Biomedical subjects

J Veitch

Publications and source records attributed to J Veitch.

At least 19 recordsLinked to original sources

PubMed2001

The clinical and laboratory features of chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies.

The clinical and laboratory phenotype of a paraproteinaemic neuropathy syndrome termed chronic sensory ataxic neuropathy with anti-disialosyl IgM antibodies is described in a series of 18 cases. Previous single case reports have outlined some features of this syndrome. All 18 cases were defined by the presence of serum IgM antibodies which react principally with NeuAc (alpha2-8)NeuAc(alpha2-3)Gal-configured disialosyl epitopes common to many gangliosides including GDlb, GD3, GTlb and GQlb. In 17 out of 18 cases, the serum contained benign IgM paraproteins, and in four of these cases at least two IgM paraproteins were present. The IgM antibodies were also cold agglutinins in 50% of cases. The clinical picture comprised a chronic neuropathy with marked sensory ataxia and areflexia, and with relatively preserved motor function in the limbs. In addition, 16 out of 18 cases had motor weakness affecting oculomotor and bulbar muscles as fixed or as relapsing-remitting features. When present in their entirety, these clinical features have been described previously under the acronym CANOMAD: chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins and disialosyl antibodies. This distribution of clinical features is reminiscent of Miller Fisher syndrome, in which acute-phase anti-disialylated ganglioside IgG antibodies are found. Clinical electrophysiology and nerve biopsy show both demyelinating and axonal features. A partial response to intravenous immunoglobulin and other treatments is reported in some cases.

Adult↗

PubMed2000

Long-term clinical and neurophysiological follow-up of patients with peripheral, neuropathy associated with benign monoclonal gammopathy.

The incidence of hematological malignancy in patients with monoclonal gammopathy of undetermined significance (MGUS) has been assessed as 17% to 25%. To ascertain whether this is true of neuropathy associated with MGUS, a long-term (5-42 years) retrospective clinical and neurophysiological follow-up was conducted in 50 cases (immunoglobulin M [IgM], n = 38; IgG, n = 11; IgA, n = 1). Only three patients developed hematological malignancy. Of 25 survivors with IgM paraproteinemia, 7 had myelin-associated glycoprotein antibodies with typical clinical features. Evoked distal muscle amplitudes were significantly smaller than for the other paraprotein classes. Preferential distal demyelination manifested by relative prolongation of distal motor latency was not apparent in the cases of long duration. Two patients with IgM antidisialosyl antibodies and cold agglutinating activity had a large fiber neuropathy with intermittent oculofacial involvement. Both responded to intravenous immunoglobulin. Findings in the remaining patients were varied. Recognition of IgM subgroups is important both for prognosis and possible response to treatment.

Adult↗

PubMed2000

Peripheral neuropathy associated with anti-GM2 ganglioside antibodies: clinical and immunopathological studies.

GM2 ganglioside is a potential peripheral nerve antigen for neuropathy-associated autoantibodies. However little data are available on their pathogenic effects, if any. In this study we have screened both neuropathy-associated and control sera for anti-GM2 antibodies and subsequently used high titre sera for immunohistological and complement mediated cytotoxicity studies. We identified abnormally elevated anti-GM2 antisera in the normal population, as well as in patients with peripheral neuropathies and other neurological diseases. GM2 antibodies were either mono-reactive, cross-reactive with GM1a, or cross-reactive with GalNAc-GM1b and/or GalNAc-GD1a. All GM2 antisera from neuropathy subjects and normal controls bound to, and were capable of complement-mediated lysis of the NSC-34 cell line which expresses high levels of membrane-associated GM2. However, in immunohistological studies on human and rodent peripheral nervous system tissues, no specific binding was seen with GM2 antisera, either cross-reactive with GalNAc-GM1b and GalNAc-GDla, or with GM1a. These data indicate that although GM2 antisera can lyse neural membranes containing GM2, this antigen(s) is not detectable by standard immunohistological techniques in human or rodent peripheral nerve. This raises doubts about their pathophysiological significance in human autoimmune neuropathy.

Adolescent↗

PubMed1999

Anti-GD1a antibody is associated with axonal but not demyelinating forms of Guillain-Barré syndrome.

Immunopathological studies suggest that the target of immune attack is different in the subtypes of Guillain-Barré syndrome (GBS). In acute motor axonal neuropathy (AMAN), the attack appears directed against the axolemma and nodes of Ranvier. In acute inflammatory demyelinating polyneuropathy (AIDP), the attack appears directed against a component of the Schwann cell. However, the nature of the antigenic targets is still not clear. We prospectively studied 138 Chinese GBS patients and found that IgG anti-GD1a antibodies were closely associated with AMAN but not AIDP. With a cutoff titer of greater than 1:100, 60% of AMAN versus 4% of AIDP patients had IgG anti-GD1a antibodies; with a cutoff titer of greater than 1:1,000, 24% of AMAN patients and none of the AIDP patients had IgG anti-GD1a antibodies. In contrast, low levels of IgG anti-GM1 antibodies (> 1:100) were detected in both the AMAN and the AIDP forms (57% vs 35%, NS). High titers of IgG anti-GM1 (>1:1,000) were more common in the AMAN form (24% vs 8%, NS). Serological evidence of recent Campylobacter infection was detected in 81% of AMAN and 50% of AIDP patients, and anti-ganglioside antibodies were common in both Campylobacter-infected and noninfected patients. Our results suggest that IgG anti-GD1a antibodies may be involved in the pathogenesis of AMAN.

Adolescent↗

PubMed1999

Miller Fisher anti-GQ1b antibodies: alpha-latrotoxin-like effects on motor end plates.

In the Miller Fisher syndrome (MFS) variant of the Guillain-Barré syndrome, weakness is restricted to extraocular muscles and occasionally other craniobulbar muscles. Most MFS patients have serum antibodies against ganglioside type GQ1b of which the pathophysiological relevance is unclear. We examined the in vitro effects of MFS sera, MFS IgG, and a human monoclonal anti-GQ1b IgM antibody on mouse neuromuscular junctions (NMJs). It was found that anti-GQ1b antibodies bind at NMJs where they induce massive quantal release of acetylcholine from nerve terminals and eventually block neuromuscular transmission. This effect closely resembled the effect of the paralytic neurotoxin alpha-latrotoxin at the mouse NMJs, implying possible involvement of alpha-latrotoxin receptors or associated downstream pathways. By using complement-deficient sera, the effect of anti-GQ1b antibodies on NMJs was shown to be entirely dependent on activation of complement components. However, neither classical pathway activation nor the formation of membrane attack complex was required, indicating the effects could be due to involvement of the alternative pathway and intermediate complement cascade products. Our findings strongly suggest that anti-GQ1b antibodies in conjunction with activated complement components are the principal pathophysiological mediators of motor symptoms in MFS and that the NMJ is an important site of their action.

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↗

PubMed1999

Physical inactivity and other health risks among Australian males in less-skilled occupations.

Male workers in less-skilled occupations have higher rates of cardiovascular disease, compared with higher-skilled workers. A representative population sample of Australian male workers was used to compare physical activity levels and selected cardiovascular disease risk factors in less-skilled versus professional and skilled workers. Workers in the less-skilled occupational categories reported significantly more vigorous work and home-based activity than did those in the professional and skilled categories. In multivariate comparisons, cigarette smoking was the only factor that discriminated between the less-skilled versus the professional and skilled employees. Although worksites can potentially provide health-promoting physical activity options for higher-risk groups, our findings suggest that smoking and possibly overweight are risk factors that are more strongly present in less-skilled occupations.

Adult↗

PubMed1999

Physical activity initiatives for male factory workers: gatekeepers' perceptions of potential motivators and barriers.

OBJECTIVE: Worksites have been argued to be a key setting for physical activity promotion, particularly for lower-paid, less-skilled workers. These occupational groups are at increased risk of cardiovascular disease. There is no strong evidence in support of the efficacy of worksite fitness and physical activity interventions. This study assessed potential motivators and barriers to worksite physical activity initiatives for less-skilled workers. METHOD: We conducted telephone interviews with 13 Victorian WorkCover insurance providers and 30 manufacturing industry worksite managers. The manufacturing industry was selected as it contains a substantial portion of workers from this high-risk occupational group. RESULTS: Most insurers incorporated physical activity elements into injury-prevention programs. Few worksite managers reported programs to encourage workers to be more active; they identified reduced premiums and lower-cost programs through insurers as possible motivators. Both groups identified workers' reluctance to participate in physical activity, lack of awareness of potential benefits and program cost as major barriers for worksite physical activity. Other barriers included potential adverse effects on productivity and increased injury risk. CONCLUSIONS: Broader occupational health and safety policies and joint initiatives between insurers and worksite managers may have the potential to provide more opportunities for workers to be more active. However, the barriers identified outweighed the perceived benefits. IMPLICATIONS: Without structural and regulatory changes or new incentives, the adoption of physical activity initiatives in Australian manufacturing-industry workplaces is unlikely.

Attitude to Health↗

PubMed1999

Monoclonal antibodies raised against Guillain-Barré syndrome-associated Campylobacter jejuni lipopolysaccharides react with neuronal gangliosides and paralyze muscle-nerve preparations.

Guillain-Barré syndrome and its variant, Miller-Fisher syndrome, are acute, postinfectious, autoimmune neuropathies that frequently follow Campylobacter jejuni enteritis. The pathogenesis is believed to involve molecular mimicry between sialylated epitopes on C. jejuni LPSs and neural gangliosides. More than 90% of Miller-Fisher syndrome cases have serum anti-GQ1b and anti-GT1a ganglioside antibodies that may also react with other disialylated gangliosides including GD3 and GD1b. Structural studies on LPS from neuropathy-associated C. jejuni strains have revealed GT1a-like and GD3-like core oligosaccharides. To determine whether this structural mimicry results in pathogenic autoantibodies, we immunized mice with GT1a/GD3-like C. jejuni LPS and then cloned mAb's that reacted with both the immunizing LPS and GQ1b/GT1a/GD3 gangliosides. Immunohistology demonstrated antibody binding to ganglioside-rich sites including motor nerve terminals. In ex vivo electrophysiological studies of nerve terminal function, application of antibodies either ex vivo or in vivo via passive immunization induced massive quantal release of acetylcholine, followed by neurotransmission block. This effect was complement-dependent and associated with extensive deposits of IgM and C3c at nerve terminals. These data provide strong support for the molecular mimicry hypothesis as a mechanism for the induction of cross-reactive pathogenic anti-ganglioside/LPS antibodies in postinfectious neuropathies.

Animals↗

PubMed1998

Mapping immunoreactive epitopes in the human peripheral nervous system using human monoclonal anti-GM1 ganglioside antibodies.

A series of monoclonal IgM anti-GM1 ganglioside antibodies has been cloned from peripheral blood lymphocytes of patients with multifocal motor neuropathy and Guillain-Barré syndrome. In solid-phase immunoassay, the antibodies react with GMI, and also in differing degrees to the structurally related glycolipids asialo-GM1 (GA1) and GD1b. Here we describe the binding patterns of six human anti-GM I antibodies to epitopes within the human nervous system. Antibodies were observed to bind to motor neurons and spinal grey matter, dorsal and ventral spinal roots, dorsal root ganglion neurons, nodes of Ranvier, neuromuscular junctions and skeletal muscle. The distribution of immunoreactive epitopes, which included sensory structures, extended beyond those sites conventionally regarded as pathologically affected in anti-GM1 antibody-associated motor nerve syndromes. This undermines a model of disease pathogenesis based solely on antigen distribution. Factors other than the presence or absence of antigen, such as the local ganglioside topography, antibody penetration into, and pathophysiological vulnerability of a particular site may also influence the clinicopathological outcome of anti-GM1 antibody-mediated autoimmune attack.

Antibodies, Monoclonal↗

PubMed1998

Campylobacter jejuni lipopolysaccharides in Guillain-Barré syndrome: molecular mimicry and host susceptibility.

OBJECTIVE: This study was designed to determine if the presence of specific ganglioside-like moieties in Campylobacter lipopolysaccharides (LPSs) is related to the development of Guillain-Barré syndrome (GBS), and to discover how frequently such moieties, including GM1, are present in these LPSs. METHODS: We studied Campylobacter isolates and sera from seven patients with GBS (five acute motor axonal neuropathy, one acute inflammatory demyelinating polyneuropathy, and one Fisher's syndrome), and compared them with similar specimens from patients with Campylobacter enteritis alone. RESULTS: All GBS patients had antiganglioside antibodies. Anti-GM1 and anti-GD1a titers were significantly elevated in post-Campylobacter GBS, both axonal and demyelinating, compared with normal control subjects or those with uncomplicated Campylobacter diarrhea. Campylobacter isolated from patients with GBS and with enteritis alone had similar ganglioside-like moieties. CONCLUSIONS: These results indicate that patients who develop GBS respond differently to the ganglioside-like epitopes on Campylobacter than do non-GBS diarrhea patients. Our findings support a role for host susceptibility as a determinant for the outcome following Campylobacter infection. These findings have important implications for the development of vaccines against Campylobacter jejuni.

Adult↗

PubMed1997

Human IgM paraproteins demonstrate shared reactivity between Campylobacter jejuni lipopolysaccharides and human peripheral nerve disialylated gangliosides.

IgM paraproteins from patients with CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, M-protein, agglutination, anti-disialosyl antibodies) react with NeuAc(alpha 2-8)NeuAc epitopes on a wide range of gangliosides including GQ1b, GT1a, GD1b and GD3. The tissue distribution of reactive antigens in human peripheral nerve has not been addressed in detail. In addition, the origin of these antibodies is unknown. Here we report that purified anti-disialosyl paraproteins from two affected patients bind a wide array of human peripheral nerve structures including dorsal root ganglia, dorsal and ventral root axons, femoral and oculomotor nerves. We also show that these paraproteins bind lipopolysaccharides of Campylobacter jejuni isolates from 3/3 cases of Miller Fisher syndrome, and to a less frequent extent, from cases of Guillain-Barré syndrome and enteritis controls. In conjunction with our previous studies, these data provide a possible causal link between the origin and pathogenic effects of anti-disialosyl antibodies in human paraproteinaemic neuropathy.

Agglutination↗

PubMed1997

Mechanisms of action of anti-GM1 and anti-GQ1b ganglioside antibodies in Guillain-Barré syndrome.

Anti-GM1 and anti-GQ1b ganglioside antibodies are found in association with acute and chronic peripheral neuropathies, including Guillain-Barré syndrome. They are believed to arise as a result of molecular mimicry with immunogenic microbial polysaccharides. Although anti-ganglioside antibodies are suspected to play a causal role in neuropathy pathogenesis, the details of this have yet to be proven. The approach in this laboratory to solving this issue has been to generate anti-GM1 and anti-GQ1b monoclonal antibodies from peripheral blood lymphocytes of affected patients and to study their immunolocalization in peripheral nerve and their electrophysiologic effects in animal models in which peripheral nerve sites are exposed to anti-ganglioside antibodies. These data show that anti-ganglioside antibody-reactive epitopes are widely distributed in peripheral nerve and can cause electrophysiologic abnormalities in a variety of model systems; thus, these data support the view that anti-ganglioside antibody-reactive epitopes may directly contribute to neuropathy pathogenesis.

Animals↗

PubMed1996

A somatically mutated human antiganglioside IgM antibody that induces experimental neuropathy in mice is encoded by the variable region heavy chain gene, V1-18.

IgM paraproteins associated with autoimmune peripheral neuropathy and anti-Pr cold agglutinins react with sialic acid epitopes present on disialylated gangliosides including GD1b, GT1b, GQ1b, and GD3. A causal relationship between the paraprotein and the neuropathy has never been proven experimentally. From peripheral blood B cells of an affected patient, we have cloned a human hybridoma secreting an antidisialosyl IgM mAb, termed Ha1, that shows identical structural and functional characteristics to its serum counterpart. Variable region analysis shows Ha1 is encoded by the same VH1 family heavy chain gene, V1-18, as the only other known anti-Pr antibody sequence and is somatically mutated, suggesting that it [correction of is] arose in vivo in response to antigenic stimulation. In the rodent peripheral nervous system, Ha1 immunolocalizes to dorsal root ganglia, motor nerve terminals, muscle spindles, myelinated axons, and nodes of Ranvier. After intraperitoneal injection of affinity-purified antibody into mice for 10 d, electrophysiological recordings from the phrenic nerve-hemidiaphragm preparation demonstrated impairment of nerve excitability and a reduction in quantal release of neurotransmitter. These data unequivocally establish that an antidisialosyl antibody can exert pathophysiological effects on the peripheral nervous system and strongly support the view that the antibody contributes to the associated human disease.

Amino Acid Sequence↗

PubMed1996

Acute oropharyngeal palsy is associated with antibodies to GQ1b and GT1a gangliosides.

Three patients with acute oropharyngeal palsy had high titre anti-GQ1b and anti-GT1a IgG antibodies. No patients had ophthalmoplegia or ptosis. In all patients limb ataxia or areflexia were present without notable limb weakness. These patients describe an oropharyngeal variant of Guillain-Barré syndrome in terms of anti-GQ1b antibody reactivity and show that high titre anti-GQ1b antibodies, serologically indistinguishable from those found in Miller Fisher syndrome, can occur in a clinical setting without ophthalmoplegia. The anti-GQ1b and anti-GT1a antibody assays may be helpful tests when considering the differential diagnosis of acute oropharyngeal palsy.

Adolescent↗

PubMed1995

Antimycobacterial hsp65 and rheumatoid factor titres in a population of normal twins: evidence of genetic control of rheumatoid factor.

Rheumatoid arthritis (RA) is an autoimmune disease and rheumatoid factor (RF), anti-IgG, has been implicated in the pathogenesis, but the exact etiology remains unclear. There are data to suggest and infectious trigger to the autoimmune process, and mycobacteria are considered a candidate. Immunization of various animals with mycobacterial heat shock protein 65 (mhsp65) protects against subsequent autoimmune arthritis in a number of experimental models. Elevated anti-mhsp65 titres have been demonstrated in RA patients, together with specific T cells isolated from inflamed synovium. Mycobacterial hsp65 has also been implicated in other autoimmune disease and in atherosclerosis. The anti-mhsp65 and RF (IgG, IgM and IgA isotypes) titres were assayed by ELISA in 123 pairs of normal twins (61 monozygotic and 62 dizygotic, age 14-79 years), to examine the population distribution and inter-relationship of these antibodies. In addition, we studied the effects of age, sex, genetics and environment on antibody titres. IgG-RF and IgM-RF were detectable in all subjects and IgA-RF in 41 subjects. None of the RF isotypes showed any significant dependence on age or sex. There was a statistically significant correlation between twins for the IgG-RF and IgM-RF, and a positive but not significant correlation for the IgA-RF. All three correlations were stronger for monozygotic than dizygotic twins, reaching statistical significance for IgM-RF (P < 0.001), and this indicates that there is a genetic influence on RF titres. Anti-mhsp65 titres were detectable in 90.5% of the study group with a range of 0.15-19.7 AU/ml. There were weak correlations between twins, stronger for dizygotic than monozygotic twins. This suggests that familial influences on anti-mhsp65 titres are very small, with no evidence of any genetic influence at all. There was no significant relationship of anti-mhsp65 titre with age, sex or RF titres.

Adolescent↗

PubMed1994

Cloning of human anti-GM1 antibodies from motor neuropathy patients.

Patients with multifocal motor neuropathy frequently have elevated titers of serum antibodies reactive with GM1 ganglioside. Although these antibodies may cause the syndrome, this has yet to be proven directly. As part of our studies on the nature and pathogenic potential of anti-GM1 antibodies, we have cloned B cells from the peripheral blood of 3 patients with multifocal motor neuropathy and generated four stable heterohybridoma cell lines secreting human monoclonal IgM anti-GM1 antibodies. In this report we describe the basic properties of these monoclonal antibodies in comparison with the patient's sera from which they were derived. The antibodies all differ in their pattern of reactivity with GM1 and other Gal(beta 1-3)GalNAc-containing glycoconjugates. They have widely varying thermal ranges and their reactivities are strongly influenced by the presence of accessory lipids. Affinity purification of the patient's sera with GM1 led to the identification of previously unrecognized paraproteins that were resolvable above the background of polyclonal anti-GM1 IgM. Our data demonstrate considerable heterogeneity in the immune response to GM1 both within individual sera and between different patients, which is likely to be of importance to their role in disease pathogenesis.

Adult↗

PubMed1994

AAEM minimonograph #42: intraoperative monitoring of peripheral and cranial nerves.

Intraoperative studies of focal neuropathies have become increasingly common both as an aid to the localization of the neuropathy and a means of monitoring the integrity of the nerve in the course of surgery. Success very often depends on careful attention to the technical problems presented by working in the operating theater. Despite these difficulties, assessment of conduction directly from the exposed nerve offers opportunities for better understanding the pathophysiology of these neuropathies and correlating these findings with conventional electrodiagnostic studies.

Action Potentials↗