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R Liblau

Publications and source records attributed to R Liblau.

47 records · Page 3Linked to original sources
PubMed1996

Different patterns of TCR transgene expression in single-positive and double-negative T cells. Evidence for separate pathways of T cell maturation.

Two lines of transgenic mice were established using the TCR alpha (V alpha 4.4-J alpha 24)- and beta (V beta 9-D beta 1.1-J beta 2.1)-chain genes from a cloned CD4-CD8-alpha beta + (double-negative; DN) T cell line from BALB/c mice. The TCR genes were expressed in CD4+CD8- and CD4-CD8+ (single-positive; SP) and double-positive (DP) T cells in the thymus, and in SP T cells in the peripheral lymphoid tissues, and marrow in one transgenic mouse line, and predominantly in DN T cells in the other. Bone marrow precursor cells from only the DN mouse line generated T cells expressing the V beta 9 transgene during tissue culture. V beta 9+ T cells were found in DN but not SP transgenic mice backcrossed to BALB/c nu/nu mice. The results suggest two separate pathways of T cell maturation, one which generates SP T cells in the thymus, and another which generates DN T cells in both the thymus and bone marrow.

Amino Acid Sequence↗
PubMed1995

Interactions among polymorphic and conserved residues in MHC class II proteins affect MHC-peptide conformation and T cell recognition.

The structural basis for MHC-restricted T cell recognition of the N-terminal peptide of myelin basic protein (MBP Ac1-11) presented by two mouse class II alleles, Ak and Au, was examined, focusing on the roles of A beta chain polymorphic residues 38 beta (in the beta sheet) and 61 beta (in the alpha helix) in controlling the responses of panels of Ak- and Au-restricted T cell hybridomas. Despite the conservative nature of the substitutions at 38 beta (k = Val, u = Leu) and 61 beta (k = Trp, u = Tyr), transfectants expressing Ak or Au proteins carrying allelic substitutions at 38 beta and/or 61 beta gave dramatically reduced T cell responses. The modest reduction in peptide binding detected using a biotinylated MBP peptide analog appear insufficient to explain the reduced responses, suggesting that changes at 38,61 beta create conformational changes in the MHC-peptide complex. The impact of allelic substitutions at 38,61 beta on T cell responses is also modulated by other residues differing between Ak and Au. To explore the structural basis for these phenomena, protein models were developed of the Ak, Au and 38,61 beta mutant proteins using self-consistent ensemble optimization methodologies. Substitutions of the alternative allelic residue at 38 beta and/or 61 beta, which are in van der Waals contact, change the configuration of this region of the peptide-binding groove, and potentially might affect the conformation of the bound peptide and its hydrogen-bonding to residue 61 beta. The models predict that this region of the groove is markedly altered by allelic differences at A beta residue 9 beta (k = His, u = Val) which determine the position of the side-chain of Tyr30 beta, adjacent to residues 38 beta and 61 beta. Thus, interactions among polymorphic and conserved residues control the antigen presentations functions of MHC class II proteins.

Alleles↗
PubMed1994

A role for non-MHC genetic polymorphism in susceptibility to spontaneous autoimmunity.

Peripheral immunological tolerance is traditionally explained by mechanisms for deletion or inactivation of autoreactive T cell clones. Using an autoimmune disease model combining transgenic mice expressing a well-defined antigen, influenza hemagglutinin (HA), on islet beta cells (Ins-HA), and a T cell receptor transgene (TCR-HNT) specific for a class II-restricted HA peptide, we demonstrate that the conventional assumptions do not apply to this in vivo situation. Double transgenic mice displayed either resistance or susceptibility to spontaneous autoimmune disease, depending on genetic contributions from either of two common inbred mouse strains, BALB/c or B10.D2. Functional studies on autoreactive CD4+ T cells from resistant mice showed that, contrary to expectations, neither clonal anergy, clonal deletion, nor receptor desensitization was induced; rather, there was a non-MHC-encoded predisposition toward differentiation to a nonpathogenic effector (Th2 versus Th1) phenotype. T cells from resistant double transgenic mice showed evidence for prior activation by antigen, suggesting that disease may be actively suppressed by autoreactive Th2 cells. These findings shed light on functional aspects of genetically determined susceptibility to autoimmunity, and should lead to new therapeutic approaches aimed at controlling the differentiation of autoreactive CD4+ effector T cells in vivo.

Animals↗
PubMed1993

Antigen-presenting cells in adoptively transferred and spontaneous autoimmune diabetes.

Histological techniques were used to identify antigen-presenting cells (APC) in adoptively transferred diabetes in NOD mice and Ins-HA transgenic mice, and in spontaneously diabetic NOD mice. In adoptively transferred disease, CD4+ T cells and F4/80+ macrophages dominated early infiltrates. By contrast, in spontaneously developing diabetes in NOD mice, lymphocytic infiltrates appeared to be well organized around a network of VCAM-1+ NLDC-145+ ICAM-1+ dendritic cells. Thus, the primary APC spontaneous autoimmune disease appears to be the strongly stimulatory dendritic cell rather than the normally resident macrophage. Next, we used chimeric animals to demonstrate that insulitis and diabetes could occur even when responding T cells were unable to recognize islet-specific antigen directly on beta cells. Altogether, the results demonstrate that immune-mediated damage does not require direct contact between CD4+ T cells and beta cells. Moreover, despite the induction of ICAM-1, VCAM-1, and class II on vascular endothelium near islet infiltrates, these experiments show that recruitment of lymphocytes occurs even when antigen presentation is not possible on vascular endothelium.

Amino Acid Sequence↗
PubMed1993

Antigen processing gene polymorphisms in HLA-DR2 multiple sclerosis.

The association between multiple sclerosis (MS) and alleles of the HLA class II genes indicates that at least one MS susceptibility gene is linked to the HLA class II region. However, the actual locus responsible has not been precisely identified. The recent cloning of new genes involved in antigen processing that map within the HLA class II region led us to investigate--using the restriction fragment length polymorphism (RFLP) technique and sequence-specific oligonucleotide analysis--whether these genes might play a role in conferring susceptibility to MS. We studied large multifunctional protease (LMP) 2 and 7 and transporter associated with antigen processing (TAP) 1 and 2 gene polymorphisms in 60 HLA-DR2 MS patients and 60 HLA-DR2 healthy subjects and found no specific or preferential RFLP patterns or coding sequence variants in the patient group. Our data do not support a role for these genes in MS susceptibility.

Adult↗
PubMed1992

The frequency of selective IgA deficiency in myasthenia gravis.

The frequency of selective IgA deficiency is unknown in myasthenia gravis. We screened a series of 333 consecutive adult myasthenic patients for selective IgA deficiency and found only one patient with a selective IgA deficiency, which is not significantly different from the normal population. Organ-specific autoimmune diseases may differ from systemic autoimmune diseases concerning their frequency of association with selective IgA deficiency.

Adult↗
PubMed1991

T cell response to myelin basic protein epitopes in multiple sclerosis patients and healthy subjects.

T cell lines and clones specific for human myelin basic protein (BP) were selected from three multiple sclerosis (MS) patients and two healthy subjects and tested for their proliferative responses to a battery of synthetic peptides, 9 to 21 amino acid residues long. The combined amino acid sequence of the peptides spanned the complete sequence of the human BP. The results suggest the development of T cells sensitized to at least four independent regions of the human BP, indicating some diversity of the human T cell repertoire to BP. However, an immunodominant T cell epitope was located in the C-terminal region, defined by residues 149-162. This epitope was recognized by T cells from three subjects out of five (one MS patient and both healthy controls) in the context of different DR specificities. Another epitope (located in the 57-75 region) which triggered one MS patient's T cell response was also recognized by a mycobacteria-specific T cell clone cross-reacting with BP.

Epitopes↗
PubMed1991

Intravenous gamma-globulin in myasthenia gravis: interaction with anti-acetylcholine receptor autoantibodies.

Clinical improvement has been observed in myasthenia gravis patients treated by intravenous immunoglobulin (IVIg). In order to investigate the mechanism of action of these IVIg, we looked for an in vitro interaction between IVIg and the anti-acetylcholine receptor autoantibodies. Significant inhibition by IVIg of anti-acetylcholine receptor autoantibody activity from 30 MG sera was observed and binding of anti-acetylcholine receptor autoantibodies on IVIg was found for four of five myasthenia gravis sera. These observations suggest that IVIg contains Ig directly binding to and inhibiting pathogenic autoantibodies.

Adolescent↗
PubMed1991

[Spinal infarction in the anterior spinal territory with possible relation with bilharziasis].

We report a case of spinal cord infarction in the anterior spinal artery territory with selective involvement of the anterior horns. A 35-year-old Mauritanian woman was hospitalized because of an acute and severe flaccid paraplegia without any sphincter dysfunction or sensory disturbance. MRI abnormalities (hypersignal on T2-weighted sequences) were restricted to the anterior horns of the lower thoracic spinal cord and conus medullaris. Adamkiewicz's artery appeared abnormally thin at arteriography. The infarction was probably related to vasculitis of schistosomal origin.

Adult↗
PubMed1987

[Migraine manifestations and lymphocyte pleocytosis of the cerebrospinal fluid].

The authors report the case of a 26 year old non-migrainous man who presented over a 5 week period with a cluster of classical migrainous attacks associated with CSF lymphocytosis. The association of this type of CSF response with attacks of migraine is unusual; in migraine the CSF is normal or may show an isolated increase in protein content (with the exception of the very rare familial hemiplegic migraine). In the reported case, other conditions liable to give rise to migraine and CSF lymphocytosis having been excluded (acute DLE, brucellosis...), this association corresponded to a benign and spontaneously regressive condition, possibly a migraine symptomatic of benign acute lymphocytic meningitis. The authors suggest that a primary meningeal inflammation may have been the cause of the cluster of migraine attacks which in this case were more accompanied perhaps because they induced a wave of depression of cortical activity.

Adult↗