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ABSTRACT: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons that results in progressive muscle weakness and limits survival to 2-5 years after disease onset. Intermediate CAG repeat expansions in ataxin 2 (ATXN2), the causative gene of spinocerebellar ataxia type 2 (SCA2), have been implicated in sporadic ALS. We studied ATXN2 in a large cohort of patients with sporadic and familial ALS.
We determined ATXN2 CAG repeat size in 1,948 sporadic and familial ALS cases and 2,002 controls from Belgium and the Netherlands.
In controls, the maximal ATXN2 repeat size was 31. In sporadic ALS, a significant amount of longer repeat sizes (≥ 32, range 32-39) were encountered (in 0.5% or 10/1,845 ALS cases, vs 0% in controls, p = 0.0006). Receiver operating characteristic analysis showed that a cutoff of ≥ 29 appeared optimal to discriminate ALS from control (p = 0.036, odds ratio [OR] 1.92, 95% confidence interval [CI] 1.04-3.64). A meta-analysis with the previously published results from the United States showed that the association between a repeat length of ≥ 29 and ALS became stronger (p < 0.0001, OR 2.93, 95% CI 1.73-4.98). In unexplained familial ALS, we found an intermediate repeat expansion of 31 and a homozygous repeat expansion of 33 each in 1.1% of families. The phenotype of patients with ALS with expanded repeat sizes ranged from rapidly progressive typical ALS to slowly progressive ALS with reduced sensory nerve action potentials.
Our data reveal a novel genetic overlap between ALS and SCA2.
Neurology 06/2011; 76(24):2066-72. · 8.31 Impact Factor
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ABSTRACT: Knowledge of genetic susceptibility to autoimmune disorders is growing exponentially. One of the messages emerging from these data is the growing overlap in genetic susceptibility to different autoimmune disorders. KIF21B is a member of the kinesin superfamily and was recently established as a susceptibility locus for inflammatory bowel disease and for multiple sclerosis.
We here replicate the association with multiple sclerosis in a Belgian study population of 791 patients and 1098 controls.
As SNPs in KIF21B increase risk for both inflammatory bowel disease and multiple sclerosis, this suggests a common pathway in the pathogenesis of these diseases.
Journal of Medical Genetics 11/2010; 47(11):775-6. · 6.36 Impact Factor
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I Taes,
A Goris,
R Lemmens,
M A van Es,
L H van den Berg,
A Chio,
B J Traynor,
A Birve,
P Andersen,
A Slowik,
B Tomik,
R H Brown,
C E Shaw,
A Al-Chalabi,
S Boonen,
L Van Den Bosch, B Dubois,
P Van Damme,
W Robberecht
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ABSTRACT: The microtubule-associated protein tau is thought to play a pivotal role in neurodegeneration. Mutations in the tau coding gene MAPT are a cause of frontotemporal dementia, and the H1/H1 genotype of MAPT, giving rise to higher tau expression levels, is associated with progressive supranuclear palsy, corticobasal degeneration, and Parkinson disease (PD). Furthermore, tau hyperphosphorylation and aggregation is a hallmark of Alzheimer disease (AD), and reducing endogenous tau has been reported to ameliorate cognitive impairment in a mouse model for AD. Tau hyperphosphorylation and aggregation have also been described in amyotrophic lateral sclerosis (ALS), both in human patients and in the mutant SOD1 mouse model for this disease. However, the precise role of tau in motor neuron degeneration remains uncertain.
The possible association between ALS and the MAPT H1/H2 polymorphism was studied in 3,540 patients with ALS and 8,753 controls. Furthermore, the role of tau in the SOD1(G93A) mouse model for ALS was studied by deleting Mapt in this model.
The MAPT genotype of the H1/H2 polymorphism did not influence ALS susceptibility (odds ratio = 1.08 [95% confidence interval 0.99-1.18], p = 0.08) and did not affect the clinical phenotype. Lowering tau levels in the SOD1(G93A) mouse failed to delay disease onset (p = 0.302) or to increase survival (p = 0.557).
These findings suggest that the H1/H2 polymorphism in MAPT is not associated with human amyotrophic lateral sclerosis, and that lowering tau levels in the mutant SOD1 mouse does not affect the motor neuron degeneration in these animals.
Neurology 05/2010; 74(21):1687-93. · 8.31 Impact Factor
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ABSTRACT: Mutations in fused in sarcoma (FUS) were recently identified as a cause of familial amyotrophic lateral sclerosis (ALS). The frequency of occurrence of mutations in FUS in sets of patients with familial ALS remains to be established.
We sequenced the FUS gene in a cohort of patients with familial ALS seen at the neuromuscular clinic in Leuven. A total of 28 patients with SOD1-negative ALS from 22 families were analyzed.
We identified a R521H mutation in 4 patients, belonging to a kindred of dominantly inherited classical ALS. The mutation segregated with disease. Mutations in FUS were observed in 2.9% of ALS pedigrees in our cohort.
These results show that mutations in FUS are also a significant cause of familial ALS in Belgium.
European Journal of Neurology 11/2009; 17(5):754-6. · 3.69 Impact Factor
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Journal of neurology, neurosurgery, and psychiatry 04/2009; 80(3):354-5. · 4.87 Impact Factor
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ABSTRACT: The human leukocyte antigen (HLA)-DRB1*1501 allele has long been established as the main genetic risk factor for multiple sclerosis (MS), and it therefore follows that stratification of study populations for this allele could aid in the identification of novel susceptibility genes and/or in establishing interactions. To this end, we have developed a simple Taqman-based assay allowing cost-efficient medium-throughput HLA-DRB1*1501 genotyping. We have validated this assay in 444 trio families with MS and 1066 individuals from the UK 1958 birth cohort (3908 independent chromosomes). In this validation cohort, the correlation coefficient (r(2)) between rs3135388*A and HLA-DRB1*1501 was >0.94. Subsequently, applying the assay to a group of MS patients and controls from Belgium confirmed the association of HLA-DRB1*1501 and MS in this population (P = 5 x 10(-21)).
Tissue Antigens 10/2008; 72(4):401-3. · 2.59 Impact Factor
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V Suppiah,
A Goris,
I Alloza,
S Heggarty, B Dubois,
H Carton,
A Antigüedad,
M Mendibe,
G McDonnell,
A Droogan,
S Hawkins,
C Graham,
K Vandenbroeck
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ABSTRACT: Cytokine gene polymorphisms are known to influence susceptibility and disease course of many autoimmune diseases. Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. We analysed both the well-known intronic variable number of tandem repeat (VNTR) and +33 C/T single-nucleotide polymorphisms (SNP) in the IL-4 gene, as well as the functional Q551R SNP in the IL4-R gene in a cohort of three distinct populations comprising sporadic cases and controls from the northern Spanish Basque Country and Northern Ireland, as well as family trios from Belgium. The IL-4 +33 TT genotype was decreased in primary progressive (PP) versus relapsing-remitting (RR) patients in the Northern Irish population (OR = 0.14; 95% CI = 0.018-1.09). Two-marker haplotype distribution of the VNTR and +33 C/T SNP in PP patients differed from that seen in RR patients in Northern Ireland (P = 0.03). The R allele of the Q551R SNP was significantly under-transmitted in the Belgian trio families (P = 0.003), although this effect was not seen in the Northern Irish and Basque data sets. We did not identify IL-4-IL4-R gene-gene interaction in determining susceptibility or clinical parameters of MS. Disease or genetic heterogeneity or both may be responsible for the observed lack of reproduction in different populations. Our data reinforce recent findings for a role of IL4-R in susceptibility to MS.
International Journal of Immunogenetics 01/2006; 32(6):383-8. · 1.29 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system white matter characterized by inflammation, demyelination and axonal damage. The cytotoxic T lymphocyte antigen-4 (CTLA-4) protein plays a key role in the down-regulation of T cell activation. We analysed the CTLA4 +49A/G and CT60 polymorphisms in a cohort of 120 MS trio families recruited from the Flanders region in Belgium. Both polymorphisms were genotyped by polymerase chain reaction-restriction fragment length polymorphism (RFLP). The +49 G-allele was significantly more transmitted to affected probands (P = 0.005). No transmission distortion was observed for the CT60 polymorphism. Haplotype analysis revealed significant overtransmission of the +49 A/G*G-CT60*G haplotype (P = 0.0025), and undertransmission of the +49 A/G*A-CT60*G haplotype (P = 0.015). The CTLA4 gene has been the focus of intense investigation in MS. Of 15 recently published papers, only six reported significant associations of various CTLA4 polymorphisms with MS, with the remainder being negative. Ours is the first report investigating the CT60 polymorphism in MS. Our data highlight a need for further scrutiny of the CTLA4 gene in MS.
Journal of Neuroimmunology 08/2005; 164(1-2):148-53. · 2.96 Impact Factor
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O H Kantarci,
A Goris,
D D Hebrink,
S Heggarty,
S Cunningham,
I Alloza,
E J Atkinson,
M de Andrade,
C T McMurray,
C A Graham,
S A Hawkins,
A Billiau, B Dubois,
B G Weinshenker,
K Vandenbroeck
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ABSTRACT: Interferon-gamma (IFNgamma) treatment is deleterious in multiple sclerosis (MS). MS occurs twice as frequently in women as in men. IFNgamma expression varies by gender. We studied a population-based sample of US MS patients and ethnicity-matched controls and independent Northern Irish and Belgian hospital-based patients and controls for association with MS, stratified by gender, of an intron 1 microsatellite [I1(761)*CAn], a single nucleotide polymorphism 3' of IFNG [3'(325)*G --> A] and three flanking microsatellite markers spanning a 118 kb region around IFNG. Men carriers of the 3'(325)*A allele have increased susceptibility to MS compared to noncarriers in the USA (P=0.044; OR: 2.58, 95% CI: 0.97-8.08) and Northern Ireland (P=0.019; OR: 2.37, 95% CI: 1.10-5.13). There is a nonsignificant trend in the same direction in Belgian men (P=0.299; OR: 1.50, 95% CI: 0.71-3.26). Men carriers of I1(761)*CA13, which is in strong linkage disequilibrium with the 3'(325)*A, have increased susceptibility (P=0.050; OR: 2.22, 95% CI: 0.98-5.40), while men carriers of I1(761)*CA12 have decreased susceptibility (P=0.022; OR: 0.46, 95% CI: 0.23-0.90) to MS in the USA. Similar associations were reported in Sardinia between the I1(761)*CA12 allele and reduced risk of MS in men. Flanking markers were not associated with MS susceptibility. Polymorphisms of IFNG may contribute to differences in susceptibility to MS between men and women.
Genes and Immunity 04/2005; 6(2):153-61. · 3.87 Impact Factor
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ABSTRACT: Polymorphic microsatellite markers in the genes for gelatinase B, PECAM-1 and MCP-3 have previously been analysed in Swedish and Sardinian individuals to test for association with multiple sclerosis (MS). Confirmation and comparison of genetic associations in various ethnic populations is mandatory and, therefore, we studied these three gene polymorphisms in 216 clinically definite MS patients and 193 normal controls, and in 148 simplex MS families, all of Belgian origin. No allelic associations were found between MS and the CA microsatellite marker in the promoter region of the gelatinase B gene, and the polymorphic CA repeat in the sixth intron of PECAM1. However, the two most abundant alleles of the CA/GA microsatellite polymorphism in the promoter-enhancer region of the MCP-3 gene, A2 (109 bp) and A3 (111 bp), were found to be significantly associated with disease in the case-control study [OR (95% CI)=0.68 (0.51-0.92), p (1 df)=0.015 and OR (95% CI)=1.62 (1.22-2.14), p (1 df)=0.0010, respectively], but not in the family study. These results are in agreement with previous findings in the Swedish and Sardinian populations and reinforce the possibility of a role for chemokines in MS pathogenesis.
Journal of the Neurological Sciences 09/2002; 200(1-2):43-8. · 2.35 Impact Factor
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ABSTRACT: Matrix metalloproteinases (MMPs) form a family of enzymes with major actions in the remodeling of extracellular matrix (ECM) components. Gelatinase B (MMP-9) is the most complex family member in terms of domain structure and regulation of its activity. Gelatinase B activity is under strict control at various levels: transcription of the gene by cytokines and cellular interactions; activation of the pro-enzyme by a cascade of enzymes comprising serine proteases and other MMPs; and regulation by specific tissue inhibitors of MMPs (TIMPs) or by unspecific inhibitors, such as alpha2-macroglobulin. Thus, remodeling ECM is the result of the local protease load, i.e., the net balance between enzymes and inhibitors. Glycosylation has a limited effect on the net activity of gelatinase B, and in contrast to the all-or-none effect of enzyme activation or inhibition, it results in a higher-level, fine-tuning effect on the ECM catalysis by proteases in mammalian species. Fast degranulation of considerable amounts of intracellularly stored gelatinase B from neutrophils, induced by various types of chemotactic factors, is another level of control of activity. Neutrophils are first-line defense leukocytes and do not produce gelatinase A or TIMP. Thus, neutrophils contrast sharply with mononuclear leukocytes, which produce gelatinase A constitutively, synthesize gelatinase B de novo after adequate triggering, and overproduce TIMP-1. Gelatinase B is also endowed with functions other than cleaving the ECM. It has been shown to generate autoimmune neo-epitopes and to activate pro-IL-1beta into active IL-1beta. Gelatinase B ablation in the mouse leads to altered bone remodeling and subfertility, results in resistance to several induced inflammatory or autoimmune pathologies, and indicates that the enzyme plays a crucial role in development and angiogenesis. The major human neutrophil chemoattractant, IL-8, stimulates fast degranulation of gelatinase B from neutrophils. Gelatinase B is also found to function as a regulator of neutrophil biology and to truncate IL-8 at the amino terminus into a tenfold more potent chemokine, resulting in an important positive feedback loop for neutrophil activation and chemotaxis. The CXC chemokines GRO-alpha, CTAP-III, and PF-4 are degraded by gelatinase B, whereas the CC chemokines MCP-2 and RANTES are not cleaved.
Journal of Leukocyte Biology 07/2001; 69(6):851-9. · 4.99 Impact Factor
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Journal of Clinical Investigation 10/2000; 106(5):627-8. · 15.39 Impact Factor
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ABSTRACT: Granulocyte chemotactic protein-2 (GCP-2) of the mouse is a potent neutrophil chemotactic and activating factor in vitro and in vivo. Gelatinase B/matrix metalloproteinase-9 is released from neutrophils within 1 h after stimulation with GCP-2. In vitro neutrophil chemotaxis by GCP-2 was not impaired by specific inhibitory monoclonal antibodies (mAb) against gelatinase B, indicating that gelatinase B is not involved in chemotaxis of neutrophils through polycarbonate filters. To investigate if gelatinase B degranulation is involved in in vivo cell migration toward GCP-2, experiments were performed with gelatinase B knockout mice. When mouse GCP-2 was injected intradermally in mice, a dose-dependent neutrophil chemotactic response was observed, and this cell migration was significantly impaired in young mice by genetic gelatinase B knockout. In adult vs. young gelatinase B-deficient mice, such compensatory mechanisms as higher basal neutrophil counts and less impairment of chemotaxis toward local GCP-2 injection were observed. These experiments prove the concept that gelatinase B release under pressure of GCP-2 is a relevant, but not exclusive, effector mechanism of neutrophil chemotaxis in vivo and that known mechanisms, other than the release of gelatinase B, allow for a full-blown chemotactic response and compensate for gelatinase B deficiency in adult life in the mouse.
Journal of Interferon & Cytokine Research 08/2000; 20(7):667-74. · 3.06 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) and Leber's hereditary optic neuropathy (LHON) have been found to occur in combination. Based on an extensive literature search and on a clinical analysis of 55 LHON pedigrees (103 patients) and 40 patients with definite MS, this study concludes that the association of LHON and MS is more than a coincidence, and that carrying a primary LHON mutation is a risk factor for developing MS. All three primary LHON mutations occurring in the European and North American populations have been found to be associated with an MS-like syndrome. The neurological characteristics of MS associated with LHON are indistinguishable from those of MS in general, but the severe and bilateral visual symptoms and signs justify considering these patients as a clinical subgroup of MS and screening them for LHON mutations. However, screening LHON patients for MS appears to be more rewarding.
Journal of Neurology 08/2000; 247(7):535-43. · 3.47 Impact Factor
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B Dubois,
S Masure,
U Hurtenbach,
L Paemen,
H Heremans,
J van den Oord,
R Sciot,
T Meinhardt,
G Hämmerling,
G Opdenakker,
B Arnold
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ABSTRACT: Regulated expression of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) plays a role in various physiological processes. To determine in vivo how unbalanced expression of these factors can promote or affect the course of pathologies, we knocked out the mouse gelatinase B gene by replacing the catalytic and zinc-binding domains with an antisense-oriented neomycin resistance gene. Adult gelatinase B-deficient mice and wild-type controls could be induced to develop experimental autoimmune encephalomyelitis (EAE) with similar scores for neurologic disease, blood-brain barrier permeability, and central nervous system histopathology. However, whereas diseased control animals showed necrotizing tail lesions with hyperplasia of osteocartilaginous tissue, adult gelatinase B-deficient mice were resistant to this tail pathology. Gelatinase B-deficient mice younger than 4 weeks of age were significantly less susceptible to the development of EAE than were age matched controls and, even as they aged, they remained resistant to tail lesions. These data illustrate that gelatinase B expression plays a role in the development of the immune system and that, in ontogenesis, the propensity to develop autoimmunity is altered by the absence of this MMP.
Journal of Clinical Investigation 01/2000; 104(11):1507-15. · 15.39 Impact Factor
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ABSTRACT: The effects of 25 recently discovered plant lectins on cell proliferation and enzyme release were compared to those of previously known lectins on rat microglia and astrocyte cell cultures. A dose-dependent proliferation of microglial cells, but not of astrocytes, was induced by seven lectins, whereas five lectins showed dose-dependent cytotoxicity on both microglia and astrocyte cell cultures. The activity of gelatinase B (MMP-9) was strongly increased in microglial cells by the aforementioned seven lectins, by concanavalin A, and by phytohemagglutinin (PHA-E4), whereas gelatinase A (MMP-2) remained at constitutive levels. The five cytotoxic lectins decreased the activity of gelatinase B in microglia and of gelatinase A in astrocytes, in a dose-dependent manner. The lectin wheat germ agglutinin induced a decrease in gelatinase B activity in microglia, but stimulated gelatinase A and B activity in astrocytes. These results indicate that lectins possess neuromodulatory effects that may motivate the study of their effects on central nervous system (CNS) function in vivo. This, in turn, may lead to better insight into whether lectin or lectin-like molecules can interact with glial cells, and whether they have a role in acute toxicity and in multifactorial diseases in which environmental factors may play a role.
Glia 08/1999; 27(1):53-61. · 4.82 Impact Factor
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ABSTRACT: The matrix metalloproteases (MMPs) are a family of structurally related proteolytic enzymes, that are involved in various physiological and pathological processes. In the central nervous system, MMPs may contribute to proteolysis of basement membranes, extracellular matrix molecules, cytokine precursors, zymogens, cell surface molecules, and myelin components. Clipping of the latter increases the local antigenic epitope load. We explain the REGA model (Remnant Epitopes Generate Autoimmunity), which may be applied to the pathophysiology of many autoimmune diseases, including multiple sclerosis, and which consists of a tight control of the enzymatic activity of the MMPs at several levels: MMP gene transcription and MMP secretion, that are regulated by cytokines and chemokines, activation of latent zymogens by proteolysis, inhibition of enzyme activity by specific inhibitors, and glycosylation. Gelatinase B, a rather complex protease, is discussed as a prototypic MMP example. Possible applications of our understanding about the regulation of MMP activity and of the influence on disease-promotion or -limitation are reviewed.
Acta neurologica Belgica 04/1999; 99(1):53-6. · 0.54 Impact Factor
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P Fiten,
K Vandenbroeck, B Dubois,
E Van Coillie,
I Nelissen,
J Van Damme,
A Ligers,
J Hillert,
M Andersson,
T Olsson,
G Opdenakker
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ABSTRACT: Monocyte chemotactic protein 3 (MCP-3) is a chemokine that attracts mononuclear cells, including monocytes and lymphocytes, the inflammatory cell types that predominate in multiple sclerosis lesions. We studied the possible association between the presence of a CA/GA microsatellite repeat polymorphism in the promoter/enhancer region of the MCP-3 gene and the occurrence of multiple sclerosis. DNA samples from 192 Swedish multiple sclerosis (MS) patients and 129 healthy controls were analysed by an automated fluorescent technique. In the whole sample population, five MCP-3 allele variants (MCP-3*A1 to MCP-3*A5) were detected with an allele frequency ranging between 0.3% and 46%. The individual MCP-3 allele frequencies did not differ significantly between MS patients and control individuals. The relative MS risk, attributable to HLA-DRB1*15 was 3.05 (chi2 = 22.25, p < 0.0001). The phenotype frequency (PF) of none of the MCP-3 alleles was significantly altered in the population of controls versus unselected MS patients. When MS patients and control subjects were stratified according to positivity for HLA-DRB1*15, the MCP-3*A4-associated risk for developing MS decreased to 0.36 (p = 0.011). In the stratified groups of patients who were negative for both HLA-DRB1*15 and HLA-DRB1*03, and hence possessed a lower risk to develop MS, the MCP-3*A2-associated risk for MS development decreased significantly (p = 0.018). We conclude that the MCP-3*A4 allele might protect against MS development on the background of the increased risk in HLA-DRB1*15+ individuals and the MCP-3*A2 allele seems protective in low-risk individuals, who are both negative for DRB1*03 and DRB1*15.
Journal of Neuroimmunology 03/1999; 95(1-2):195-201. · 2.96 Impact Factor
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ABSTRACT: The etiology and the pathogenesis of multiple sclerosis are not yet known. There might be a role for genetic susceptibility, for environmental factors and for inflammatory and immunological changes. Most of the actual therapies are based on the latter two phenomena. We review here corticosteroids, interferon beta and copolymer 1 as the current drugs of choice and compare schematically the immunological basis of the mechanisms of action of these three substances with those of experimental or other treatments.
Archivum Immunologiae et Therapiae Experimentalis 02/1999; 47(1):7-16. · 2.54 Impact Factor
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ABSTRACT: The stimulatory or inhibitory effects of plant lectins on the production of gelatinase A (MMP-2) and gelatinase B (MMP-9) by mononuclear white blood cells was investigated by substrate zymography. Leukocyte cultures from 24-h old buffy coats were spontaneously activated and produced high levels of gelatinase B. Using such cultures the suppressing activity of the Datura stramonium, Viscum album, Bauhinia purpurea, Triticum aestivum and Maackia amurensis lectins on gelatinase B induction were demonstrated. When fresh leukocyte preparations from single blood donors were used, low levels of gelatinase B were produced. The induction of gelatinase B was confirmed for concanavalin A and phytohaemagglutinin (PHA-L4). In addition, the Urtica dioica, Calystegia sepium, Convolvulus arvensis and Colchicum autumnale lectins were documented as novel and potent inducers of gelatinase B. Since high circulating gelatinase B levels are associated with specific pathologies, including shock syndromes, the acute toxicity of many lectins might be partially mediated or influenced by gelatinase induction.
FEBS Letters 06/1998; 427(2):275-8. · 3.54 Impact Factor
