IgG dimers with Fcgamma receptors. Because phagocyte activation may also lead to the release of other inflammatory mediators, recombinant PAF acetylhydrolase (rPAF-AH) provides a useful tool to determine whether PAF plays a role in the clinical side effects of IVIG. If so, rPAF-AH can be used for the treatment of those adverse reactions. (Blood. 2000;95:1856-1861)

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2000

Point mutations in the promoter region of the CYBB gene leading to mild chronic granulomatous disease.

Chronic granulomatous disease (CGD) is a clinical syndrome of recurrent bacterial and fungal infections caused by a rare disorder of phagocytic cells. In CGD, the phagocytes are unable to generate oxygen radicals after stimulation of these cells, due to a defect in the NADPH oxidase system. This NADPH oxidase is a multicomponent enzyme of at least four subunits, of which the beta-subunit of cytochrome b558, gp91-phox, is encoded by an X-linked gene (called CYBB). We report here five patients from two families; in each family we found a different mutation in the promoter region of CYBB. Both mutations prevented the expression of gp91-phox in the patients' neutrophils and thus caused inability of these cells to generate oxygen radicals. However, the mutations left the gp91-phox expression and the function of the NADPH oxidase in the patients' eosinophils intact. The relatively mild course of the CGD in these patients can probably be attributed to the fact that the eosinophils have retained their oxidative capacity. Furthermore, our results indicate that neutrophils and eosinophils differ in their regulation of gp91-phox expression.

Adolescent↗
PubMed1999

Clinical and laboratory work-up of patients with neutrophil shortage or dysfunction.

Neutrophils have a crucial function in the defense against bacteria and fungi. Indeed, during chronic, severe neutropenia and in case of severe neutrophil dysfunctions, the patients may suffer recurrent and sometimes life-threatening infections. This article describes the clinical symptoms, the theory behind the antimicrobial systems of neutrophils, the methods to diagnose the various aberrations, and the possibilities for treating these patients. A few of the most common causes of neutropenia and neutrophil dysfunctions are described in detail, including recent genetic information regarding the cause of these diseases.

Animals↗