Retinal changes associated with multivitamin deficiency before and after supplementation.

BACKGROUND: Nutritional visual defects are apparently uncommon nowadays in developed nations. Retinal change-related visual defects caused by hypovitaminoses may be underdiagnosed. AIM OF THE STUDY: To investigate the retinal structural and functional changes in a patient with multivitamin deficiency before and during vitamin supplementation. METHODS: A 51-year-old female had been on vegetarian diet as a child, and on restrict vegan diet during the last 2 years, developing severe bilateral deterioration of visual function and polyneuropathy. Blood test revealed low levels of vitamin A, B6 and D. The patient underwent examinations with optical coherence tomography (OCT), computerized visual field examination (VF), electroretinography (ERG), visual evoked potentials (VEP) and neurography before and after vitamin supplementation. RESULTS: Visual acuity (VA) was 20/1000 and VF examination showed central scotoma in both eyes. Color vision was significantly affected. Full-field ERG showed normal rod and cone function, but a clearly reduced central peak was registered in multifocal ERG (mf-ERG), indicating impaired fovea function. VEP showed delayed latency and low amplitude of P100 in both eyes. Neurography showed sensory polyneuropathy. OCT showed significant thinning of macular ganglion cell plus inner plexiform layer (GCIPL) with rapid progression. Retinal nerve fiber layer (RNFL) was preserved and normal, which is in contrast to neuroinflammatory conditions. After 2.5 years of multivitamin supplementation, the visual functions were improved. GCIPL thickness was stable without further deterioration. CONCLUSIONS: Multivitamin deficiency results in progressive thinning of GCIPL with severe visual deterioration. In contrast to neuroinflammation, RNFL is preserved and normal. Stabilized GCIPL during vitamin supplementation was associated with improved visual function. OCT provides a sensitive and objective measure for differential diagnosis, monitoring retinal change and response to therapy.

Retinal thinning and brain atrophy in early MS and CIS.

BACKGROUND: Optical coherence tomography (OCT) could be complementary to magnetic resonance imaging (MRI) of the brain in monitoring course of multiple sclerosis (MS) and clinically isolated syndrome (CIS). Thinning of neurons in ganglion cell-inner plexiform layer (GCIPL) measured by OCT is assumed to be associated with brain atrophy. OBJECTIVES: To evaluate association of GCIPL with brain parameters detected by quantitative MRI (qMRI) and MR-spectroscopy (MRS) in early MS and CIS. METHODS: Seventeen newly diagnosed MS and 18 CIS patients were prospectively included. The patients were assessed at baseline as well as at 1 year follow-up by OCT, qMRI and MRS. Brain parenchymal and myelin volumes (BPV, MYV respectively) and the corresponding fractions (BPF, MYF) were measured with qMRI. Metabolites including myo-inositol (myo-Ins) were measured in the normal-appearing white matter (NAWM) using MRS. T-tests and ANOVA were used to analyze group differences, and linear regression models to evaluate association of GCIPL with BPV, MYV and myo-Ins after correlation analysis. RESULTS: Disease activity reflected by lesions on MRI and presence of CSF oligoclonal IgG bands were more prominent in MS compared to CIS. GCIPL, BPV, MYV, BPF and MYF were reduced, while concentration of myo-Ins was increased in MS compared to CIS. Follow-up showed consistency of thinner GCIPL in MS compared to CIS. GCIPL thinning correlated with reduced BPV and MYV (P < .05 for both), but with increased myo-Ins (P < .01). CONCLUSIONS: Significant GCIPL thinning occurs in early MS and is associated with enhanced brain inflammation and atrophy.

Playing God and the intrinsic value of life: moral problems for synthetic biology?

Most of the reports on synthetic biology include not only familiar topics like biosafety and biosecurity but also a chapter on 'ethical concerns'; a variety of diffuse topics that are interrelated in some way or another. This article deals with these 'ethical concerns'. In particular it addresses issues such as the intrinsic value of life and how to deal with 'artificial life', and the fear that synthetic biologists are tampering with nature or playing God. Its aim is to analyse what exactly is the nature of the concerns and what rationale may lie behind them. The analysis concludes that the above-mentioned worries do not give genuine cause for serious concern. In the best possible way they are interpreted as slippery slope arguments, yet arguments of this type need to be handled with care. It is argued that although we are urged to be especially vigilant we do not have sufficiently cogent reasons to assume that synthetic biology will cause such fundamental hazards as to warrant restricting or refraining from research in this field.

The Importance of Optical Coherence Tomography in the Diagnosis of Atypical or Subclinical Optic Neuritis: A Case Series Study.

Background: Optic neuritis (ON) is an inflammatory condition of the optic nerve. ON is associated with development of demyelinating diseases of the central nervous system (CNS). CNS lesions visualized by magnetic resonance imaging (MRI) and the finding of oligoclonal IgG bands (OB) in the cerebrospinal fluid (CSF) are used to stratify the risk of MS after a "first" episode of ON. However, the diagnosis of ON in absence of typical clinical manifestations can be challenging. Methods and Materials: Here we present three cases with changes in the optic nerve and ganglion cell layer in the retina over the disease course. (1) A 34-year-old female with a history of migraine and hypertension had suspect amaurosis fugax (transient vision loss) in the right eye. This patient developed MS four years later. Optical coherence tomography (OCT) showed dynamic changes of the thickness of peripapillary retinal nerve fiber layer (RNFL) and macular ganglion cell-inner plexiform layer (GCIPL) over time. (2) A 29-year-old male with spastic hemiparesis and lesions in the spinal cord and brainstem. Six years later he showed bilateral subclinical ON identified using OCT, visual evoked potentials (VEP) and MRI. The patient fulfilled diagnosis criteria of seronegative neuromyelitis optica (NMO). (3) A 23-year-old female with overweight and headache had bilateral optic disc swelling. With OCT and lumbar puncture, idiopathic intracranial hypertension (IIH) was excluded. Further investigation showed positive antibody for myelin oligodendrocyte glycoprotein (MOG). Conclusions: These three cases illustrate the importance of using OCT to facilitate quick, objective and accurate diagnosis of atypical or subclinical ON, and thus proper therapy.

Homonymous visual field defect and retinal thinning after occipital stroke.

INTRODUCTION: Stroke is the most common cause of homonymous visual field defects (VFD). About half of the stroke patients recover from VFD. However, relationship between VFD and retinal changes remains elusive. PURPOSE: To investigate the association between occurrence of VFD, changes of macular ganglion cell and inner plexiform layer (GCIPL) and its axon retinal nerve fiber layer (RNFL) detected with optical coherence tomography (OCT). PATIENTS AND METHODS: The study consists of retrospective review of medical records and follow-up examinations. Patients with acute occipital stroke were registered. VFD was identified with confrontation and/or perimetry tests at the onset. At follow-up, the patients were examined with visual field tests and OCT measurements. RESULTS: Thirty-six patients met the inclusion criteria. At onset, 26 patients (72%) had VFD. At follow-up >1 year after stroke, 13 patients (36%) had remaining VFD: 5 had homonymous hemianopia, 5 had homonymous quadrantanopia, and 3 had homonymous scotomas. Average thickness of GCIPL and RNFL were significantly reduced in each eye in patients with VFD compared to non-VFD (NVFD) (p < .01 for all comparisons). Thickness of superior and inferior RNFL quadrants was significantly reduced in VFD compared to NVFD (p < .01 for both). Among these 13 patients, 4 had characteristic homonymous quadrant-GCIPL thinning, 2 had characteristic homonymous hemi-GCIPL thinning, and 7 had diffuse GCIPL thinning. CONCLUSION: GCIPL and RNFL thinning were observed in the patients with VFD. GCIPL thinning appears in two forms: atypical diffuse thinning, or homonymous hemi-GCIPL thinning. Examining GCIPL and RNFL provides easy and reliable objective measures and is therefore proposed to be of predictive value on visual function.

IL-12/IFN-gamma/NO axis plays critical role in development of Th1-mediated experimental autoimmune encephalomyelitis.

The importance of the IL-12/IFN-gamma/nitric oxide (NO) axis in the pathogenesis of autoimmune diseases remains controversial. In parallel experiments, we explored the role of the IL-12/IFN-gamma/NO axis in the development of MOG 35-55-induced experimental autoimmune encephalomyelitis (EAE) in mice lacking IL-12, IFN-gamma receptor (IFN-gammaR) and inducible nitric oxide synthase (NOS2), respectively. In comparison with wide-type control mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice displayed more severe clinical signs of EAE both in remission and at subsequent relapse. Given the relatively low IFN-gamma production in IL-12-/- mice and the lack of IFN-gamma/IFN-gammaR signaling pathway in IFN-gammaR-/- mice, IL-12-/-, IFN-gammaR-/- and NOS2-/- mice with EAE exhibited low NO production. This correlated negatively with MOG 35-55-induced T cell proliferation. Both ED1-positive macrophages and CD4-positive T cells were increased in spinal cords from IL-12-/-, IFN-gammaR-/- and NOS2-/- compared to control mice. In vitro experiments demonstrate that spleen mononuclear cells from IL-12-/-, IFN-gammaR-/- and NOS2-/-mice with EAE present stronger migration capacity when compared to control mice. These results reveal that the IL-12/IFN-gamma/NO axis plays a critical role in the development of MOG 35-55-induced EAE, possibly over failing NO production.

Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness.

Two or more oligoclonal IgG bands (OB) detected by separation of cerebrospinal fluid (CSF) proteins while not demonstrable in corresponding serum reflect a local B-cell response accompanying central nervous system (CNS) inflammation. Using optimized, standardized methodology, preferentially protein separation by isoelectric focusing followed by immunoblotting, more than 95% of patients with multiple sclerosis (MS) have CSF OB of IgG class not detectable in serum, thereby providing powerful evidence for the diagnosis of MS. Once present, CSF OB persists in the individual patient irrespective of MS course or therapy. Because of the high sensitivity of CSF OB in MS as well as its high specificity in the appropriate clinical setting, examination of CSF for OB of IgG class can be strongly recommended to obtain support for the diagnosis of MS and identify patients with clinically isolated syndrome (CIS) at increased risk of developing MS. The IgG index equal to CSF/serum IgG:CSF/serum albumin is elevated in about 70% of MS patients, but rarely in CSF OB-negative MS. Because of lower diagnostic sensitivity, IgG index cannot be recommended as replacement of CSF OB in the diagnosis of MS but, when elevated, as additional evidence for an augmented B-cell response within the CNS that is compatible with MS. Although the clinical picture as well as findings from magnetic resonance imaging of the brain and spinal cord are essential for an MS diagnosis, this should be re-evaluated in CSF OB-negative patients, keeping in mind the many disease entities imitating MS. Recommended diagnostic criteria for MS must include definitions of the role of lumbar puncture and of clearly specified, optimized and standardized routine CSF investigations including for the presence of CSF IgG OB. There is a need for concerted long-term follow-up studies of the subgroup of MS patients without CSF OB regarding e.g. prognostic and immunologic features. For inclusion in trials of disease-modulating drugs, it is recommended that patients with MS or CIS are selected regarding presence vs. absence of CSF OB. Development and evaluation of new technologies to define local vs. systemic B-cell responses in patients with MS or CIS vs. patients with other inflammatory neurological diseases should shed new light on the role of CSF OB, which remains enigmatic.

CD24 and myosin light polypeptide 2 are involved in prevention of experimental autoimmune encephalomyelitis by myelin basic protein-pulsed dendritic cells.

We previously demonstrated that injection of myelin basic protein-pulsed (MBP-pulsed)--but not of unpulsed--autologous bone marrow-derived dendritic cells (DC) efficiently prevents experimental autoimmune encephalomyelitis (EAE) in Lewis rats. To define the molecules involved, we used 3 groups of rats pretreated subcutaneously with MBP-DC, or unpulsed DC, or PBS (control EAE). Four weeks later, all rats were immunized with encephalitogenic MBP peptide and adjuvant. Microarray analyses were done to screen for genes that differ among the 3 groups. Based on microarray analysis data, we used real-time PCR to measure expression of six probably involved genes in draining lymph node cells obtained on day 0, day 7 and day 14 post immunization (p.i.). Two of these 6 genes were consistently altered in both microarray analyses and RT-PCR. They are CD24 antigen being persistently low, and myosin light polypeptide 2 (Myl2) being high in the acute immune response in MBP-DC pretreated rats that develop resistance to EAE. These two genes could be targeted to treat EAE and, possibly, multiple sclerosis.

Benign Multiple Sclerosis is Associated with Reduced Thinning of the Retinal Nerve Fiber and Ganglion Cell Layers in Non-Optic-Neuritis Eyes.

BACKGROUND AND PURPOSE: It is exceedingly difficult to differentiate benign multiple sclerosis (BMS) from relapsing-remitting multiple sclerosis (RRMS) based on clinical characteristics, neuroimaging, and cerebrospinal fluid tests. Optical coherence tomography (OCT) allows quantification of retinal structures, such as the retinal nerve fiber layer (RNFL) thickness, at the optic disc and the ganglion cell layer (GCL) at the macula, on a micrometer scale. It can also be used to trace minor alterations and the progression of neurodegeneration, help predict BMS, and influence the choice of therapy. To utilize OCT to detect the extent of changes of the optic disk and macular microstructure in patients with BMS and RRMS compared to healthy controls (HCs), with special focus on changes related to the presence/absence of optic neuritis (ON). METHODS: Spectral-domain OCT was applied to examine eyes from 36 patients with multiple sclerosis (MS), comprising 11 with BMS and 25 with RRMS, and 34 HCs. RESULTS: The RNFL and GCL were significantly thinner in eyes previously affected by ON, irrespective of the type of MS (i.e., BMS or RRMS), than in HCs. Significant thinning of the GCL was also observed in non-ON RRMS (and not non-ON BMS) compared to HCs. Correspondingly, a significant association between disease duration and thinning rates of the RNFL and GCL was observed only in non-ON RRMS (-0.54±0.24 and -0.43±0.21 µm/year, mean±SE; p<0.05 for both), and not in non-ON BMS (-0.11±0.27 and -0.24±0.24 µm/year). CONCLUSIONS: The RNFL and GCL were thinner in both ON- and non-ON MS, but the change was more pronounced in ON MS, irrespective of the MS subtype studied herein. GCL thinning and the thinning rate of both the GCL and RNFL were less pronounced in non-ON BMS than in non-ON RRMS. These findings may help to predict the course of BMS.

Inflammation in the central nervous system: the role for dendritic cells.

Dendritic cells (DCs) are a subclass of antigen-presenting cells critical in the initiation and regulation of adaptive immunity against pathogens and tumors, as well as in the triggering of autoimmunity. Recent studies have provided important knowledge regarding distribution of DCs in the central nervous system (CNS) and their role in intrathecal immune responses. DCs are present in normal meninges, choroid plexus, and cerebrospinal fluid, but absent from the normal brain parenchyma. Inflammation is accompanied by recruitment and/or development of DCs in the affected brain tissue. DCs present in different compartments of the CNS are likely to play a role in the defence against CNS infections, and also may contribute to relapses/chronicity of CNS inflammation and to break-down of tolerance to CNS autoantigens. CNS DCs can therefore be viewed as a future therapeutic target in chronic inflammatory diseases such as multiple sclerosis.

Dendritic cells are present in ischemic brain after permanent middle cerebral artery occlusion in the rat.

BACKGROUND AND PURPOSE: Cerebral ischemia is associated with inflammation involving accumulation of polymorphonuclear neutrophils. T cells have been suggested to contribute to the secondary progression of ischemic brain injury. Dendritic cells (DC) are potent regulators of immunity by activating and tolerizing T cells. DC have previously been detected in rat meninges and choroid plexus. Hypothesizing that DC are involved in inflammation associated with cerebral ischemia, we investigated DC in the brain of Sprague-Dawley rats after permanent middle cerebral artery occlusion (pMCAO) versus sham operation. METHODS: All experimental rats (n=24) had the right MCA permanently occluded by inserting a nylon monofilament through the right external carotid artery. Immunohistochemistry was used to detect DC (OX62(+)), microglia/macrophages (OX42(+)) that developed into DC, and activated DC expressing major histocompatibility complex class II (OX6(+)) in the brain hemispheres at 1 hour to 6 days after pMCAO or sham operation. RESULTS: Levels of DC were elevated at 1 hour in the ischemic versus sham hemispheres (P<0.001) and ischemic versus nonischemic hemispheres (P<0.001). Activated DC expressing major histocompatibility complex class II (OX62(+)OX6(+)) were still elevated at 6 days after pMCAO in the ischemic versus nonischemic hemispheres (P<0.01). The area of brain lesion correlated with numbers of OX62(+) DC per 100-mm2 brain tissue section (r=0.79; P<0.0001). CONCLUSIONS: Increased levels of DC in the brain after pMCAO and correlation between DC numbers and brain lesion area indicate a role for DC in cerebral ischemia. This observation could constitute a basis for further studies on the role of DC in inflammation related to cerebral ischemia.

Secondary lymphoid organ chemokines are elevated in the cerebrospinal fluid during central nervous system inflammation.

Secondary lymphoid organ chemokines have been implicated in chronic inflammation. Their expression in the central nervous system (CNS) has not been studied. Here, levels of secondary lymphoid organ chemokines CCL19 (Exodus-3, MIP-3beta), CCL21 (Exodus-2, 6Ckine, SLC) and CXCL12 (SDF-1alpha) were analysed by ELISA in cerebrospinal fluid (CSF) and plasma from patients with multiple sclerosis (MS); acute optic neuritis (ON) with oligoclonal IgG in the CSF (i.e., first bout of MS); acute ON without oligoclonal IgG (non-MS-type ON); other inflammatory neurological diseases (OIND); and non-inflammatory neurological diseases (NIND). NIND CSF contained CCL19 and CXCL12, while CCL21 was not detected. Intrathecal production of CCL19 and CCL21 was elevated in MS, MS-type ON, and OIND, but not in non-MS-type ON. In MS, CSF levels of CCL19 weakly correlated with CSF cell counts. Intrathecal production of CXCL12 was elevated only in OIND. The role of elevated CCL19 and CCL21 in MS could be retention of mature dendritic cells (DC) in the CNS, recruitment of nai;ve T cells and activated B cells, as well as de novo formation of secondary lymphoid structures in MS plaques.

Effect of glatiramer acetate (Copaxone) on CD4+CD25high T regulatory cells and their IL-10 production in multiple sclerosis.

CD4(+)CD25(high) T regulatory (Tr) cells, representing high IL-2 receptor alpha chain expressing cells, have been shown to inhibit proliferation and cytokine secretion by CD4(+) T cells that are assumed to represent important effector cells in auto-aggressive immunity. Tr cells may therefore be considered of importance in the pathogenesis of multiple sclerosis (MS). Glatiramer acetate (GA; Copaxone) is approved as a disease-modulating agent that ameliorates the course of MS. The goal of this study was to examine in vitro effects of GA on Tr cells from MS patients subgrouped according to treatment without or with disease-modulating drugs, and healthy controls (HC). Three-colour flow cytometry was used to investigate in vitro influence of GA, and of the encephalitogenic myelin basic protein (MBP) peptide 83-89 as control, on the blood Tr cell proportion and on their functionally important cell surface molecules CD45RO, CD69, CD95 and HLA-DR, and on intracellular CTLA-4 and IL-10. Irrespective of exposure to GA or MBP((83-99)), levels of blood Tr cells expressing HLA-DR remained low in untreated MS patients and HC compared to the three treated MS patient groups. In vitro exposure to GA resulted in elevated levels of IL-10 producing Tr cells in all MS patient groups irrespective of receiving treatment as well as in HC. Exposure to GA or MBP((83-99)) had no effects on levels of Tr cells expressing other above-mentioned molecules. We conclude that GA induces elevated IL-10 production by Tr cells that is uniform and independent of ongoing MS treatment with IFN-beta or GA or IFN-beta+GA.

Laquinimod (ABR-215062) suppresses the development of experimental autoimmune encephalomyelitis, modulates the Th1/Th2 balance and induces the Th3 cytokine TGF-beta in Lewis rats.

The new orally active drug laquinimod (ABR-215062) was evaluated in experimental autoimmune encephalomyelitis (EAE) in the Lewis rat. EAE shares important immunological and clinical features with multiple sclerosis (MS). Doses of 16, 1.6 and 0.16 mg/kg/day laquinimod dose-dependently inhibited disease and showed better disease inhibitory effects as compared to roquinimex (Linomide). Furthermore, laquinimod inhibited the inflammation of both CD4+ T cells and macrophages into central nervous tissues, i.e. the spinal cord. It also changed the cytokine balance in favour of TH2/TH3 cytokines IL-4, IL-10 and TGF-beta. Laquinimod therefore represents a new orally active immunoregulatory drug without general immunosuppressive properties with a potential for the treatment of severe autoimmune diseases like MS.

Dendritic cells exposed to estrogen in vitro exhibit therapeutic effects in ongoing experimental allergic encephalomyelitis.

Immunomodulatory effects of estrogen have been demonstrated by clinical and experimental observations, but the mechanisms by which estrogen exhibits the effects remain to be defined. One possible mechanism by which estrogen inhibits the development of experimental allergic encephalomyelitis (EAE), a commonly used model of multiple sclerosis (MS) in humans, is over the functions of dendritic cells (DC). Here, we describe that splenic DC from Lewis rats obtained on day 12 post-immunization (p.i.) with myelin basic protein (MBP) encephalitogenic peptide 68-86+Freund's complete adjuvant (FCA), after being exposed in vitro 17beta-estradiol, exhibited therapeutic effects on acute EAE when injected subcutaneously on day 5 p.i. Blood mononuclear cells (MNC) were isolated from thus treated rats on day 12 p.i. Administration of estrogen-exposed DC prevented the expansion of CD4+ T cells and increased proportions of regulatory T cells producing IL-10 and CD4+CD28- suppressor T cells, accompanied with increased IL-10 and IFN-gamma, and reduced TNF-alpha production. Infiltrates of CD68+ macrophages within the central nervous system and MBP 68-86-induced T cell proliferation were inhibited in rats injected with estrogen-exposed DC compared to rats injected with naive DC. Estrogen up-regulated the expression of indoleamine 2,3-dioxygenase, which promotes tolerogenic properties of DC. The results suggest that in vitro exposure of DC to estrogen modulates DC functions and results in a therapeutic effect of DC.

Dendritic cells activate autologous T cells and induce IL-4 and IL-10 production in myasthenia gravis.

Dendritic cells (DC), as initiators and orchestrators of immune responses, control both naive and primed T cell responses. Depending on their maturation stage, DC promote immunity or tolerance. Here we investigated (1) the phenotype and cytokine secretion patterns of IL-10-modulated immature DC (IL-10-DC) and lipopolysaccharide (LPS)-driven mature DC (LPS-DC) in comparison with unmodulated immature DC (imDC) and (2) the effects of IL-10-DC, and of LPS-DC, vs. imDC on autologous T cell responses in patients with myasthenia gravis (MG) compared with healthy controls (HC). All three types of DC derived from MG significantly increased the levels of CD4+CD25+ T cells and of their subfraction expressing CD69, when compared to DC derived from HC. IL-10-DC induced production of IL-10 and IL-4 by T cells from MG patients, but only IL-10 production from HC. LPS-DC activated autologous T cells as reflected by augmented CD25, CD69 and CTLA-4 expression on CD4+ T cells, without differences between MG and HC. This was associated with increased production of both Th1 (IFN-gamma) and Th2 (IL-10 and IL-4) cytokines by T cells. These results indicate that DC-induced activation of autologous T cells is more pronounced in MG than in HC. In addition, DC-induced T cell responses in MG vs. HC are more Th2-prone.

Monocyte-derived dendritic cells express and secrete matrix-degrading metalloproteinases and their inhibitors and are imbalanced in multiple sclerosis.

Dendritic cells (DC) are antigen-presenting cells (APC) that most efficiently initiate and control immune responses. Migration processes of blood DC are crucial to exert their professional antigen-presenting functions. Matrix-degrading metalloproteinases (MMP) are proteolytic enzymes, which are considered to be key enzymes in extracellular matrix (ECM) turnover and mediators of cell migration. Tissue inhibitors of metalloproteinases (TIMP) are important regulators of MMP activity. Here we investigate whether blood monocyte-derived immature DC (iDC) and mature DC (mDC) express, produce and secrete functionally active MMP-1, -2, -3 and -9 and their inhibitors TIMP-1 and -2, and examine their involvement in multiple sclerosis (MS). On mRNA level, we observed high numbers of MMP-2 and TIMP-2 mRNA expressing iDC in MS. On protein level, high percentages of MMP-1, -2 and -9 expressing iDC by flow cytometry, and high MMP-1 secretion by Western blot together with high MMP-2 and -9 activities in iDC supernatants as studied with zymography were observed. Similarly, MS is associated with high percentages of MMP-2 and -3 and of TIMP-1 expressing mDC by flow cytometry together with high MMP-3 secretion and high MMP-9 activity in culture supernatants. Spontaneous migratory capacity of both iDC and mDC over ECM-coated filters was higher in MS compared to healthy controls (HC). In conclusion, blood monocyte-derived iDC and mDC express, produce and secrete several MMP and TIMP. Alterations in these molecules as observed in MS may be functionally important for DC functioning.

Recruitment of dendritic cells to the cerebrospinal fluid in bacterial neuroinfections.

Dendritic cells (DC) accumulate in the CNS during inflammation and may contribute to local immune responses. Two DC subsets present in human cerebrospinal fluid (CSF) are probably recruited from myeloid (CD11c(+)CD123(dim)) and plasmacytoid (CD11c(-)CD123(high)) blood DC. In bacterial meningitis and especially in Lyme meningoencephalitis, numbers of myeloid and plasmacytoid DC in CSF were increased, compared to non-inflammatory neurological diseases, and correlated with chemotactic activity of CSF for immature monocyte-derived DC (moDC). Multiple DC chemoattractants, including macrophage inflammatory protein (MIP)-1beta, monocyte chemotactic protein (MCP)-1, MCP-3, RANTES and stromal cell-derived factor (SDF)-1alpha were elevated in CSF in these two neuroinfections. Chemotaxis of immature moDC induced by these CSFs could be partially inhibited by mAbs against CXCR4, the receptor for SDF-1alpha, and CD88, the receptor for C5a. SDF-1alpha present in CSF also chemoattracted mature moDC, which in vivo could correspond to a diminished migration of antigen-bearing DC from the CSF to secondary lymphoid organs. Regulation of DC trafficking to and from the CSF may represent a mechanism of controlling the CNS inflammation.

Birth cohort effects in multiple sclerosis.

PURPOSE: To identify potential birth cohort effects in multiple sclerosis in Sweden and particularly in Stockholm county. METHODS: Data on multiple causes of death from multiple sclerosis during 1962 to 1995 in Sweden and 1968 to 1995 in Stockholm county were analyzed using age-period-cohort models and curvature. RESULTS: Mortality from multiple sclerosis was higher in Sweden than in Stockholm county, with stable time trends, slight period effects and marked age effects. Cohorts born before or after a central period, from 1910 through 1930, registered lower mortality. A periodic wave-form mortality pattern was identified, following a 5-to-6-year cycle for cohorts born before 1925 both in and outside Stockholm county, and changing to longer or irregular cycles for cohorts born after 1930. CONCLUSIONS: Although methodological constraints inducing the saw-tooth pattern cannot be excluded, these results are consistent with etiologic hypotheses claiming a role for environmental factors in multiple sclerosis.

Dendritic cell vaccine design: strategies for eliciting peripheral tolerance as therapy of autoimmune diseases.

Dendritic cells (DC), as potent antigen-presenting cells (APC), constitute a complex system of cells that initiate and regulate immune responses that result in two opposite outcomes: immunity or tolerance. The fine regulation of these two distinct functions is not completely understood. After loading with antigen, DC exhibit the properties of both antigen and adjuvant, the functional components of vaccines. For a long time, attention has focused on the exceptional ability of DC as professional APC capable of eliciting T and B cell-mediated responses, and on their potential as immunotherapy in cancer. DC exhibit both heterogeneity and plasticity. On the one hand, distinct DC subsets exhibit distinct functions. On the other hand, DC functions can be altered by the cytokine environment or other factors. There is increasing evidence that DC could be used as a tool to induce peripheral tolerance. Because DC-based immunotherapy in autoimmune diseases depends on tolerogenic DC, discerning markers for tolerogenic DC is of great importance. Immature DC, plasmacytoid DC and interleukin-10-modified DC can mediate immune tolerance by inducing T-cell anergy or T-helper type 2 responses. Several possibilities exist for rational modulation of DC to achieve therapeutic tolerance against autoimmune diseases. The final goal is to create optimal prerequisites to use autologous DC that are prepared from the individual patient with autoimmune disease, to render such DC tolerogenic by exposure in vitro to factors that promote tolerogenicity, and to re-infuse these pretreated DC to the patient in order to treat the ongoing autoimmune disease and prevent its future exacerbation.