Langerhans cell histiocytosis: a cytokine/chemokine-mediated disorder?

Langerhans cell histiocytosis (LCH) is a rare disorder characterized by an abnormal accumulation and/or proliferation of cells with a Langerhans cell phenotype. Although no clear cause of LCH has been identified, it has been postulated that LCH might be the consequence of an immune dysregulation, causing Langerhans cells to migrate to and accumulate at various sites. Production of cytokines and chemokines is a central feature of immune regulation. Cytokines are abundantly present within LCH lesions. We review here the potential role of cytokines and chemokines in the pathogenesis of LCH. The type, distribution, and number of different cytokines released within lesions can provide clues to the possible aetiology of LCH and, ultimately, might offer therapeutic possibilities using recombinant cytokines or antagonists for this disorder.     

Probing cytokines, chemokines and matrix metalloproteinases towards better immunotherapies of multiple sclerosis

Multiple sclerosis (MS) is an autoimmune disease with a spectrum of clinical evolutions. We here summarize recent insights into the neuroinflammatory processes of demyelination, vascular cuffing, destruction of the blood brain barrier (BBB), neuronal toxicity and the ensuing (re)activation of autoreactive lymphocytes. Translation of these processes in molecular terms indicates that cytokines, including interferons, ligands of the tumor necrosis factor receptor family and interleukins, and also chemokines and matrix metalloproteinases play pivotal roles in MS. This not only helps to understand disease mechanisms in the central nervous system of affected patients, but also forms a solid scientific basis to improve present therapies. Treatment of MS with parenterally administered anti-inflammatory agents may be improved, based on present knowledge and new insights obtained with animal models. Such innovations include better use of knowledge about the formulation, administration, turnover and glycosylation of interferon-β (IFN-β), combinations of IFN-β with inhibitors of IFN-β-degrading proteinases in MS, and new ways to diminish vascular cuffs and the transmigration of leukocytes across the two basement membranes of the BBB. Novel molecules interfering with matrix metalloproteinases and chemokines, such as EMMPRIN, COAM and monoclonal antibodies are currently being investigated, demonstrating continued efforts to find new drugs for MS treatment.     

Natural haemozoin modulates matrix metalloproteinases and induces morphological changes in human microvascular endothelium

Severe malaria, including cerebral malaria (CM), is characterized by the sequestration of parasitized erythrocytes in the microvessels after cytoadherence to endothelial cells. Products of parasite origin, such as haemozoin (HZ), contribute to the pathogenesis of severe malaria by interfering with host inflammatory response. In human monocytes, HZ enhanced the levels of matrix metalloproteinase-9 (MMP-9), a protease involved in neuroinflammation. Here the effects of HZ on the regulation of MMPs by the human microvascular endothelial cell line HMEC-1 were investigated. Cells treated with natural (n)HZ appeared elongated instead of polygonal, and formed microtubule-like vessels on synthetic basement membrane. nHZ enhanced total gelatinolytic activity by inducing proMMP-9 and MMP-9 without affecting basal MMP-2. The level of the endogenous tissue inhibitor of MMP-9 (TIMP-1) was not altered by nHZ, while TIMP-2, the MMP-2 inhibitor, was enhanced. Additionally, nHZ induced MMP-1 and MMP-3, two enzymes sequentially involved in collagenolysis and proMMP-9 proteolytic activation. Lipid-free HZ did not reproduce nHZ effects. Present data suggest that the lipid moiety of HZ alters the MMP/TIMP balances and promotes the proteolytic activation of proMMP-9 in HMEC-1, thereby enhancing total gelatinolytic activity, cell activation and inflammation. These findings might help understanding the mechanisms of blood brain barrier damage during CM.     

Mechanisms of DNA methylation and demethylation in mammals

Cytosine methylation is an epigenetically propagated DNA modification that can modify how the DNA molecule is recognized and expressed. DNA methylation undergoes extensive reprogramming during mammalian embryogenesis and is directly linked to the regulation of pluripotency and cellular identity. Studying its regulation is also important for a better understanding of the many diseases that show epigenetic deregulations, in particular, cancer. In the recent years, a lot of progress has been made to characterize the profiles of DNA methylation at the genome level, which revealed that patterns of DNA methylation are highly dynamic between cell types. Here, we discuss the importance of DNA methylation for genome regulation and the mechanisms that remodel the DNA methylome during mammalian development, in particular the involvement of the rediscovered modified base 5-hydroxymethylcytosine.     

How morphological constraints affect axonal polarity in mouse neurons

Neuronal differentiation is under the tight control of both biochemical and physical information arising from neighboring cells and micro-environment. Here we wished to assay how external geometrical constraints applied to the cell body and/or the neurites of hippocampal neurons may modulate axonal polarization in vitro. Through the use of a panel of non-specific poly-L-lysine micropatterns, we manipulated the neuronal shape. By applying geometrical constraints on the cell body we provided evidence that centrosome location was not predictive of axonal polarization but rather follows axonal fate. When the geometrical constraints were applied to the neurites trajectories we demonstrated that axonal specification was inhibited by curved lines. Altogether these results indicated that intrinsic mechanical tensions occur during neuritic growth and that maximal tension was developed by the axon and expressed on straight trajectories. The strong inhibitory effect of curved lines on axon specification was further demonstrated by their ability to prevent formation of multiple axons normally induced by cytochalasin or taxol treatments. Finally we provided evidence that microtubules were involved in the tension-mediated axonal polarization, acting as curvature sensors during neuronal differentiation. Thus, biomechanics coupled to physical constraints might be the first level of regulation during neuronal development, primary to biochemical and guidance regulations.     

Coxiella burnetii vaginal shedding and antibody responses in dairy goat herds in a context of clinical Q fever outbreaks

This study, carried out in three goat herds, was aimed at describing individual responses to Q fever infection in an abortive context, focusing on both antibody and shedding levels. Seroprevalence of Coxiella burnetii (Cb) infection and vaginal shedding of 1083 goats were investigated using ELISA and realtime qPCR assays, respectively. At the end of the outbreaks, a seroprevalence of 45.0% was found, and vaginal shedding appeared massive with levels above 10(4) Cb per swab in 42.3% of the whole population and above 10(6) Cb per swab for 90.9% of aborted goats. Susceptible animals (i.e. seronegative nonshedders) were unfrequent (31.2%), most of them being kids (94.7%). Seronegative females were predominant among nonshedders and conversely seropositive ones, predominant among high shedders (above 10(6) Cb per swab). Nevertheless, at least 43.3% of seronegative goats shed bacteria confirming the need of interpreting serology on a herd scale. The subsequent farrowing period was characterized by a significant reduction in the number of clinical cases. Females that had already aborted were more often involved than others. Shedding quantities remained high, particularly for primiparous does, mainly when facing infection for the first time. Thus, Q fever control must be based on both preventive measures directed to the preherd and environmental precautions.     

Cytokine and CXC chemokine expression patterns in aqueous humor of patients with presumed tuberculous uveitis

Aqueous humor (AH) samples from 14 patients with presumed tuberculous uveitis (PTU), and 30 control patients were assayed for the proinflammatory cytokines interleukin IL-4, IL-12, IL-15, IL-17, interferon (IFN)-γ, and tumor necrosis factor (TNF)-α, the immunosuppressive cytokine IL-10, and the chemokines GRO-α/CXCL1, IL-8/CXCL8, MIG/CXCL9, IP-10/CXCL10 and SDF-1/CXCL12 with the use of a multiplex assay. Among cytokines, IL-4 and IL-12 were not detected. IL-15, IL-17, IFN-γ, TNF-α and IL-10 levels in AH were significantly higher in patients than in controls (p<0.001; p=0.004; p<0.001; p<0.001; p<0.001, respectively). Among chemokines, SDF-1 levels did not differ significantly between patients and controls, whereas GRO-α, IL-8, MIG and IP-10 levels were significantly higher in patients than in controls (p=0.001; p<0.001; p<0.001; p<0.001, respectively). Mean GRO-α levels in AH of PTU patients were 6-fold higher than IL-8 levels and mean IP-10 levels were 15-fold higher than MIG levels. Clinical disease activity correlated significantly with the levels of IL-15, IFN-γ, TNF-α and IP-10. Logistic regression analysis demonstrated a significant positive association between PTU and high levels of IFN-γ, IL-8, MIG and IP-10. These data suggest that both T helper (Th) Th(1) and Th(17) cells are involved in PTU and that the cytokine profile is polarized toward a Th(1) response. GRO-α and IP-10 might be involved in neutrophil and activated T lymphocyte chemoattraction in PTU, respectively.