T. K. van den Berg

Regulation of CD163 on human macrophages: cross-linking of CD163 induces signaling and activation

CD163 is a member of the group B scavenger receptor cysteine‐rich (SRCR) superfamily. This study describes aspects of the tissue distribution, the regulation of expression, and signal transduction after cross‐linking of this receptor at the cell surface of macrophages. CD163 showed an exclusive expression on resident macrophages (e.g., red pulp macrophages, alveolar macrophages). The expression was inducible on monocyte‐derived macrophages by glucocorticoids but not by interleukin‐4 (IL‐4), granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), and interferon‐γ. The combination of IL‐4 or GM‐CSF with glucocorticoids resulted in a further increase. Subcellular analysis of alveolar macrophages by immunoelectron microscopy showed a plasma membrane localization of the antigen. Cross‐linking of CD163 with monoclonal antibody induced a protein tyrosine kinase‐dependent signal that resulted in (1) slow‐type calcium mobilization, (2) inositol triphosphate production, and (3) secretion of IL‐6 and GM‐CSF. The data suggest a function for the SRCR‐superfamily receptor CD163 in the regulation of inflammatory processes by macrophages. J. Leukoc. Biol. 66: 858–866; 1999.

Mechanism of immune complex trapping by follicular dendritic cells

The follicular dendritic cell (FDC) is a major constituent of the microenvironment of the lymphoid follicle. FDC have the characteristic and unique property of binding antigens in the form of antigen-antibody complexes and retaining these complexes, without ingestion, for long periods of time. The presence of antigen-antibody complexes, also called immune complexes, on FDC is believed to play a crucial role in the development of B cell memory and the affinity maturation of the antibody response against T cell-dependent antigens.

Systemic anti-IFN-gamma treatment and role of macrophage subsets in the foreign body reaction to dermal sheep collagen in rats

The application of a biomaterial induces a foreign body reaction. By controlling this reaction, biocompatibility could be improved. We previously demonstrated that impregnation of a biodegradable biomaterial with antibodies against interferon-gamma (IFN-gamma) inhibits the foreign body reaction. In this study we investigate whether systemic administration of the antibody can induce similar reactions. Several parameters are compared between control and anti-IFN-gamma-treated rats: cellular ingrowth; degradation of the biomaterial; ingrowth of macrophage (MO) subsets, T cells, B cells, NK cells, and granulocytes; and expression of the major histocompatibility complex class II (MHC class II) molecule on antigen presenting cells. Treatment with anti-IFN-gamma results in increased cellular ingrowth and biomaterial degradation and a decreased expression of MHC class II. Overall, systemic treatment with anti-IFN-gamma is insufficient to modulate the foreign body reaction. This suggests an alternative mechanism for MO activation besides IFN-gamma. The role of T cells and MO subsets in the foreign body reaction is discussed.

Nonallelic homologous recombination of the FCGR2/3 locus results in copy number variation and novel chimeric FCGR2 genes with aberrant functional expression.

The human FCGR2/3 locus, containing five highly homologous genes encoding the major IgG receptors, shows extensive copy number variation (CNV) associated with susceptibility to autoimmune diseases. Having genotyped >4000 individuals, we show that all CNV at this locus can be explained by nonallelic homologous recombination (NAHR) of the two paralogous repeats that constitute the majority of the locus, and describe four distinct CNV regions (CNRs) with a highly variable prevalence in the population. Apart from CNV, NAHR events also created several hitherto unidentified chimeric FCGR2 genes. These include an FCGR2A/2C chimeric gene that causes a decreased expression of FcγRIIa on phagocytes, resulting in a decreased production of reactive oxygen species in response to immune complexes, compared with wild-type FCGR2A. Conversely, FCGR2C/2A chimeric genes were identified to lead to an increased expression of FCGR2C. Finally, a rare FCGR2B null-variant allele was found, in which a polymorphic stop codon of FCGR2C is introduced into one FCGR2B gene, resulting in a 50% reduction in protein expression. Our study on CNRs and the chimeric genes is essential for the correct interpretation of association studies on FCGR genes as a determinant for disease susceptibility, and may explain some as yet unidentified extreme phenotypes of immune-mediated disease.

Study on the Protective Effect of the KIR3DL1 Gene in Ankylosing Spondylitis

Ankylosing spondylitis (AS) is an autoimmune disease that mainly affects the sacroiliac joints and the spine of the lower back. The disease is strongly associated with HLA–B27. Additional genes, single‐nucleotide polymorphisms, and molecular components have been identified to be associated with AS, but the exact mechanism that drives disease development remains poorly understood. The killer cell immunoglobulin‐like receptors (KIRs) are regulators of cytotoxicity of natural killer cells and T cell subsets and may be relevant in binding to HLA–B27 and the development of AS. We undertook this study to identify possible associations of KIR genotype with susceptibility to AS and disease characteristics including the presence of the HLA–B27 allele, disease severity, and uveitis.

Macrophage subpopulations and reticulum cells in rat placenta

SummaryThe placenta is a unique mixture of histoincompatible cells derived from mother and fetus. The aim of the present study was to obtain information on the development of macrophage subpopulations and reticulum cells during pregnancy in the placenta. Placentas of Wistar rats were removed at several stages of gestation, and were studied by immunohistochemical techniques applying monoclonal antibodies against macrophage subpopulations, lymphoid cells and reticulum cells. The expression of MHC class-II antigens was also studied. Throughout gestation macrophages were demonstrable in large numbers in the endometrium, in the myometrium and in the metrial gland, which is a compartment developing in the myometrium of pregnant rodents. In the labyrinth, a placenta compartment consisting of fetal cells, macrophages (probably of fetal origin) were already found on day 15. In the spongiotrophoblast and decidua basalis, which are layers of the placenta containing both maternal and fetal cells, only a few macrophages were recognized throughout gestation. The monoclonal antibody ED11, raised against reticulum cells, recognized fiber-like structures lining the blood sinuses of the spongiotrophoblast, in which only maternal blood is circulating. As the antigen recognized by ED11 is believed to play a role in the trapping of immune complexes, the spongiotrophoblast may play a role in the protection of the fetus from circulating immune complexes.

Sixty-Five years of international criminal justice : The facts and figures

The international criminal justice system comprises nine international criminal courts and tribunals; six are still operational and three have closed down. On average, they operated for almost nine years apiece and concluded 172 cases in which over 250 judges and 23 chief prosecutors were involved. All in all 745 suspects were indicted, 356 were actually tried and, of these, some 281 defendants were convicted. Currently 34 suspects are on trial and 22 are still at large. The ‘average’ convicted perpetrator is male, aged 40 and a member of a military or paramilitary organisation from Europe, Asia or Africa who is acting on behalf of his government. These are just some of the facts and figures which we present in this article: an overview of the empirical reality of the international criminal justice system which has currently been functioning for just over 65 years.

Manipulation of Macrophage Activities Using Liposomes

Abstract Macrophages are of critical importance in a variety of pathological conditions and selective manipulation of macrophage functions may offer new possibilities for therapy. At present, the signalling pathways that control the different activities of macrophages, including phagocytosis and inflammatory mediator production, are being resolved and selective (ant)agonists of the relevant signalling components will gradually become available. However, the activities of such signalling components are generally not restricted to macrophages and this may result in undesirable effects. We suggest that liposomes may overcome these problems by allowing the selective targeting of drugs to the interior of the macrophage in vivo. (macrophages, liposomes, phagocytosis, activation)

KIR3DL1 and KIR3DL2 gene copy number variation in axial spondyloarthritis

Axial spondyloarthritis (axSpA), including the subgroup ankylosing spondylitis (AS) is strongly genetically determined. HLA-B27 is the strongest known risk factor (1) and in recent years genome-wide association studies (GWAS) based on single nucleotide polymorphisms (SNPs) have yielded new genetic risk factors for AS (2). However, it is thought that HLA-B27 and the SNPs discovered in GWAS only account for a small part of the total genetic risk for AS. In order to fully understand the origin of axSpA, a complete risk analysis is required. We therefore performed a pilot study to determine the genetic risk of known binding partners of HLA-B27. Human leukocyte antigen (HLA) class I molecules constitute natural ligands for a number of killer immunoglobulin-like receptors (KIRs), which are expressed by natural killer (NK) cells and a subset of T-cells. KIRs are involved in the regulation of the cytotoxic activity of these cells. The HLA-B27 molecule is known to be recognized by KIR3DL1 and KIR3DL2 (3), and binding of HLA-B27 to KIR3DL2 activates Th17 cells in AS (4). The KIR locus is subject to genetic variation, which is because of gene polymorphisms and gene copy number variation (CNV), as we have previously shown (5). Although KIR genes and polymorphisms have been studied in SpA, nothing is known of gene CNV in relation to this disease. In this study, we investigated the distribution of KIRs and their CNV in a panel of Caucasian AS and early axSpA patients [from the Leiden Early Arthritis cohort (EAC) and Spondyloarthritis Caught Early (SPACE) cohort, respectively] (6, 7) (Table 1). All patients fulfill the Assessment of Spondyloarthritis International Society (ASAS) axSpA criteria (8). An unusual characteristic of the AS patients in the EAC was the low percentage of inflammatory back pain (IBP) according to ASAS expert criteria. Information on IBP was retrieved from patient files and at the time of inclusion of patients in the EAC, the ASAS IBP criteria had not been published.We observed that the ‘pain at night’ feature was not commonly used in clinical practice which has likely led to a lower percentage of IBP-positive patients in the EAC cohort. Consistent with this explanation is that a much higher percentage of more than 80% of AS patients had IBP according to the Calin criteria, which is consistent with other cohorts (9).

Reticulum cells in the ontogeny of nasal-associated lymphoid tissue (NALT) in the rat

This study concerns the ontogeny of reticulum cells (RC) in the nasal-associated lymphoid tissue (NALT) of Wistar and Brown-Norway rats. A panel of monoclonal antibodies (mAb) directed against RC in peripheral lymphoid organs (antibodies ED10-ED15) was used, together with a recently developed antibody ED17, which recognizes macrophages and Langerhans cells. Early in embryogenesis, staining with common connective tissue markers, ED14 and ED15, was found. ED17-positive cells were present before cells positive to ED1, a pan-macrophage marker, or Ia glycoproteins were observed. The first differentiation of reticulum was seen at the day of birth, when ED10 recognized a distinct area in the nasal mucosa. The first T-lymphocytes were found at the same time. Two days after birth, B-cells and ED11-positive cells were present in the NALT area. Fourteen days after birth, T- and B-cell compartments were recognizable. ED10 was found predominantly in the T-cell area and ED11 was mainly confined to the B-cell compartment. We conclude that the development of the NALT is closely accompanied by the phenotypic specialization of the reticulum. This suggests that the reticulum plays an important role in the compartmentalization of NALT tissue and in the retention of lymphocyte subsets within these compartments.