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R Liblau

Publications and source records attributed to R Liblau.

At least 19 recordsLinked to original sources
PubMed2005

Changes in enteric neurone phenotype and intestinal functions in a transgenic mouse model of enteric glia disruption.

AIMS: The influence of enteric glia on the regulation of intestinal functions is unknown. Our aim was to determine the phenotype of enteric neurones in a model of glia alterations and the putative changes in intestinal motility and permeability. METHODS: Transgenic mice expressing haemagglutinin (HA) in glia were used. Glia disruption was induced by injection of activated HA specific CD8+ T cells. Control mice consisted of non-transgenic littermates injected with activated HA specific CD8+ T cells. Immunohistochemical staining for choline acetyltransferase (ChAT), substance P (SP), vasoactive intestinal peptide (VIP), and nitric oxide synthase (NOS) was performed on jejunal submucosal plexus (SMP) and myenteric plexus (MP). Neurally induced jejunal muscle activity was characterised in vitro. Gastrointestinal transit and paracellular permeability were measured using fluorescein isothiocyanate-dextran markers. RESULTS: CD3 positive T cells infiltrates were observed in the MP of transgenic mice. In the SMP, the proportions of VIP and SP positive neurones decreased in transgenic mice compared with control mice. ChAT remained unchanged. In the MP, the proportions of ChAT and NOS positive neurones increased and decreased, respectively, in transgenic mice. In contrast, VIP and SP remained unchanged. Neurally mediated jejunal relaxation was lower in transgenic mice than in controls. This relaxation was reduced by NG-nitro-L-arginine methyl ester in control mice but not in transgenic mice. Gastrointestinal transit was delayed and intestinal permeability increased in transgenic mice compared with control mice. CONCLUSION: Glia disruption induces changes in the neurochemical coding of enteric neurones, which may partly be responsible for dysfunctions in intestinal motility and permeability.

Adoptive Transfer↗
PubMed2001

Treatment of multiple sclerosis patients with interferon-beta primes monocyte-derived macrophages for apoptotic cell death.

Although interferon (IFN)-beta has shown a significant clinical benefit in multiple sclerosis (MS), its mechanism of action remains unclear. We found that IFN-beta treatment of patients with MS resulted in a significant increase in apoptotic cell death (measured by annexin V staining and nuclear fragmentation) of monocyte-derived macrophages, as compared with cells derived from patients before treatment. Stimulation of the cells with IFN-beta in vitro resulted in an even further increase of annexin V binding, as well as increased Fas (CD 95, APO-1) expression. However, no increased Fas expression, apoptotic monocytes, or monocytopenia were observed upon in vivo treatment. This indicates that IFN-beta does not deliver a death signal to monocytes but rather primes for subsequent macrophage apoptosis upon activation or differentiation.

Adult↗
PubMed2001

[Contribution of biology to diagnosis of multiple sclerosis].

The analysis of the cerebrospinal fluid is the only biological test included in the diagnostic criteria for MS. A search for intrathecal IgG synthesis by isoelectrofocussing should always be performed when the cerebrospinal fluid is analyzed for a possible diagnosis of MS. Intrathecal IgG synthesis is detected in about 95 p. 100 of MS cases. However, it is not specific for MS and only signs the inflammatory nature of the nervous system lesions. In our opinion, analysis of the CSF should be proposed systematically for primary progressive MS, in most cases of monosymptomatic demyelinating syndromes, and according to the clinical context and the result of the MRI analyses in the remaining forms. To date, no prognostic criteria can be drawn from the analysis of the CSF. Other biological tests can be performed in order to eliminate other diagnosis. These tests only have a great interest in atypical forms of the disease.

Diagnosis, Differential↗
PubMed2000

Systemic administration of agonist peptide blocks the progression of spontaneous CD8-mediated autoimmune diabetes in transgenic mice without bystander damage.

Insulin-dependent diabetes is an autoimmune disease targeting pancreatic beta-islet cells. Recent data suggest that autoreactive CD8+ T cells are involved in both the early events leading to insulitis and the late destructive phase resulting in diabetes. Although therapeutic injection of protein and synthetic peptides corresponding to CD4+ T cell epitopes has been shown to prevent or block autoimmune disease in several models, down-regulation of an ongoing CD8+ T cell-mediated autoimmune response using this approach has not yet been reported. Using CL4-TCR single transgenic mice, in which most CD8+ T cells express a TCR specific for the influenza virus hemagglutinin HA512-520 peptide:Kd complex, we first show that i.v. injection of soluble HA512-520 peptide induces transient activation followed by apoptosis of Tc1-like CD8+ T cells. We next tested a similar tolerance induction strategy in (CL4-TCR x Ins-HA)F1 double transgenic mice that also express HA in the beta-islet cells and, as a result, spontaneously develop a juvenile onset and lethal diabetes. Soluble HA512-520 peptide treatment, at a time when pathogenic CD8+ T cells have already infiltrated the pancreas, very significantly prolongs survival of the double transgenic pups. In addition, we found that Ag administration eliminates CD8+ T cell infiltrates from the pancreas without histological evidence of bystander damage. Our data indicate that agonist peptide can down-regulate an autoimmune reaction mediated by CD8+ T cells in vivo and block disease progression. Thus, in addition to autoreactive CD4+ T cells, CD8+ T cells may constitute targets for Ag-specific therapy in autoimmune diseases.

Animals↗
PubMed2000

Delayed and separate costimulation in vitro supports the evidence of a transient "excited" state of CD8+ T cells during activation.

Although the two-signal model for T cell activation states that a signal-1 through the TCR and a costimulatory signal-2 are required for optimal stimulation, it is now clear that the requirement for costimulation can be bypassed under certain conditions. We previously reported that this is the case for naive CD8+ T cells in vitro. In the present study we tested the effect of signal-2 when delivered after signal-1 has been disrupted. Naive CD8+ T cells from TCR transgenic mice were stimulated in vitro by using immobilized recombinant single-chain MHC molecules alone as signal-1. This signal was then stopped after different lengths of time, and anti-CD28 mAb as signal-2 was given either immediately or after a time lag. We found that signal-2 can potentiate a short signal-1 when added sequentially. Moreover, a time lag between the two signals does not abolish this potentiation. If the strength of signal-1, but not its duration, is increased, then the time lag between the delivery of signals 1 and 2 can be lengthen without loss of potentiation. Together, our results indicate that the two signals do not need to be delivered concomitantly to get optimal T cell activation. We suggest that the CD8+ T cells can reach a transient "excited" state after being stimulated with signal-1 alone, characterized by the cell's ability to respond to separate and delayed signal-2.

Animals↗
PubMed2000

Cytokines in genetic susceptibility to multiple sclerosis: a candidate gene approach. French Multiple Sclerosis Genetics Group.

The immune system is involved in the pathophysiology of multiple sclerosis (MS) but the initiating antigen(s) is not yet identified. Since cytokines control both the intensity and the quality of the immune response they may be relevant candidates for the genetic susceptibility to MS. To analyze the contribution of type 1 and type 2 cytokine and cytokine receptor genes in the genetic susceptibility to MS, we have examined, in 116 French MS sibpairs, whether there is significant linkage between MS and 15 cytokine or cytokine receptor genes using 31 highly polymorphic genetic markers. The data were analyzed using the maximum likelihood score and the transmission disequilibrium approaches. None of the candidate genes tested was significantly linked to MS on the whole population. However, after stratification of the analysis on the basis of sharing (or not) of the HLA-DRB1*1501 allele, indication of linkage was found for the IL2-RB gene. These findings suggest that the IL2-RB locus contributes to the genetic susceptibility in a subgroup of MS patients.

Cytokines↗
PubMed2000

EFNS task force report: a questionnaire-based survey on the service provision and quality assurance for determination of diagnostic autoantibody tests in European neuroimmunology centres. European Federation of Neurological Societies.

Autoantibodies to a wide variety of neural components are frequently sought in the sera of patients with neurological diseases suspected to have an antibody-associated autoimmune basis. Variations in assay methodology and availability are likely to exist throughout European diagnostic immunology centres, and interlaboratory discrepancies in performance for some assays have been reported. The availability of quality assurance is largely unknown. In this questionnaire-based EFNS task force, all 18 national representatives of the Neuroimmunology Panel within the EFNS were invited to estimate the service provision within their country; 12 panel members responded. From these responses, it emerged that a range of assays are being performed throughout European centres, involving over 20 separate antigens, using a broad array of immunodetection techniques. With the exception of the estimation of anti-AChR antibodies for the diagnosis of myasthenia gravis, no systematic quality assurance schemes are available, this being conducted on an ad hoc basis, or not at all. Since quality is a central component of assay sensitivity and specificity, we conclude that there is an urgent need to introduce pan-European quality assurance schemes, based on provision of positive and negative test sera from a central source, and in which all neuroimmunology laboratories should participate.

Autoantibodies↗
PubMed2000

[Role of autoimmunity in multiple sclerosis].

A number of evidences indicate that an antigen-specific immune reaction is responsible for the formation and/or the maintenance of multiple sclerosis (MS) lesions. This disease is characterized by the following: 1), an infiltration of the white matter of the brain and spinal cord by inflammatory cells; 2), the T and B lymphocytes, present in the lesions or in the cerebrospinal fluid of patients, show signs of activation; i.e., the classic IgG oligoclonal bands of the cerebrospinal fluid (activation of B lymphocytes) and the presence of activation markers on the surface of the T lymphocytes; 3), the presence of an association, and a linkage between the disease and the genes of the HLA complex. The HLA molecules are implicated in the presentation of the antigen to the T lymphocytes; 4), finally, it should be noted that the therapeutic approaches aimed at reducing (immunosuppressants) or at modulating (beta-interferon, copolymer 1) the immune responses have a positive effect on this disease, whereas those treatments which activate the immune system (gamma-interferon) have a negative effect.

Animals↗
PubMed2000

HLA, molecular mimicry and multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system in which an autoimmune response most probably contributes to pathogenesis. To date, the best characterized susceptibility-associated gene has been mapped to the HLA complex. The HLA-DRB1*1501 - DRB5*0101 - DQA1*0102 - DQB1*0602 haplotype is both associated and linked to MS in different ethnic groups. The locus within the HLA class II region encoding the MS-susceptibility gene is under intensive investigation. Epidemiological studies, however, have suggested that environmental antigens also play a critical role in MS pathogenesis. One of the ways a pathogen could trigger autoimmune disease is via immunological cross-reactivity or molecular mimicry. This concept argues that a microbial peptide with certain degree of homology to a self peptide can stimulate pathogenic self-reactive specific T cells to cause an autoimmune disease. Many microbial agents have regions of sequences that may serve as binding motifs for HLA-DR2. HLA genetics and molecular mimicry may therefore be intimately interlinked in the disease process. In the present review, we focus on the HLA association with MS and the role of microbial antigens in MS, with special reference to the molecular mimicry hypothesis.

Animals↗
PubMed1999

[Environment, genetics and immunology in multiple sclerosis].

The cause of multiple sclerosis remains unknown. Epidemiological studies indicate that it is a multi-factorial disease. The environmental factors are still unknown. No virus has been yet demonstrated to play a role in multiple sclerosis. The role of HLA in the genetic susceptibility has been known since the seventies; the detailed analysis is underway. Immunological factors playing a role in the course of multiple sclerosis are better known and may serve as basis to new therapeutical approaches.

Environment↗
PubMed1999

Localized proton magnetic resonance spectroscopy in relapsing remitting versus secondary progressive multiple sclerosis.

OBJECTIVE: To determine the efficacy of MRS in discriminating between relapsing remitting (RR) and secondary progressive (SP) MS. METHODS: MRS at long and short echo times was carried out in 104 patients with MS stratified for clinical course (RR or SP), and the results were compared with those of 15 control subjects. Normal-appearing white matter (NAWM) was studied in 55 patients, and a high-T2-signal area on MRI in 49 others. RESULTS: At long echo times, there was a highly significant decrease in the ratios N-acetyl-aspartate/creatine (NAA/Cr) and NAA/ choline (Cho) in high-T2-signal areas and in the NAWM in patients with an SP course compared with control subjects and patients with an RR course. There was a significant negative correlation between these ratios and clinical disability measured by Expanded Disability Status Scale score, which was independent of disease duration. Discriminant values between patients with RR and SP courses were found in the NAWM (NAA/Cr = 1.75 and NAA/Cho = 1.5), but not in high-T2-signal areas. At short echo times, there was a significant increase in the ratio myoinositol/Cr in high-signal areas of patients with an SP course compared with control subjects, and the presence of abnormal resonances in the lesions and NAWM for free amino acids and lipids (in 30% and 8%, respectively) and GLX complex (glutamine, glutamate, gamma-aminobutyric acid; 16% and 20%, respectively). CONCLUSIONS: Studying normal-appearing white matter on MRI with MRS allows discrimination between relapsing remitting and secondary progressive patients. In the NAWM of patients with MS and an SP course, severe axonal loss/dysfunction is negatively correlated to clinical disability and independent of the duration of the disease.

Adolescent↗
PubMed1999

Encephalitis after hepatitis B vaccination: recurrent disseminated encephalitis or MS?

OBJECTIVE: To describe clinical and MRI features of patients with a disease suggestive of CNS inflammation after hepatitis B vaccination. METHODS: Eight patients with confirmed CNS inflammation occurring less than 10 weeks after hepatitis B vaccination are described. They received follow-up clinically and on MRI for a mean period of 18 months. RESULTS: Clinical and MRI findings were compatible with acute disseminated encephalomyelitis. However, clinical follow-up, repeated MRI, or both showed the persistence of inflammatory activity, which makes this encephalitis more suggestive of MS than of acute disseminated encephalomyelitis. CONCLUSION: The persistent inflammatory activity observed clinically and on MRI in these patients is comparable with that usually observed in MS. Epidemiologic studies are currently testing the hypothesis of a triggering role of hepatitis B vaccination in CNS demyelination.

Adult↗
PubMed1999

Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes.

We recently evidenced a dramatic enrichment for T cells reactive against Epstein-Barr virus (EBV) within inflamed joints of two rheumatoid arthritis patients. To assess the generality of this phenomenon and its relevance to autoimmunity, we studied the responses of CD8 T cells from patients with either acute or chronic inflammatory diseases (rheumatoid arthritis: n = 18, ankylosing spondylitis: n = 5, psoriatic arthritis: n = 4, Reiter's syndrome: n = 3, arthrosis: n = 2, uveitis: n = 2, multiple sclerosis: n = 2, encephalitis: n = 1) against viral proteins derived from EBV and another common herpes virus, human cytomegalovirus (CMV). T cell responses against EBV and/or CMV epitopes were frequently observed within CD8 T cells derived from chronic inflammatory lesions, irrespective of their location (knee, eye, brain) and autoimmune features. In most cases, CD8 T cells derived from affected organs yielded stronger anti-viral T cell responses than CD8 T cells derived from patients' PBL, even in chronic inflammatory diseases devoid of autoimmune features or induced by defined bacterial agents. Taken together, these results suggest that the presence of virus-specific T cells within inflamed lesions of patients suffering from autoimmune diseases is a general phenomenon associated with chronic inflammation rather than the initiating cause of the autoimmune process. Since this phenomenon was sometimes associated with long-term T repertoire biases within inflamed lesions, the physiopathological significance of T cell clonal expansions found in a recurrent fashion within chronically inflamed autoimmune lesions should be interpreted with caution.

Adult↗
PubMed1999

Cell-mediated autoimmunity in paraneoplastic neurological syndromes with anti-Hu antibodies.

Paraneoplastic encephalomyelitis or subacute sensory neuronopathy associated with small-cell lung cancer (SCLC) and high titers of anti-HuD antibodies, also called the "anti-Hu syndrome," is believed to result from an immune response triggered by tumor antigens and misdirected to the neurons. To further assess the issue of cell-mediated immunity in this disease, the peripheral blood lymphocyte surface phenotype was studied in 15 patients suffering from the anti-Hu syndrome (seropositive group) and in two control groups consisting of 12 seronegative SCLC patients without neurological syndrome and 15 healthy volunteers. In addition, the recombinant human HuD protein was used to stimulate in vitro peripheral blood mononuclear cells of 10 seropositive patients and of 10 patients from each control group. Phenotypic analysis of the peripheral blood lymphocytes revealed a significant increase of the memory helper (CD45RO+CD4+) T cells in the seropositive group in comparison with the two control groups. Antigen-specific proliferation of peripheral blood mononuclear cells, measured by [3H]thymidine uptake after HuD antigen stimulation, was much higher in the seropositive group than in the two control groups, and phenotypic analysis of proliferating cells revealed a significant expansion of the CD45RO subpopulation of T cells in the seropositive group. Furthermore, after HuD stimulation, a significant increase of the interferon-gamma/interleukin-4 ratio was found in culture supernatants of the seropositive group compared with seronegative SCLC patients and normal controls. Taken together, these results indicate that HuD protein is an antigenic target for autoreactive CD4+ T cells, presumably of the Th1 subtype, which could therefore be directly involved in cell-mediated injury of the nervous system as well as in antitumoral immunity.

Autoantibodies↗
PubMed1999

Chromosome 17q22-q24 and multiple sclerosis genetic susceptibility. American-French Multiple Sclerosis Genetic Group.

Recently, genome-wide searches for multiple sclerosis (MS) susceptibility genes have suggested that the chromosome 17q22-q24 region might contain susceptibility genes in two sets of families of different ethnic backgrounds (Finnish and British). Therefore, we decided to test this region in two sets of families of different ethnic backgrounds (American and French), but collected according to the same diagnostic criteria. All lod-score values were non-significant. Moreover, we could exclude that the 17q22-24 region might contain a gene increasing the sibling recurrence risk of MS over 1.4, rendering the existence of such a gene very unlikely, at least in the group of tested families.

Chromosome Mapping↗
PubMed1998

Antigen-dependent and -independent Ca2+ responses triggered in T cells by dendritic cells compared with B cells.

Dendritic cells (DCs) are much more potent antigen (Ag)-presenting cells than resting B cells for the activation of naive T cells. The mechanisms underlying this difference have been analyzed under conditions where ex vivo DCs or B cells presented known numbers of specific Ag-major histocompatibility complex (MHC) complexes to naive CD4(+) T cells from T cell antigen receptor (TCR) transgenic mice. Several hundred Ag-MHC complexes presented by B cells were necessary to elicit the formation of a few T-B conjugates with small contact zones, and the resulting individual T cell Ca2+ responses were all-or-none. In contrast, Ag-specific T cell Ca2+ responses can be triggered by DCs bearing an average of 30 Ag-MHC complexes per cell. Formation of T-DC conjugates is Ag-independent, but in the presence of the Ag, the surface of the contact zone increases and so does the amplitude of the T cell Ca2+ responses. These results suggest that Ag is better recognized by T cells on DCs essentially because T-DC adhesion precedes Ag recognition, whereas T-B adhesion requires Ag recognition. Surprisingly, we also recorded small Ca2+ responses in T cells interacting with unpulsed DCs. Using DCs purified from MHC class II knockout mice, we provide evidence that this signal is mostly due to MHC-TCR interactions. Such an Ag-independent, MHC-triggered calcium response could be a survival signal that DCs but not B cells are able to deliver to naive T cells.

Animals↗
PubMed1998

Antagonistic action of IFN-beta and IFN-gamma on high affinity Fc gamma receptor expression in healthy controls and multiple sclerosis patients.

Monocyte-macrophage activation by IFN-gamma is characterized by a pronounced increase of high affinity Fc receptors for IgG (Fc gamma RI), capable of triggering respiratory burst, phagocytosis, Ab-dependent cytotoxicity, and release of proinflammatory cytokines. In view of the antagonism of IFN-beta on IFN-gamma action, of interest in the chronic inflammatory disorder multiple sclerosis, we examined the possible effect of IFN-beta on IFN-gamma induction of Fc gamma RI gene expression. We found that IFN-beta significantly down-regulated IFN-gamma-induced Fc gamma RI surface expression in peripheral blood monocytes from healthy donors, in a dose- and time-dependent manner. This down-regulation of Fc gamma RI surface levels did not correspond to a decrease in Fc gamma RI mRNA, suggesting a posttranscriptional effect of IFN-beta. Down-regulation of Fc gamma RI surface expression correlated with diminished cellular signaling through Fc gamma RI, since the IFN-gamma-induced increase in Fc gamma receptor-triggered respiratory burst was nearly completely abrogated by simultaneous addition of IFN-beta. Finally, the same antagonism between both IFNs on Fc gamma RI surface expression was observed in peripheral blood monocytes derived from multiple sclerosis patients; inhibition by IFN-beta was even increased (82+/-11%), as compared with healthy controls (67+/-4%). These results may partially help explain the beneficial effect of IFN-beta in multiple sclerosis.

Adult↗