Biomedical subjects

J D Laman

Publications and source records attributed to J D Laman.

At least 19 recordsLinked to original sources

PubMed2006

Mannose-binding lectin levels during pregnancy: a longitudinal study.

BACKGROUND: Pregnancy is associated with changes in the immune system. Although previous studies have focussed mainly on adaptive immunity, there are indications that components of innate immunity, such as mannose-binding lectin (MBL), are associated with pregnancy outcome. Although this would suggest that pregnancy also involves adaptations in innate immunity, there are few studies in this area. Therefore, we aimed to determine whether MBL concentrations and the following steps in complement pathway activation are influenced by pregnancy. METHODS: MBL and Ficolin-2 concentrations, MBL-MBL-associated serine protease (MASP) complex activity, MBL pathway activity and classical complement pathway activity were determined by enzyme-linked immunosorbent assay (ELISA) in sera from pregnant women (n=32) during each trimester and post-partum. MBL genotyping was performed by PCR. RESULTS: During pregnancy, MBL concentrations increased to 140% [interquartile range (IQR) 116-181%, P < 0.0001]. This increase was already present at 12 weeks of pregnancy and was most pronounced in the high-production AA-genotype. Directly Post-partum MBL concentrations dropped to 57% of baseline (IQR 44-66%, P < 0.0001). Variations in MBL levels were reflected by similar changes in the following steps of complement activation, r > 0.93 (P < 0.01). Ficolin-2 levels and classical complement pathway activity were not similarly influenced by pregnancy. CONCLUSIONS: Pregnancy and the post-partum period profoundly influence MBL serum concentration and MBL complement pathway activity.

Adult↗

PubMed2006

Peptidoglycan and peptidoglycan-specific Th1 cells in psoriatic skin lesions.

We have previously demonstrated, in psoriatic skin lesions, the presence of a subset of dermal CD4+ T cells that produce interferon-gamma (IFN-gamma) in response to a mixture of cell wall proteins extracted from group A streptococci. However, the identity of the antigen(s) involved is unknown. To investigate the hypothesis that peptidoglycan (PG), the major constituent of the streptococcal cell wall, acts as a T cell activator in psoriasis, we performed in situ analysis to detect antigen-presenting cells containing PG in lesional versus non-lesional skin, and determined proliferation and IFN-gamma responses of lesional skin T cells. Increased numbers of PG-containing cells were detected in the dermal papillae and cellular infiltrates of guttate and chronic plaque skin lesions compared with normal and non-lesional psoriatic skin. A varying proportion of these were CD68+ macrophages, but the remaining cells did not double stain for either Langerhans' or dendritic cell markers. Psoriatic dermal streptococcal-specific CD4+ T cell lines proliferated and produced IFN-gamma in a self HLA-DR allele-restricted manner in response to streptococcal PG, excluding mitogenic or superantigenic stimulation, but were unresponsive to staphylococcal PG. Similarly, psoriatic staphylococcus-specific T cell lines recognized staphylococcal, but not streptococcal, PG by IFN-gamma production. The presence of PG-containing macrophages in close association with PG-specific CD4+ T cells in lesional skin suggests that PG may be responsible, at least in part, for T cell activation in psoriasis.

Antigen-Presenting Cells↗

PubMed2005

Toll-like receptor 2 stimulation induces intimal hyperplasia and atherosclerotic lesion development.

BACKGROUND: Toll like receptors (Tlr) are essential in activation of the innate immune system. We recently described that peptidoglycan, an exogenous Tlr2 specific ligand, is present in human atherosclerotic plaques and associated with histological markers for plaque vulnerability. Also, endogenous Tlr2 ligands can be expressed in atherosclerotic tissues. Here, we determined whether Tlr2 stimulation promotes pro-inflammatory cytokine/chemokine production in vitro and augments neointima formation and development of atherosclerotic plaques in vivo. METHODS AND RESULTS: We detected Tlr2 using Western blot and RT-PCR in human coronary arteries and primary adventitial fibroblasts. RNAse protection assay demonstrated significant induction of IL-1, IL-6, IL-8 and MCP-1 mRNA after Tlr2 stimulation in human adventitial fibroblasts in vitro. ELISA demonstrated induction of IL-6, IL-8 and MCP-1. In vivo application of Pam(3)Cys-SK(4), a synthetic Tlr2 ligand, on femoral arteries of C57BL/6 wild type (WT) mice using a peri-adventitial cuff, significantly enhanced neointima formation compared to control arteries. This increased inflammatory response was not observed in Tlr2 knockout (Tlr2-/-) mice. In ApoE knockout mice (ApoE-/-), application of the same Tlr2 ligand led to a significant increase in atherosclerotic plaque development. CONCLUSION: Local arterial Tlr2 stimulation induced neointima and atherosclerotic plaque formation in mouse femoral arteries. Tlr2 stimulation may be an important mediator in arterial occlusive disease.

Animals↗

PubMed2005

HLA class II alleles are not a general susceptibility factor in Guillain-Barré syndrome.

OBJECTIVE: To assess whether human leukocyte antigen (HLA)-DRB1 and HLA-DQB1 alleles confer susceptibility to Guillain-Barre syndrome (GBS) or are related to specific clinical or serologic subgroups of GBS. METHODS: The HLA-DRB1 and HLA-DQB1 loci were genotyped by PCR amplification with sequence-specific primers in 164 well-documented Dutch patients with GBS and 207 healthy Dutch control subjects. Patients with GBS were divided into subgroups based on clinical features, severity of disease, antecedent infection, and anti-ganglioside antibodies. Data were compared with those of all case-control HLA studies in GBS performed previously. RESULTS: In this case-control study, HLA-DRB1 and HLA-DQB1 alleles did not differ between GBS patients and control subjects. The frequency of HLA-DRB1*01 was increased in patients who needed mechanical ventilation (odds ratio 4.2; 95% CI 1.9 to 9.6; p(c) = 0.02). Multivariate logistic regression analysis showed that this association was independent of the severity of paresis and the presence of cranial nerve involvement (all p < 0.05). There was a tendency toward an association between certain HLA alleles and several anti-ganglioside antibodies. CONCLUSIONS: Human leukocyte antigen (HLA) class II antigens are not a general susceptibility factor in Guillain-Barre syndrome (GBS). However, HLA class II alleles may be a determinant in distinct subgroups of GBS, indicating the need for further exploration in large-scale studies.

Adolescent↗

PubMed2004

Human hepatic lymph nodes contain normal numbers of mature myeloid dendritic cells but few plasmacytoid dendritic cells.

We investigated whether the hyporesponsiveness of the adaptive arm of the liver immune system is related to the composition of the dendritic cell (DC) population in hepatic lymph nodes. Noninflamed human hepatic lymph nodes (LN) were obtained from multiorgan donors, inflamed hepatic LN from liver transplant recipients with autoimmune cholestatic liver diseases, and inguinal LN from kidney transplant recipients. Quantitative immunohistochemistry showed that all three types of LN contained comparable numbers of mature and immature myeloid DC, but that noninflamed and inflamed hepatic LN contained significantly fewer plasmacytoid DC as compared to inguinal LN. Likewise, DC-enriched cell preparations from hepatic LN contained relatively few plasmacytoid DC. The difference in numbers of plasmacytoid DC was confirmed in comparisons of hepatic LN and ileacal LN from the same organ-donors. Myeloid DC from hepatic LN showed similar expressions of HLA-DR, CD83, and CD86, and higher expression of CD80 compared to myeloid DC from inguinal LN. In conclusion, hepatic LN contain similar numbers of myeloid DC as muscle/skin lymph-draining LN, with no signs of immaturity, but relatively few plasmacytoid DC.

Antigens, CD↗

PubMed2004

Potato tuber proteins efficiently inhibit human faecal proteolytic activity: implications for treatment of peri-anal dermatitis.

BACKGROUND: Frequent diarrhoea after intestinal resections and faecal incontinence in healthy infants may lead to perianal injury. A causative agent may be a high concentration of pancreatic proteases in faeces. The aim of the present study was to assess whether protease inhibitors are applicable for treating and preventing peri-anal dermatitis by inhibiting the initial cause of the inflammation, the faecal proteases. DESIGN: Proteolytic activity was estimated in faeces of subjects frequently suffering from peri-anal dermatitis: patients with intestinal resections and healthy infants. The development of perianal dermatitis was studied after the construction of a reservoir with ileoanal anastomosis. The inhibitory effect of crude and partly purified potato juice on proteolytic activity of faecal output from patients with intestinal resections and healthy infants was investigated in vitro and in vivo (skin tests). RESULTS: Faecal protease activity in faeces from patients with intestinal resections and healthy infants was found to be significantly higher than in healthy adults. After the construction of an ileum reservoir, 46 of 48 patients developed a protease-related peri-anal dermatitis. The partly purified protein fraction from potatoes inhibited the larger part of faecal proteases in vitro and completely prevented skin irritation by pancreatic proteases dissolved in sterilized faecal fluid, in a 24-h skin test, on the back of healthy human volunteers. CONCLUSIONS: Potato proteins contain protease inhibitors, which suppress almost the complete proteolytic activity in faeces. Topical application of potato protease inhibitors might be a novel approach in preventing protease-induced peri-anal dermatitis, and therapeutic studies are needed to confirm our results.

Adenomatous Polyposis Coli↗

PubMed2003

The role of intrahepatic immune effector cells in inflammatory liver injury and viral control during chronic hepatitis B infection.

Cytotoxic T lymphocytes (CTL) and Kupffer cells play an important role in the immune control of hepatitis B virus (HBV), but may also induce liver injury during infection. We investigated the intrahepatic immune response in liver biopsies of chronic HBV patients in relation to inflammatory liver injury and viral control. Forty-seven liver biopsies from patients with chronic HBV with varying degrees of inflammation (ALT values) were selected. Acute hepatitis and normal liver specimens served as controls. Immune effector cells, cytotoxic effector molecules and cytokine producing cells were quantified after immunohistochemical staining in lobular and portal areas of the biopsies. The intralobular number of CD8+ T-lymphocytes was significantly decreased in biopsies of patients with high ALT (r = -0.54; P < 0.001). Higher ALT-values were correlated with increased numbers of granzyme+ cells in portal areas (r = 0.65; P < 0.001) and higher numbers of intralobular Fas-L+ cells (r = 0.32; P = 0.05). Fas-L was expressed on Kupffer and lymphoid cells. More intralobular CD8+ T-lymphocytes were found in HBeAg- than in HBeAg+ patients (P = 0.002). But IFN-gamma and TNF-alpha producing cells were observed sporadically in chronic HBV patients. Hence, in chronic HBV infection, low viral replication and HBeAg negativity is related to increased presence of intralobular CD8+ T-lymphocytes. Persistence of the virus may be caused by the absence of cells producing anti-viral cytokines in the liver. Inflammatory liver injury during chronic HBV infection is probably not the result of increased numbers of infiltrating CD8+ T-lymphocytes, but of Fas-L expression by Kupffer cells and increased cytolytic activity of cells in portal areas.

Adolescent↗

PubMed2002

Prospective study on the relationship between infections and multiple sclerosis exacerbations.

One of the characteristics of multiple sclerosis is the unpredictable occurrence of exacerbations and remissions. These fluctuations in disease activity are related to alterations in (auto-)immune activity. Exacerbations lead to short-term morbidity, but may also influence long-term disability. This longitudinal study in 73 patients with relapsing-remitting multiple sclerosis assessed the contribution of systemic infections to the natural course of exacerbations. In addition, we analysed whether infections lead to an increase in the number of gadolinium-enhancing lesions. A total of 167 infections and 145 exacerbations were observed during 6466 patient weeks. During a predefined at-risk period (ARP) of 2 weeks before until 5 weeks after the onset of a clinical infection (predominantly upper airway infections), there was an increased risk of exacerbations (rate ratio 2.1), which is in accordance with previous studies. Exacerbations with onset during the ARP led more frequently to sustained deficit [increase of > or =1 Expanded Disability Status Scale (EDSS) point or > or =0.5 above EDSS 5.5 for >3 months] than exacerbations with onset outside the ARP, with a rate ratio of 3.8. Minor and major exacerbations were equally distributed between the ARP and non-ARP onset groups. ARP exacerbations were associated with significantly higher plasma levels of the inflammatory marker soluble intracellular adhesion molecule 1 than non-ARP exacerbations, indicating relatively enhanced immune activation during ARP relapses. Three serial MRI scans were performed after the onset of an infection over a 6-week period. There was no difference in the number of gadolinium-enhancing lesions between the three time points. In conclusion, exacerbations in the context of a systemic infection lead to more sustained damage than other exacerbations. There is no indication that this effect occurs through enhanced opening of the blood-brain barrier.

Adult↗

PubMed2002

Structure of Campylobacter jejuni lipopolysaccharides determines antiganglioside specificity and clinical features of Guillain-Barré and Miller Fisher patients.

Ganglioside mimicry in the lipopolysaccharide (LPS) fraction of Campylobacter jejuni isolated from Guillain-Barré syndrome (GBS) and Miller Fisher syndrome (MFS) patients was compared with isolates from patients with an uncomplicated enteritis. The antibody response to C. jejuni LPS and gangliosides in neuropathy patients and controls was compared as well. LPS from GBS and MFS-associated isolates more frequently contained ganglioside-like epitopes compared to control isolates. Almost all neuropathy patients showed a strong antibody response against LPS and multiple gangliosides in contrast to enteritis patients. Isolates from GBS patients more frequently had a GM1-like epitope than isolates from MFS patients. GQ1b-like epitopes were present in all MFS-associated isolates and was associated with anti-GQ1b antibody reactivity and the presence of oculomotor symptoms. These results demonstrate that the expression of ganglioside mimics is a risk factor for the development of post-Campylobacter neuropathy. This study provides additional evidence for the hypothesis that the LPS fraction determines the antiganglioside specificity and clinical features in post-Campylobacter neuropathy patients.

Antibodies, Bacterial↗

PubMed2002

Ganglioside mimicry of Campylobacter jejuni lipopolysaccharides determines antiganglioside specificity in rabbits.

The core oligosaccharides of Campylobacter jejuni lipopolysaccharides (LPS) display molecular mimicry with gangliosides. Cross-reactive anti-LPS-antiganglioside antibodies have been implicated to show a crucial role in the pathogenesis of the Guillain-Barré and Miller Fisher syndrome. The specificity of the antiganglioside response is thought to depend on the oligosaccharide structure of the ganglioside mimic. To test this hypothesis and to investigate the potential of LPS from Campylobacter strains from enteritis patients to induce an antiganglioside response, we immunized rabbits with purified LPS from eight Campylobacter jejuni reference strains with biochemically well-defined distinct ganglioside mimics and determined the presence of antiganglioside antibodies. All rabbits produced immunoglobulin G (IgM) and IgG anti-LPS antibodies, and the specificity of the cross-reactive antiganglioside response indeed corresponded with the biochemically defined mimic. Most rabbits also had antibody reactivity against additional gangliosides, and there were slight differences in the fine specificity of the antibody response between rabbits that had been immunized with LPS from the same Campylobacter strain. High anti-LPS and antiganglioside titers persisted over a 10-month period. In conclusion, the structure of the LPS only partly determines the antiganglioside specificity. Other strain-specific as well as host-related factors influence the induction and fine-specificity of the cross-reactive anti-LPS-antiganglioside response.

Animals↗

PubMed2001

Novel monoclonal antibodies against proteolipid protein peptide 139-151 demonstrate demyelination and myelin uptake by macrophages in MS and marmoset EAE lesions.

Experimental autoimmune encephalomyelitis (EAE) induced by immunization of mice with epitopes of the proteolipid protein (PLP), a major myelin constituent, forms a useful model for the study of multiple sclerosis (MS). In addition, MS patients display PLP-specific T- and B-cell responses, suggesting that PLP reactivity is relevant to pathogenesis.Here, the generation and characterization of a panel of mouse monoclonal antibodies (Mab) against PLP139-151, the prominent encephalitogenic sequence in SJL/J mice is described. Five Mab were generated by conventional immunization of an SJL/J mouse and hybridoma generation. These Mab reacted well with the PLP139-151 peptide in ELISA and belonged to the IgG2a and IgG2b subclasses, consistent with CD4+ T helper 1-cell-supported antibody formation. The Mab also efficiently detected PLP peptide-BSA conjugates in Western blot, confirming their multi-assay applicability. The Mab were subsequently used to determine the occurrence of demyelination in brains of MS patients and marmoset monkeys with EAE. Immunohistochemistry on both paraffin and frozen sections demonstrated a homogeneous expression of PLP139-151 in normal myelin, and a complete absence in lesions containing demyelinated areas, confirming that the Mab can be used as a general myelin marker. In active demyelinating MS lesions, the Mab visualized the peptide in the cytoplasm of macrophages containing phagocytosed myelin. In conclusion, this panel of Mab against the encephalitogenic PLP139-151 epitope forms a useful tool for further study of autoantigen expression, demyelination/remyelination and the staging of lesional activity in MS patients, as well as in EAE models in distinct animal species.

Animals↗

PubMed2001

Prevention of experimental autoimmune encephalomyelitis in the common marmoset (Callithrix jacchus) using a chimeric antagonist monoclonal antibody against human CD40 is associated with altered B cell responses.

Inhibition of CD40-CD40 ligand interaction is a potentially effective approach for treatment of autoimmune diseases, such as multiple sclerosis. We have investigated this concept with a chimeric antagonist anti-human CD40 mAb (ch5D12) in the marmoset monkey experimental autoimmune encephalomyelitis (EAE) model. Marmosets were immunized with recombinant human myelin oligodendrocyte glycoprotein (rMOG) and treated from the day before immunization (day -1) until day 50 with either ch5D12 (5 mg/kg every 2-4 days) or placebo. On day 41 after the induction of EAE, four of four placebo-treated monkeys had developed severe clinical EAE, whereas all animals from the ch5D12-treated group were completely free of disease symptoms. High serum levels of ch5D12 associated with complete coating of CD40 on circulating B cells were found. At necropsy placebo- and ch5D12-treated animals showed similar MOG-specific lymphoproliferative responses in vitro, but ch5D12 treatment resulted in strongly reduced anti-MOG IgM Ab responses and delayed anti-MOG IgG responses. Most importantly, treatment with ch5D12 prevented intramolecular spreading of epitope recognition. Postmortem magnetic resonance imaging and immunohistologic analysis of the CNS showed a markedly reduced lesion load after ch5D12 treatment. In conclusion, the strong reduction of clinical, pathological, and radiological aspects of EAE by ch5D12 treatment in this preclinical model points to a therapeutic potential of this engineered antagonist anti-CD40 mAb for multiple sclerosis.

Animals↗

PubMed2001

Carrier-mediated enhancement of cognate T cell help: the basis for enhanced immunogenicity of meningococcal outer membrane protein polysaccharide conjugate vaccine.

Haemophilus influenzae type b capsular polysaccharide (PRP) conjugate vaccines, which are thought to induce T cell-dependent antibody production, induce protective responses after a single dose in individuals under 15 months of age. However, multiple doses of these vaccines are required to induce protective antibody responses in infants, with the exception of PRP conjugated to meningococcal outer membrane proteins (OMPC), which does so after a single dose. The basis for this difference is not fully understood, although others have proposed that OMPC and porins, the major protein component of OMPC, act as adjuvants or mitogens. In this report OMPC is shown to enhance CD40 ligand-mediated, T cell-dependent antibody production in mice. This paralleled the induction by OMPC of CD86, CD80 and CD40 costimulatory molecules on human neonatal and murine B cells and of Th1 cytokines. Neither porins nor lipopolysaccharide fully reproduced the effects of OMPC. These studies indicate that OMPC acts both as carrier and adjuvant, and thereby enhances T cell-dependent antibody responses in human infants.

Adjuvants, Immunologic↗

PubMed2001

A modified ex vivo skin organ culture system for functional studies.

To investigate the immunological function of cells in normal and diseased skin under conditions approximating the in vivo situation, it is necessary to maintain the structural integrity of the tissue. To achieve this, freshly isolated skin has to be cultured ex vivo, or an in vitro-constructed complete skin equivalent may be used. Different skin organ culture systems have been described. Basically two systems prevail: submerged or air-exposed skin organ cultures. The former model has been used for measuring cytokine secretion by skin cells in the medium, and the latter to study the expression of cell membrane proteins in situ and the kinetics of epidermal Langerhans cells. Here we present a modified ex vivo skin organ culture system which approaches the in vivo situation by maintaining the normal skin architecture without spontaneous induction of the regenerative maturation markers. This method allowed the expression of cell membrane proteins in situ to be measured, and the cytokine secretion by skin cells in the culture medium to be quantitated in the same experiment. In this system, both general and specific stimuli (LPS and IL-1beta) upregulated the expression of skin-derived cytokines IL-8 and IL-6 in the medium and different markers (ICAM-1, CD40 and CD86) on cells in the tissue in a 24-hour culture-formed. Elevation of both cytokine and cell marker expression could be blocked by dexamethasone and by IL-1ra which acts specifically on IL-1beta-mediated responses. The system presented here is both quick and simple and can be used as a model to study the behaviour of skin cells in their natural microenvironment.

Antigens, CD↗

PubMed2001

Non-human primate models of multiple sclerosis.

The phylogenetic proximity between non-human primate species and humans is reflected by a high degree of immunological similarity. Non-human primates therefore provide important experimental models for disorders in the human population that are caused by the immune system, such as autoimmune diseases. In this paper we describe non-human primate models of multiple sclerosis, a chronic inflammatory and demyelinating disease of the human central nervous system. While reviewing data from the literature and our own research we will discuss the unique role of such models in the research of basic disease mechanisms and the development of new therapies.

Animals↗

PubMed2001

Reduced systemic IgG levels against peptidoglycan in rheumatoid arthritis (RA) patients.

The gut flora is believed to play a role in the pathogenesis of RA. Peptidoglycan, a major cell wall component of Gram-positive bacteria, is a candidate antigen because of its capability to trigger production of proinflammatory cytokines, to induce arthritis in rodents, and because of its presence in antigen-presenting cells in RA joints. We investigated whether the systemic and local antibody levels against a peptidoglycan-polysaccharide (PG-PS) are related to the presence and disease activity of RA. Significantly lower levels of systemic IgG directed against PG-PS were found in healthy females compared with healthy males, and systemic IgA levels specific for PG-PS were negatively correlated with age. Levels of systemic IgG directed against PG-PS were significantly reduced in RA patients compared with sex- and age-matched healthy controls. Local (synovial fluid) levels of IgG did not correlate with disease activity whereas synovial fluid levels of IgA correlated positively with disease activity. These data suggest that IgG in healthy people mediates protection against spreading of PG to non-mucosal sites.

Adult↗

PubMed2001

Bacterial peptidoglycan and immune reactivity in the central nervous system in multiple sclerosis.

Multiple sclerosis is believed to result from a CD4+ T-cell response against myelin antigens. Peptidoglycan, a major component of the Gram-positive bacterial cell wall, is a functional lipopolysaccharide analogue with potent proinflammatory properties and is conceivably a mediator of sterile inflammation. Here we demonstrate that peptidoglycan is present within antigen-presenting cells in the brain of multiple sclerosis patients. These cells have macrophage and dendritic cell characteristics, and are immunocompetent as evidenced by co-expression of inflammatory cytokines and co-stimulatory molecules. In addition, intrathecal plasma cells specific for peptidoglycan are present in multiple sclerosis brain tissue, and antibodies binding peptidoglycan are present in CSF during active disease. Peptidoglycan may thus contribute to T- and B-cell activity during brain inflammation without a requirement for local bacterial replication.

Adult↗

PubMed2001

Peptidoglycan from sterile human spleen induces T-cell proliferation and inflammatory mediators in rheumatoid arthritis patients and healthy subjects.

OBJECTIVES: Peptidoglycan (PG), a component of Gram-positive bacteria, may be involved in rheumatoid arthritis (RA) because of its ability to induce production of proinflammatory cytokines, to induce arthritis in rodents, and its presence in antigen-presenting cells in RA joints. METHODS: In the present study, physiologically relevant PG was able to induce T-cell proliferation in peripheral blood and synovial fluid samples of RA patients, but the magnitude of the response did not differ from that of cells from healthy subjects. In addition, production of cytokines associated with RA (interleukins (IL)-1beta, IL-6, IL-8, IL-10, IL-12 and tumour necrosis factor alpha) and of the matrix metalloproteinase, gelatinase B (MMP-9), was induced in blood and synovial fluid cultures of RA patients. CONCLUSION: The fact that PG, which can be found in synovial tissues of RA patients is able to induce the production of inflammatory mediators supports the hypothesis that PG plays a role in the pathogenesis of RA by influencing the inflammatory microenvironment of the joint.

Adult↗