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Biomedical subjects

N A Gregson

Publications and source records attributed to N A Gregson.

At least 37 records · Page 2Linked to original sources
PubMed2000

Phase variation of a beta-1,3 galactosyltransferase involved in generation of the ganglioside GM1-like lipo-oligosaccharide of Campylobacter jejuni.

Ganglioside mimicry by Campylobacter jejuni lipo-oligosaccharide (LOS) is thought to be a critical factor in the triggering of the Guillain-Barré and Miller-Fisher syndrome neuropathies after C. jejuni infection. The combination of a completed genome sequence and a ganglioside GM1-like LOS structure makes C. jejuni NCTC 11168 a useful model strain for the identification and characterization of the genes involved in the biosynthesis of ganglioside-mimicking LOS. Genome analysis identified a putative LOS biosynthetic cluster and, from this, we describe a putative gene (ORF Cj1139c), which we have termed wlaN, with a significant level of similarity to a number of bacterial glycosyltransferases. Mutation of this gene in C. jejuni NCTC 11168 resulted in a LOS molecule of increased electrophoretic mobility, which also failed to bind cholera toxin. Comparison of LOS structural data from wild type and the mutant strain indicated lack of a terminal beta-1,3-linked galactose residue in the latter. The wlaN gene product was demonstrated unambiguously as a beta-1,3 galactosyltransferase responsible for converting GM2-like LOS structures to GM1-like by in vitro expression. We also show that the presence of an intragenic homopolymeric tract renders the expression of a functional wlaN gene product phase variable, resulting in distinct C. jejuni NCTC 11168 cell populations with alternate GM1 or GM2 ganglioside-mimicking LOS structures. The distribution of wlaN among a number of C. jejuni strains with known LOS structure was determined and, for C. jejuni NCTC 12500, similar wlaN gene phase variation was shown to occur, so that this strain has the potential to synthesize a GM1-like LOS structure as well as the ganglioside GM2-like LOS structure proposed in the literature.

Amino Acid Sequence↗
PubMed1999

Cytomegalovirus is not associated with IgM anti-myelin-associated glycoprotein/sulphate-3-glucuronyl paragloboside antibody-associated neuropathy.

Monoclonal antibodies reactive with the HNK-1 epitope of myelin-associated glycoprotein (MAG) and the sulphate-3-glucuronyl paragloboside (SGPG)-like glycolipids are often found in the serum of patients with IgM paraprotein-associated demyelinating neuropathy. The presence of such antibodies in patients with chronic polyneuropathy has recently been associated with evidence of active cytomegalovirus (CMV) infection by the polymerase chain reaction. We wished to test these findings and examined sera from patients with MAG-reactive or MAG-nonreactive paraproteinemic neuropathy and patients with paraproteinemia only for the presence of CMV DNA and anti-CMV antibodies. CMV DNA was not detected in sera from any patient group. Furthermore, anti-CMV antibody prevalence was normal and similar in all 3 groups. We therefore report no evidence of an association between CMV infection and anti-MAG/SGPG antibodies associated with paraproteinemic peripheral neuropathy.

Aged↗
PubMed1999

Pathogenesis of Guillain-Barré syndrome.

Recent neurophysiological and pathological studies have led to a reclassification of the diseases that underlie Guillain-Barré syndrome (GBS) into acute inflammatory demyelinating polyradiculoneuropathy (AIDP), acute motor and sensory axonal neuropathy (AMSAN) and acute motor axonal neuropathy (AMAN). The Fisher syndrome of ophthalmoplegia, ataxia and areflexia is the most striking of several related conditions. Significant antecedent events include Campylobacter jejuni (4-66%), cytomegalovirus (5-15%), Epstein-Barr virus (2-10%), and Mycoplasma pneumoniae (1-5%) infections. These infections are not uniquely associated with any clinical subtype but severe axonal degeneration is more common following C. jejuni and severe sensory impairment following cytomegalovirus. Strong evidence supports an important role for antibodies to gangliosides in pathogenesis. In particular antibodies to ganglioside GM1 are present in 14-50% of patients with GBS, and are more common in cases with severe axonal degeneration associated with any subtype. Antibodies to ganglioside GQ1b are very closely associated with Fisher syndrome, its formes frustes and related syndromes. Ganglioside-like epitopes exist in the bacterial wall of C. jejuni. Infection by this and other organisms triggers an antibody response in patients with GBS but not in those with uncomplicated enteritis. The development of GBS is likely to be a consequence of special properties of the infecting organism, since some strains such as Penner 0:19 and 0:41 are particularly associated with GBS but not with enteritis. It is also likely to be a consequence of the immunogenetic background of the patient since few patients develop GBS after infection even with one of these strains. Attempts to match the subtypes of GBS to the fine specificity of anti-ganglioside antibodies and to functional effects in experimental models continue but have not yet fully explained the pathogenesis. T cells are also involved in the pathogenesis of most or perhaps all forms of GBS. T cell responses to any of three myelin proteins, P2, PO and PMP22, are sufficient to induce experimental autoimmune neuritis. Activated T cells are present in the circulation in the acute stage, up-regulate matrix metalloproteinases, cross the blood-nerve barrier and encounter their cognate antigens. Identification of the specificity of these T cell responses is still at a preliminary stage. The invasion of intact myelin sheaths by activated macrophages is difficult to explain according to a purely T cell mediated mechanism. The different patterns of GBS are probably due to the diverse interplay between antibodies and T cells of differing specificities.

Animals↗
PubMed1999

Inter-laboratory validation of an ELISA for the determination of serum anti-ganglioside antibodies.

Anti-ganglioside antibodies are frequently sought in the sera of patients with autoimmune peripheral neuropathy, using an enzyme-linked immunosorbent assay (ELISA) as the principal method for antibody detection. Wide variations in assay performance between laboratories have been reported. In this study, we established a standardized ELISA method between laboratories within the European Inflammatory Neuropathy Cause and Treatment (INCAT) group and determined the inter-laboratory variance in assay performance using both the standardized INCAT method and in-house local methods. As expected, the inter-laboratory variances were greater using local methods than using the standardized method, producing titre estimates which could be 24.8 or 7.6 times larger or smaller, respectively, than the true means for these laboratories. Using the standardized method, the within laboratory measurement error accounted for 41% of the inter-laboratory variation, providing a theoretical upper limit to which technical improvements within laboratories could reduce inter-laboratory variation. These data describe the intrinsic weaknesses within the widely used ganglioside antibody ELISA methods and reinforce the importance of inter-laboratory cooperation within this area. Standardized serological reagents used in this study are available from INCAT members.

Antibodies↗
PubMed1998

Characterization and partial purification of a novel 36 kDa peripheral myelin protein recognized by the sera of patients with neurological disorders.

Sera of some patients with acquired sensory neuropathy, chronic inflammatory demyelinating polyradiculoneuropathy and motor neuron disease have high titres of IgG autoantibodies to a minor human peripheral nerve glycoprotein of approximately 36 kDa. This protein cofractionated with PNS myelin and was also found in bovine and rat nerve but not in CNS myelin or other nonneural human tissues. The N-terminal sequence revealed that this protein is related to the major myelin protein P0. Monoclonal antibodies to P0 and to the carbohydrate epitope HNK-1 did not recognize the 36-kDa protein, and the human anti-36-kDa antibodies did not bind to P0. IgG binding to this protein was not abolished after periodate oxidation or deglycosylation, suggesting that the epitope recognized by the human antibodies is peptidic. Differential glycosylation did not account for the differences in the apparent molecular weight between these two proteins. Overall our results indicate that the 36-kDa protein is a variant of P0.

Amino Acid Sequence↗
PubMed1998

The distribution of CD1 molecules in inflammatory neuropathy.

The CD1 molecules have been shown to present non-protein antigens, such as complex lipids to Mycobacteria, and may be important in presenting glycolipids which are involved in inflammatory neuropathies. To study the expression of CD1 molecules in peripheral nerve, we examined nerve biopsies from two patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), five with acute axonal neuropathy, six with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), nine with chronic axonal neuropathy, six with vasculitic neuropathy and three with no histological abnormality. Immunocytochemical studies showed strong labelling of CD1b on endoneurial macrophages (CD68+) and on myelinated nerve fibres in both AIDP patients, but it was rarely observed in the other patients. Weaker staining was seen on endoneurial macrophages and/or other endoneurial cells in some of the patients with other peripheral neuropathies, but none of the control nerves. CD1a had a weaker, but similar pattern. There was endoneurial infiltration of CD4+ and CD8+ T cells in the AIDP and CIDP nerves and sometimes in the other peripheral neuropathy nerves, but not in the normal nerves. Most T cells had alpha beta+ T cell receptors (TCR), but gamma delta+ TCR T cells were found in the nerves of both AIDP patients and sometimes in the nerves of other patients with peripheral neuropathy. Staining for mannose receptor was almost universal, being more intense in AIDP, chronic axonal neuropathy and vasculitis patients. We conclude that CD1 molecule expression is upregulated in peripheral neuropathy, especially in association with inflammation.

Aged↗
PubMed1998

A rat model of spontaneous myopathy and malignant hyperthermia.

Malignant hyperthermia is a main cause of death during general anesthesia, particularly in children. However, research has been hampered by the lack of a convenient animal model, the only one available being a special strain of pig. In this study, we describe spontaneous myopathy and a fatal syndrome of generalized muscle rigidity triggered by halothane in an outbred strain of rat. Histological examination of skeletal muscle reveals severe abnormalities indicating chronic underlying myopathy. The association of histological abnormalities with an acute, fatal syndrome clinically resembling malignant hyperthermia provides a strong basis for a new and extremely useful animal model to study this fatal disorder.

Animals↗
PubMed1997

T cell receptor V beta gene usage in Guillain-Barré syndrome.

We set out to determine whether the T cell receptor (TCR) V beta gene usage in acute inflammatory demyelinating polyradiculoneuropathy (AIDP) is restricted. We separated activated from non-activated peripheral blood T cells with anti-IL2 receptor (anti-CD25) antibody-labelled magnetic beads from four AIDP patients and four normal control (NC) subjects. The TCR V beta gene usage of circulating activated and non-activated T cells was heterogeneous in all the patients and controls, but the activated T cells of all four of the AIDP patients showed a more limited usage of V beta genes and enhanced V beta 15 usage, as compared to the non-activated T cells. This was not seen in the healthy controls. The activated and non-activated T cells from a patient with acute motor and sensory axonal neuropathy (AMSAN) showed a similar V beta gene usage to that of the controls. From a further patient with AIDP, we studied the V beta gene usage of short-term T cell lines reactive to the peripheral nerve myelin proteins P2, P0 and the P0 peptide amino acid sequence 194-208. The V beta gene usage of the lines was heterogeneous, with enhanced usage of V beta 15 in the cell line responsive to the Pzero peptide. We conclude that T cells activated during the immune response associated with AIDP preferentially used V beta 15, which may indicate a restricted response to a common antigen, or a role for an as yet undefined superantigen in the pathogenesis of AIDP.

Adult↗
PubMed1997

Reactivity of serum IgG anti-GM1 ganglioside antibodies with the lipopolysaccharide fractions of Campylobacter jejuni isolates from patients with Guillain-Barre syndrome (GBS).

Campylobacter jejuni (Cj) enteritis is the most frequently recognised infection preceding Guillain-Barre syndrome (GBS) and this combination is commonly associated with anti-GM1 ganglioside (anti-GM1) antibodies. We have examined the hypothesis that the anti-GM1 antibodies represent an immune response against the Cj lipopolysaccharide (LPS). We prepared the LPS fraction from 8 isolates of Cj, 3 from GBS patients with acute inflammatory demyelinating polyradiculoneuropathy (AIDP), 3 from patients with Miller Fisher syndrome (MFS) and 2 from enteritis patients without neurological disease. We looked for IgG antibodies against LPS and GM1 in the serum of 10 GBS and 10 MFS patients, including the patients from whom the Cj had been isolated, and 11 normal control subjects. The highest levels of IgG binding to LPS fractions were found in the GBS patient sera and were with one of the LPS fractions extracted from the C. jejuni isolated from a GBS patient, one from a MFS patient and two Cj isolates from enteritis patients without neurological disease. The level of IgG binding to these LPS fractions was related to the level of IgG anti-GM1 antibody in the serum. Affinity-purified anti-GM1 antibodies showed the same pattern of differential binding to the LPS fractions as the serum from which they were derived. Cholera toxin bound to the same LPS fractions as GBS patients' IgG, the binding of which was blocked by the toxin indicating specific antibody reactivity with a GM1 hapten. The presence of serum anti-GM1 antibodies did not coincide with the presence of the GM1 hapten on the LPS of the infecting strain of Campylobacter indicating that anti-GM1 antibodies do not necessarily arise as part of a simple immune response against the LPS. The IgG antibodies binding to LPS were predominantly of the IgG2 isotype but patients with anti-GM1 IgG had mainly antibodies of IgG1 subclass against both LPS and GM1, implying their production by a T-cell dependent mechanism.

Adult↗
PubMed1997

Immunological investigation of chronic inflammatory demyelinating polyradiculoneuropathy.

In order to investigate the hypothesis that chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disease related to the acute inflammatory form of Guillain-Barre Syndrome (GBS), we studied 40 patients, 40 age and sex matched controls with other forms of peripheral neuropathy (ONP) and 37 controls from the same family or household (FC). We sought antibodies to gangliosides GM1 and LM1 by enzyme linked immunoassay (ELISA) confirmed by immuno-overlay. Only 6 (15%) CIDP patients had IgM antibodies to ganglioside GM1 (GM1) and none had IgG antibodies. We found IgM antibodies to ganglioside LM1 in 2 (5%) and IgG antibodies in 4 (10%) CIDP patients. Antibodies of IgG or IgM class were detected by ELISA to chondroitin sulphate C or sulfatide in up to 7.5% of CIDP patients. There were IgM antibodies in 3 (7.5%) and IgG in 4 (10%) patients against 25, 28 or 36 kD myelin proteins identified by immunoblot. Antibodies to any of these candidate myelin autoantigens were not significantly more frequent in CIDP than FC or ONP controls. Sera from 5 CIDP patients with active disease which subsequently responded to plasma exchange did not induce more demyelination upon intraneural injection into rat sciatic nerve than ONP sera. Serum tumor necrosis factor alpha (TNFalpha) concentrations were not increased in any of the CIDP patients. Serological evidence of Campylobacter jejuni (Cj) infection was present in 4 (10%) CIDP patients. IgM antibodies to cytomegalovirus (CMV) were not detected in any sera. CIDP is not commonly associated with either of these infections or with an antibody-mediated response to any of these glycolipid or myelin autoantigens.

Adult↗
PubMed1997

A combined inhibitor of matrix metalloproteinase activity and tumour necrosis factor-alpha processing attenuates experimental autoimmune neuritis.

Matrix metalloproteinases (MMPs) and the cytokine tumour necrosis factor (TNF)-alpha are implicated in the pathology of inflammatory demyelinating diseases of the CNS, and may also be involved in peripheral demyelinating diseases such as acute inflammatory demyelinating polyradiculoneuropathy. We have tested an inhibitor of MMP activity and TNF-alpha processing, BB-1101, in experimental autoimmune neuritis (EAN), an animal model of Guillain-Barré syndrome. Treatment with BB-1101 from the time of immunization prevented the development of EAN, and when given from the onset of symptoms, it significantly reduced disease severity. These results indicate that MMPs and/or TNF-alpha are involved in the pathogenesis of EAN, and that drugs of this type may have potential as novel therapeutic agents in the therapy of peripheral nervous system demyelinating diseases.

Animals↗
PubMed1997

Human immunoglobulin ameliorates rat experimental autoimmune neuritis.

Human immunoglobulin is an effective treatment for Guillain-Barré syndrome, although the mechanism of action is not understood. We have investigated the effect of human immunoglobulin in an animal model of Guillain-Barré syndrome, namely experimental autoimmune neuritis (EAN), induced in Lewis rats by immunization with bovine spinal root myelin. Human immunoglobulin administered intraperitoneally at the time of onset of disease accelerated the rate of recovery from EAN. This improvement was associated with a reduction in the titre of anti-rat myelin antibodies and may be due to earlier remyelination of demyelinated nerve fibres. This model may facilitate further investigation of the mechanism of therapeutic action of immunoglobulin in inflammatory neuropathy.

Animals↗
PubMed1997

Treatment of inflammatory neuropathy.

Experimental autoimmune neuritis (EAN) provides an accurate model for understanding the mechanism of acute and chronic inflammatory demyelinating polyradiculoneuropathy (AIDP and CIDP). Treatments aimed at every stage of the immune process in EAN have been effective in inhibiting or treating the disease, including antibodies directed against cell adhesion molecules on the endothelium, inhibition of T cells, removal or blockade of antibodies, depletion of complement, and interference with the release or action of macrophage effector molecules. In human disease the only proven treatments are plasma exchange and intravenous immunoglobulin (IVIg) in AIDP, and either of these regimens and also corticosteroids in CIDP. However the outcome from AIDP and CIDP remains unsatisfactory with existing immunosuppressive regimens. This problem arises from the fact that while demyelination appears to be effectively and promptly repaired by remyelination, it may be accompanied by axonal degeneration which can cause severe persistent disability. In addition to limiting demyelination, it will also be important to develop strategies to protect axons from degeneration and to enhance regeneration.

Animals↗
PubMed1995

Campylobacter jejuni infection and Guillain-Barré syndrome.

BACKGROUND: Although infection with Campylobacter jejuni is recognized as a common antecedent of the Guillain-Barré syndrome, the clinical and epidemiologic features of this association are not well understood. METHODS: We performed a prospective case-control study in a cohort of patients with Guillain-Barré syndrome (96 patients) or Miller Fisher syndrome (7 patients) who were admitted to hospitals throughout England and Wales between November 1992 and April 1994. Bacteriologic and serologic techniques were used to diagnose preceding C. jejuni infection. RESULTS: There was evidence of recent C. jejuni infection in 26 percent of the patients with Guillain-Barré or Miller Fisher syndrome, as compared with 2 percent of household controls and 1 percent of age-matched hospital controls (P < 0.001). Of the 27 patients with C. jejuni infection, 19 (70 percent) reported having had a diarrheal illness within 12 weeks before the onset of the neurologic illness. No specific serotypes were associated with Guillain-Barré syndrome. C. jejuni infection was slightly more common in men (P = 0.14) and was more likely to be associated with a pure motor syndrome and a slower recovery (P = 0.03). The patients with preceding C. jejuni infection were more likely to have acute axonal neuropathy or axonal degeneration in association with acute inflammatory demyelinating polyradiculoneuropathy, and they had greater disability after one year (P = 0.02). C. jejuni infection was significantly associated with a poor outcome even after correction for other factors associated with a poor prognosis. CONCLUSIONS: Infection with C. jejuni often precedes the Guillain-Barré syndrome and is associated with axonal degeneration, slow recovery, and severe residual disability.

Campylobacter Infections↗
PubMed1995

Anti-ganglioside GM1 antibodies in Guillain-Barré syndrome and their relationship to Campylobacter jejuni infection.

To clarify the association between Campylobacter jejuni (Cj) infection and antibodies to ganglioside GM1 (anti-GM1) in Guillain-Barré syndrome (GBS), we have carried out a prospective case-control study of 96 patients with GBS. Cj infection occurred in 25 (26%) patients. IgG and/or IgM anti-GM1 were identified in 24 (25%) patients and in 1 of 71 (1.4%) household controls (p < 0.001). Thirteen of the 25 (52%) Cj-positive patients had anti-GM1 compared with 11 of the 71 (15%) Cj-negative patients (p < 0.001). Neither the peak overall disability nor the 1-year disability differed between the anti-GM1-positive and anti-GM1-negative patients. However, patients with the combination of Cj infection and anti-GM1 positivity recovered more slowly than Cj/anti-GM1-negative patients (p = 0.05), were more likely to have axonal degeneration, and were significantly more disabled at the end of 1 year (p = 0.02). The presence of Cj infection is more important than anti-GM1 positivity in determining the extent of axonal involvement and, hence, prognosis. Since the presence of anti-GM1 is not a significant poor-prognostic factor, a search should be made for other properties of Cj infection that would account for its relationship to axonal degeneration.

Autoantibodies↗