Loes M Kuijk

University Medical Center Utrecht, Utrecht, Provincie Utrecht, Netherlands

Are you Loes M Kuijk?

Claim your profile

Publications (10)40.84 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Mevalonate kinase deficiency (MKD) is a hereditary autoinflammatory syndrome marked by recurrent attacks of fever and inflammation. Severe enzyme deficiency results in mevalonic aciduria (MA) and milder deficiency in hyperimmunoglobulin D syndrome (HIDS). Treatment remains a challenge. To observe the effect of the recombinant interleukin-1 receptor antagonist anakinra in patients with MKD. A prospective observational study was undertaken. Two patients with MA started continuous treatment with anakinra (1-2 mg/kg/day) and nine patients with HIDS chose between continuous treatment and on-demand treatment (starting at first symptoms of attack, 100 mg/day or 1 mg/kg/day for 5-7 days). Anakinra induced partial remission in one patient with MA but there was no response in the other patient with MA. In one patient with HIDS continuous treatment induced complete remission for 7 months but was stopped because of side effects. Eight patients with HIDS preferred on-demand treatment from the start. This induced a clinical response (≥50% reduction in duration) in 8 of 12 treated attacks without a change in attack frequency. Anakinra prevented fever attacks due to vaccination without inhibiting antibody induction. No major side effects were seen. On-demand treatment with anakinra in HIDS decreases the duration and severity of fever attacks. Because of the burden of daily injections and relatively long asymptomatic intervals of HIDS, all patients with HIDS preferred on-demand treatment.
    Annals of the rheumatic diseases 08/2011; 70(12):2155-8. · 8.11 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mevalonate kinase deficiency (MKD) is an autoinflammatory disorder characterized by recurring fever episodes and results from disturbed isoprenoid biosynthesis. Lipopolysaccharide-stimulated peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin-1beta (IL-1beta) because of the presence of hyperactive caspase-1, and this has been proposed to be the primary cause of recurring inflammation. Here we show that inhibition of HMG-CoA reductase by simvastatin treatment, mimicking MKD, results in increased IL-1beta secretion in a Rac1/PI3K-dependent manner. Simvastatin treatment was found to activate protein kinase B (PKB)/c-akt, a primary effector of PI3K, and ectopic expression of constitutively active PKB was sufficient to induce IL-1beta release. The small GTPase Rac1 was activated by simvastatin, and this was required for both PKB activation and IL-1beta secretion. IL-1beta release is mediated by caspase-1, and simvastatin treatment resulted in increased caspase-1 activity in a Rac1/PI3K-dependent manner. These data suggest that, in MKD, dysregulated isoprenoid biosynthesis activates Rac1/PI3K/PKB, resulting in caspase-1 activation with increased IL-1beta release. Importantly, inhibition of Rac1 in peripheral blood mononuclear cells isolated from MKD patients resulted in a dramatic reduction in IL-1beta release. These data suggest that pharmacologic inhibition of Rac1 could provide a novel therapeutic strategy for treatment of MKD.
    Blood 09/2008; 112(9):3563-73. · 9.78 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mevalonate kinase deficiency (MKD) is a hereditary syndrome characterized by recurring episodes of fever and inflammation. Peripheral blood mononuclear cells from MKD patients secrete high levels of interleukin (IL)-1beta when stimulated with lipopolysaccharide (LPS), which is thought to be a primary cause of the inflammation. However, the link between a deficient mevalonate kinase and excessive IL-1beta release remains unclear. To investigate this we made use of a model in which monocytic cells (THP-1) were treated with simvastatin. Statins are compounds that inhibit 3-hydroxy-3-methylglutaryl CoA (HMG-CoA) reductase and thereby artificially impair the isoprenoid biosynthesis pathway, mimicking mevalonate kinase deficiency. Our study revealed that LPS-stimulated THP-1 cells treated with simvastatin had an increased caspase-1 mediated processing of proIL-1beta. This increased processing was caused by enhanced autoprocessing of caspase-1, rather than enhanced transcription or translation of caspase-1 or proIL-1beta. Simvastatin-induced activation of caspase-1 was caused by an impairment of non-sterol isoprenoid biosynthesis, as the isoprenyl intermediate GGPP could block activation of caspase-1 and mIL-1beta release. In addition, inhibition of both farnesyl pyrophosphate synthase and geranylgeranyltransferase I also induce mIL-1beta release. Taken together, these results demonstrate that simvastatin augments LPS-induced IL-1beta release post-translationally, by inducing caspase-1 activity. These findings suggest that MKD patients may have overactive caspase-1, causing enhanced IL-1beta processing and subsequent inflammation in response to bacterial components.
    Molecular Immunology 05/2008; 45(8):2158-65. · 2.65 Impact Factor
  • Source
    Pediatric Rheumatology 01/2008; 6:1-1. · 1.47 Impact Factor
  • Source
    L.M. Kuijk
    [Show abstract] [Hide abstract]
    ABSTRACT: Mevalonate kinase deficiency (MKD) is a rare autoinflammatory disorder characterised mainly by recurrent episodes of fever. Other symptoms include skin rashes, arthritis, vomiting, headache and diarrhoea. Furthermore, patients often have high C-reactive protein levels and white blood cell counts during these febrile episodes, indicating a state of inflammation. These episodes of inflammation usually last a couple of days and return every 3 to 6 weeks. They are often triggered by some kind of immunological stimulus, such as childhood vaccinations or minor infections. The disease is caused by missense mutations in the gene encoding the enzyme mevalonate kinase. This enzyme is crucial for the biosynthesis of cholesterol and of other, non-sterol, intermediates such as isoprenyl groups. The latter are large fatty acid tails that are covalently attached to small GTPases such as Rac and Rho, and are needed to localize these proteins in the plasma membrane. The characteristic inflammatory episodes of MKD are quite likely caused by a spontaneous secretion of the pro-inflammatory cytokine interleukin-1beta (IL-1beta) by monocytic cells. This cytokine was shown to induce the secretion of other pro-inflammatory cytokines such as TNF-alpha and IL-18, thus initiating the inflammatory response. The suggested importance of IL-1beta is confirmed by the successful treatment of MKD patients with the IL-1 receptor antagonist Anakinra. Using an in vitro model for MKD, secretion of IL-1beta was shown to occur in two steps: first an immunological trigger initiates transcription and translation of proIL-1beta, the inactive precursor of IL-1beta. The second step is provided by the cleavage of proIL-1beta into the active, secreted form by the enzyme caspase-1. The in vitro model demonstrated that monocytic cells with an artificially impaired isoprenoid biosynthesis, thereby mimicking MKD, have increased activity of caspase-1. This suggests that patients with MKD are also likely to have hyperactive caspase-1, which causes monocytic cells to inappropriately secrete active IL-1beta after a small immunological trigger, such as vaccinations, resulting in inflammation. Using the same in vitro model for MKD it was shown that a lack of isoprenyl groups, specifically of geranylgeranylpyrophosphate, was causing an increase in activity of the small GTPase Rac1, which resulted in activation of a phosphatidylinositol 3 kinase (PI3K) and protein kinase B (PKB/c-Akt)-dependent signal transduction route. Activation of this signal transduction route eventually led to activation of caspase-1, providing the molecular link between impaired mevalonate kinase functionality and inflammation. The described research has thus identified Rac1, PI3K and PKB as potential new therapeutic targets in MKD.
    01/2008;
  • Source
    Annals of the Rheumatic Diseases 12/2007; 66(11):1545-6. · 9.11 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Several autoinflammatory disorders such as Muckle-Wells syndrome are characterized by mutations in the NALP3/cryopyrin gene. NALP3 and NALP1 proteins can assemble to inflammasomes that activate caspase-1, resulting in the processing of pro-inflammatory cytokines IL-1beta and IL-18. The present study was designed to determine which cells and tissues express NALP1 and NALP3. Monoclonal antibodies were developed and their use revealed distinct distribution profiles of NALP1 and NALP3. Granulocytes, monocytes (very weakly), dendritic cells, and B and T cells all express NALP1 and NALP3. Highest levels of NALP1 are found in T cells and Langerhans cells. Furthermore, NALP1 is present in glandular epithelial structures such as stomach, gut, lung, and, surprisingly, in neurons and testis. In contrast to NALP1, NALP3 shows a more restricted tissue distribution with expression mainly in non-keratinizing epithelia in the oropharynx, esophagus, and ectocervix. Moreover, NALP3 expression is found in the urothelial layer in the bladder. Likewise, a difference in subcellular distribution between NALP1 and NALP3 is observed because NALP1 is localized mainly in the nucleus, whereas NALP3 is predominantly cytoplasmic. We propose that the presence of NALP3 in epithelial cells lining the oral and genital tracts allows the rapid sensing of invading pathogens, thereby triggering an innate immune response.
    Journal of Histochemistry and Cytochemistry 06/2007; 55(5):443-52. · 2.26 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Mevalonate kinase deficiency (MKD) is an autosomal-recessive disorder characterized by recurring episodes of inflammation. MK catalyzes the phosphorylation of mevalonic acid, which is an early step in isoprenoid biosynthesis. The goal of our study was to determine whether a temporary shortage of certain isoprenoid end products and/or the accumulation of mevalonic acid is the cause of interleukin-1beta (IL-1beta) secretion in MKD. We studied the effect of the addition of intermediate metabolites and inhibitors of the isoprenoid biosynthesis pathway on IL-1beta secretion by peripheral blood mononuclear cells (PBMCs) of patients with MKD and healthy controls. Inhibition of enzymes involved in geranylgeranyl pyrophosphate (GGPP) synthesis or geranylgeranylation of proteins led to a marked increase of lipopolysaccharide-stimulated IL-1beta secretion in PBMCs of control subjects. Furthermore, the increased IL-1beta secretion by PBMCs of patients with MKD was reversed by supplementation with GGPP as well as with mevalonic acid. IL-1beta secretion was increased only when control PBMCs were incubated with excessive amounts of mevalonic acid. Finally, a reduction in IL-1beta secretion by MKD PBMCs was also observed when sterol biosynthesis was inhibited, favoring nonsterol isoprenoid biosynthesis. Our results indicate that a shortage of geranylgeranylated proteins, rather than an excess of mevalonate, is likely to cause increased IL-1beta secretion by PBMCs of patients with MKD.
    Arthritis & Rheumatology 12/2006; 54(11):3690-5. · 7.48 Impact Factor
  • Source
    Hal M Hoffman, Loes M Kuijk