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Biomedical subjects

A Vincent

Publications and source records attributed to A Vincent.

At least 55 records · Page 3Linked to original sources
PubMed2003

A sensitive radioimmunoprecipitation assay for assessing the clinical relevance of antibodies to IFN beta.

BACKGROUND: Some multiple sclerosis (MS) patients treated with interferon beta (IFN beta) develop antibodies to the drug. Neutralising antibody (NAB) assays for IFN beta are expensive and the clinical relevance of the results has been debated. OBJECTIVE: To establish a cheap, sensitive, and reliable assay for antibodies to (125)I-IFN beta, and to correlate levels of antibodies with clinical response to IFN beta treatment. METHODS: We established a radioimmunoprecipitation assay (RIPA) using (125)I-IFN beta. We tested NAB positive sera, healthy control sera, and serial samples of 33 IFN beta-1b treated MS patients from the Vancouver cohort of the Berlex pivotal trial who had a high incidence of NABs. RESULTS: We found that the RIPA was highly sensitive for the detection of antibodies to IFN beta-1a and -1b, and that there was a strong correlation between reactivity of NAB positive sera for (125)I-IFN beta-1b and for (125)I-IFN beta-1a. The RIPA was more sensitive and consistent than the NAB. Moreover, there was a trend towards poorer MRI outcomes in RIPA positive patients, but not in NAB-positive patients. CONCLUSIONS: The RIPA assay is sensitive and easy to perform. It should be of value in assessing the clinical impact of IFN beta antibodies, and its use could help target expensive INF beta treatments to those who will respond best.

Antibodies↗
PubMed2003

Scenarios for autoimmunization of T and B cells in myasthenia gravis.

We have studied responses in thymoma patients to interferon-alpha and to the acetylcholine receptor (AChR) in early-onset myasthenia gravis (EOMG), seeking clues to autoimmunizing mechanisms. Our new evidence implicates a two-step process: (step 1) professional antigen-presenting cells and thymic epithelial cells prime AChR-specific T cells; then (step 2) thymic myoid cells subsequently provoke germinal center formation in EOMG. Our unifying hypothesis proposes that AChR epitopes expressed by neoplastic or hyperplastic thymic epithelial cells aberrantly prime helper T cells, whether generated locally or infiltrating from the circulation. These helper T cells then induce antibody responses against linear epitopes that cross-react with whole AChR and attack myoid cells in the EOMG thymus. The resulting antigen-antibody complexes and the recruitment of professional antigen-presenting cells increase the exposure of thymic cells to the infiltrates and provoke local germinal center formation and determinant spreading. Both these and the consequently enhanced heterogeneity and pathogenicity of the autoantibodies should be minimized by early thymectomy.

Age of Onset↗
PubMed2002

AChR phosphorylation and indirect inhibition of AChR function in seronegative MG.

BACKGROUND: Approximately 10% to 20% of patients with autoimmune MG do not have antibodies to the acetylcholine receptor (AChR), so-called seronegative MG (SNMG). IgG antibodies from up to 70% of SNMG patients bind to the muscle-specific receptor tyrosine kinase, MuSK. The plasmas and non-IgG fractions from SNMG patients (and some with AChR antibodies) also contain a factor, perhaps an IgM antibody, that inhibits AChR function, but it is not clear how this factor acts and whether it is related to the MuSK IgG antibodies. METHODS: The authors studied 12 unselected SNMG plasmas and their non-IgG fractions; seven were positive for MuSK IgG antibodies. Ion flux assays, electrophysiology, phosphorylation, and kinase assays were used to look at mechanisms of action. RESULTS: Eight of the 12 plasmas and their non-IgG fractions inhibited AChR function, but the inhibitory activity was transient and did not correlate with the presence of MuSK IgG antibodies. Two of three plasmas added outside of a cell-attached patch pipette inhibited AChR function within the patch, and these two plasmas also increased AChR phosphorylation. CONCLUSIONS: The authors propose that a plasma factor(s) in SNMG patients, distinct from MuSK IgG antibodies, binds to a muscle membrane receptor and activates a second messenger pathway leading to AChR phosphorylation and reduced AChR function. Identifying the target for this factor should lead to improved diagnosis of MG in MuSK antibody-negative patients and may provide new insights into the function of the neuromuscular junction and pathophysiological mechanisms in MG.

Adenosine Triphosphate↗
PubMed2002

Effects of prenatal stress on maternal behavior in the rat.

Some authors reported a link between maternal stress and disturbances in their infants. Because of difficulties due to human research, the effects of prenatal stress have to be examined in animal models. Our approach was original in that the stressor was an ecological one and was applied at a given gestational day. Indeed, the stressor was a cat and the effects of stress on maternal behavior were investigated in five groups of 10 female rats: two groups were composed of females which were acutely stressed either at the 10th or the 14th gestational day; two other groups were composed of females which were repeatedly stressed either at the 10th or the 14th gestational day; the fifth group comprised non-stressed females. Plasma corticosterone concentrations measured in blood samples collected from dams just after stress were significantly higher than in controls showing that cat represents an efficient stressor for rats. Maternal behavior was recorded during 30 min at the 2nd, 4th, and 6th postnatal days. In all cases, stressed dams' activities directly directed towards the pups (retrieving, sniffing and licking), those non-directly directed towards the pups (carrying its tail and digging the sawdust), and those directed towards themselves (eating, drinking and resting) were altered to different degrees. These alterations in maternal behavior can explain, at least in part, the mortality and the low growth rate observed in pups born from stressed dams.

Animals↗
PubMed2002

Regulation of fusion activity by the cytoplasmic domain of a paramyxovirus F protein.

SER virus is a member of the family Paramyxoviridae, genus Rubulavirus, which has been isolated from pigs. It is very closely related to SV5 virus serologically, in protein profile, and in nucleotide sequence. However, unlike SV5, SER induces minimal syncytium formation in infected CV-1 or BHK cells. Fluorescence transfer experiments between labeled erythrocytes and infected MDBK cells revealed that SER also induces hemifusion and pore formation with reduced efficiency. The virion polypeptide profiles of SER and SV5 are very similar, except that the SER F1 subunit shows an apparent molecular weight that is about 2 kDa higher than that of SV5. Comparison of the deduced amino acid sequences revealed the SER F (551 aa) to be longer than SV5 F (529 aa) by 22 residues in the cytoplasmic tail (CT) domain. The HN and M gene sequences of the viruses were found to be very similar. The SER F showed minimal fusion activity when coexpressed with either SV5 or SER HN. In contrast, SV5 F was highly fusogenic when coexpressed with either HN protein, indicating that the restricted fusion capacity of SER virus is a property of its F protein. Truncation in the CT of SER F by 22 residues completely rescued its ability to cause syncytium formation, whereas other truncations rescued syncytium formation partially. These results demonstrate that an elongated CT of a paramyxovirus F protein suppresses its membrane fusion activity.

Animals↗
PubMed2002

P/Q type calcium-channel antibodies in paraneoplastic cerebellar degeneration with lung cancer.

Raised levels of P/Q type voltage-gated calcium-channel (VGCC) antibodies were found in 16 (41%) of 39 patients with paraneoplastic cerebellar degeneration (PCD) and Hu antibodies were found in nine (23%). Seven of the 16 VGCC antibody-positive patients had Lambert-Eaton myasthenic syndrome (LEMS). Seven of 15 CSF samples had VGCC antibodies, with evidence of intrathecal synthesis in four. VGCC antibodies should be looked for in PCD, even if there are no symptoms of LEMS, and may be related to the cerebellar dysfunction.

Animals↗
PubMed2002

Recessive inheritance and variable penetrance of slow-channel congenital myasthenic syndromes.

BACKGROUND: Slow-channel congenital myasthenic syndromes (SCCMS) typically show dominant inheritance. They are caused by missense mutations within the subunits of muscle nicotinic acetylcholine receptors (AChR) that result in prolonged ion channel activations. SCCMS mutations within the AChR subunit are located in various functional domains, whereas fully described mutations in AChR non- subunits have, thus far, been located only in the M2 channel-lining domain. The authors identified and characterized two -subunit mutations, located outside M2, that underlie SCCMS in three kinships. In two of the three kinships, the syndrome showed an atypical inheritance pattern. METHODS: These methods included clinical diagnosis, mutation detection, haplotype analysis, and functional expression studies using single-channel recordings of mutant AChR transiently transfected into HEK293 cells. RESULTS: The authors identified two SCCMS mutations in the AChR subunit, L78P and L221F. Both mutations prolonged ACh-induced ion channel activations. L78P is present in a consanguineous family and appears to be pathogenic only when present on both alleles, and L221F shows variable penetrance in one of the two families that were identified harboring this mutation. CONCLUSION: SCCMS mutations may show a recessive inheritance pattern and variable penetrance. A diagnosis of SCCMS should not be ruled out in cases of CMS with an apparent recessive inheritance pattern.

Adolescent↗
PubMed2002

Effects of pre- and postnatal stimulation on developmental, emotional, and cognitive aspects in rodents: a review.

Interactions between the organism and its environment, during pregnancy as well as during the postnatal period, can lead to important neurobehavioral changes. We briefly review the literature, and successively present the main results from our laboratory concerning the behavioral effects of prenatal stress, differential rearing conditions, and postnatal handling. We show that submitting primiparous DA/HAN rats to an acute emotional stress (exposure to a cat) at gestational day10, 14, or 19 leads to greatly increased mortality of pups and to decreased body weight of surviving animals. The effects of such a stressor on emotional reactivity are less obvious. Cognitive processes are impaired depending on the learning task. Enriched environments restore abnormal behaviors (emotional reactivity, motor skills, motor and spatial learning) due to brain trauma or genetic deficiencies. In any case, environmental enrichment does prevent or slow down aging effects. The effects of postnatal handling noted when using classical tests of emotional reactivity also are clear when defensive reaction paradigms are used. Furthermore, pregnant females that are early handled are less anxious than nonhandled females. We hypothesize that, when subjected to a stressor, the offspring of early-handled females would be protected from the deleterious effects of this stress compared to pups of nonhandled females.

Animals↗
PubMed2002

Mycophenolate mofetil for the treatment of acute and chronic GVHD is effective and well tolerated but induces a high risk of infectious complications: a series of 21 BM or PBSC transplant patients.

The use of mycophenolate mofetil (MMF) for prophylaxis of aGVHD and/or for treatment of acute or chronic GVHD is increasing. However, the benefit of MMF as an alternative to commonly used immunosuppressive agents still needs to be assessed. We ran a retrospective study on 21 consecutive patients (median age, 36 years; range, 20-63) with aGVHD or extensive cGVHD following related (17) or unrelated (4) matched donor SCT (BM, 16; PBSC, 5) who received MMF (2 g/day) because of intolerance to or failure of CsA-containing combinations. Four of the six patients with aGVHD responded, and the response rate was 69% in cGVHD patients. We observed neither significant differences in terms of response rate for skin, liver and bowel nor dissociated response in cases of multiple organ involvement (67% of the patients). Response was the same for lichenoid and sclerodermatous skin cGVHD subtypes. No adverse effects, except diarrhea (three patients), were observed. However, 22 opportunistic or serious viral or bacterial infections occurred in 10 patients. Analysis of trough plasma levels showed a trend for a higher mean MPA concentration in patients responding to MMF. Our study highlights the high risk of infectious complications induced by the administration of MMF, an otherwise efficient and well-tolerated treatment for GVHD.

Acute Disease↗
PubMed2002

A role for autoantibodies in some cases of acquired non-paraneoplastic gut dysmotility.

BACKGROUND: Antibody-mediated autoimmunity underlies a diverse range of disorders, particularly in the nervous system where domains of ion channels and receptors are potential targets. The aetiology of many adult-onset conditions of severe gut dysmotility is not known. We looked for antibodies to neuronal antigens in patients with severe (slow-transit-type) constipation (STC). METHODS: Eleven sera from adult-onset STC patients and 18 from childhood onset cases were tested by routine immunoprecipitation assays for antibodies against neuronal antigens including voltage-gated potassium channels (VGKCs), calcium channels (VGCCs), both muscle and neuronal acetylcholine receptor and glutamic acid decarboxylase (GAD). Results were compared with positive and negative control populations. RESULTS: Two of the 11 sera from patients with adult-onset STC showed highly positive anti-VGKC antibodies. Both had onset of symptoms de novo in adulthood without evidence of autoimmune, neoplastic or neurological disease. One of these patients, and one other, had anti-GAD antibodies. None of the childhood-onset STC had evidence of anti-neuronal antibodies. CONCLUSIONS: Anti-neuronal antibodies are found in some patients with a condition of severe acquired gut dysmotility of previously unknown aetiology. Future studies may demonstrate an autoimmune role for such antibodies.

Adult↗
PubMed2001

Do titin and cytokine antibodies in MG patients predict thymoma or thymoma recurrence?

BACKGROUND: Patients with MG often have other autoantibodies in addition to those against the acetylcholine receptor (AChR). It has been suggested that antibodies to the muscle protein titin may be diagnostic of a thymoma, but they have also been found in patients with late-onset MG. Antibodies to certain cytokines have also been detected in patients with MG and thymoma, and it is not clear whether these antibodies could be more useful clinically. The authors measured antibodies against titin and the cytokines interferon alpha (IFNalpha) and interleukin 12 (IL12) in patients with MG and thymoma or thymoma recurrence, and in patients with MG but without thymoma presenting before (early-onset MG) or after (late-onset MG) 40 years of age. METHOD: Levels of titin, IFNalpha, and IL12 antibodies were determined by radioimmunoassay in 191 patients with MG and 82 controls. RESULTS: As previously reported, titin antibodies were uncommon in patients with early-onset MG. However, in patients with late-onset MG, titin antibodies had similar prevalence and levels to those in patients with MG and thymoma, although the antibodies were uncommon in patients between 40 and 60 years of age presenting without a tumor. By contrast, cytokine antibodies were more common in patients with thymoma than in patients without thymoma, and cytokine antibodies typically increased substantially if the thymoma recurred. CONCLUSIONS: Measurement of titin antibodies has limited use in predicting the presence of a tumor, unless the patient is less than 60 years of age, but measurement of IFNalpha and IL12 antibodies may be helpful in identifying patients with a thymoma recurrence, particularly when mediastinal imaging is equivocal.

Adult↗
PubMed2001

Structures of two molluscan hemocyanin genes: significance for gene evolution.

We present here the description of genes coding for molluscan hemocyanins. Two distantly related mollusks, Haliotis tuberculata and Octopus dofleini, were studied. The typical architecture of a molluscan hemocyanin subunit, which is a string of seven or eight globular functional units (FUs, designated a to h, about 50 kDa each), is reflected by the gene organization: a series of eight structurally related coding regions in Haliotis, corresponding to FU-a to FU-h, with seven highly variable linker introns of 174 to 3,198 bp length (all in phase 1). In Octopus seven coding regions (FU-a to FU-g) are found, separated by phase 1 introns varying in length from 100 bp to 910 bp. Both genes exhibit typical signal (export) sequences, and in both cases these are interrupted by an additional intron. Each gene also contains an intron between signal peptide and FU-a and in the 3' untranslated region. Of special relevance for evolutionary considerations are introns interrupting those regions that encode a discrete functional unit. We found that five of the eight FUs in Haliotis each are encoded by a single exon, whereas FU-f, FU-g, and FU-a are encoded by two, three and four exons, respectively. Similarly, in Octopus four of the FUs each correspond to an uninterrupted exon, whereas FU-b, FU-e, and FU-f each contain a single intron. Although the positioning of the introns between FUs is highly conserved in the two mollusks, the introns within FUs show no relationship either in location nor phase. It is proposed that the introns between FUs were generated as the eight-unit polypeptide evolved from a monomeric precursor, and that the internal introns have been added later. A hypothesis for evolution of the ring-like quaternary structure of molluscan hemocyanins is presented.

Amino Acid Sequence↗
PubMed2001

Presentation by myoblasts of an epitope from endogenous acetylcholine receptor indicates a potential role in the spreading of the immune response.

It is generally considered that myoblasts are unable to prime naive T cell responses without help from professional antigen-presenting cells (APC). However, their ability to present endogenous antigens to previously primed T lymphocytes in the secondary phase of a T cell response has not been well studied. We show here that primary human myoblasts, when stimulated with IFNgamma to express class II MHC, can present an endogenous epitope, probably an acetylcholine receptor (AChR) peptide, to a CD4(+) AChR-specific T helper lymphocyte clone. Presentation leads to secretion of IFNgamma by the T cell clone and, in addition, killing of the myoblast. Our results suggest that, during the effector phase of the immune response, myoblasts could enhance the inflammatory response by presenting endogenous antigen, and thereby become targets for CD4(+) T lymphocyte-induced cytotoxicity; subsequent release of myoblast antigens could then lead to inter- and intra-molecular determinant spreading.

Antigen Presentation↗
PubMed2001

Restricted IgG1 subclass of anti-Yo antibodies in paraneoplastic cerebellar degeneration.

Paraneoplastic cerebellar degeneration (PCD) occurs as a non-metastatic manifestation of cancer in a small proportion of patients with certain breast or gynaecological tumours, and is characterised by widespread Purkinje cell loss. Antibodies against a Purkinje cell cytoplasmic antigen, called Yo, that is expressed by the tumours, are present in the majority of these patients, but the pathogenic role of the antibodies is not clear. To characterise further the immune response in these cases, 13 anti-Yo positive sera were tested for IgG subclasses by immunohistochemistry and western blotting and, in four cases, PHA-stimulated cytokine secretion by peripheral blood lymphocytes was measured. Surprisingly, anti-Yo antibodies were entirely restricted to the IgG1 subclass, whereas antibodies against the small cell cancer-associated antigen, Hu, were found in all four IgG subclasses. There was a trend towards raised IgG1 levels in the total IgG of the anti-Yo positive patients and, in two, PHA-stimulated peripheral blood lymphocytes secreted raised levels of IFN-gamma. By contrast, in the other two cases tested, raised levels of IL-4 were secreted. Patients with PCD associated with anti-Yo antibodies appear to have strong immune responses that are polarised with respect to the IgG subclass and Th cytokine profiles.

Animals↗