Transient immunosuppression: a bridge between infection and the atypical autoimmunity of Guillain-Barré syndrome?

Guillain-Barré syndrome (GBS) is an acute, usually monophasic, disorder of the peripheral nervous system that is assumed to be of immune-mediated pathogenesis. However, several clinical features and experimental findings of GBS are uncharacteristic for an immune-mediated disorder and set this condition apart from other disorders with a putative immune-mediated pathogenesis. These features include, among others, the monophasic nature of GBS, the lack of response to immunosuppressive (unlike immunomodulatory) therapy, the absence of a typical association with immunogenetic background and the inability to establish a valid and relevant animal model. We suggest a comprehensive hypothesis for the pathogenesis of GBS that is based on the assumption that the condition is due to a transient (or occasionally chronic) immune deficiency, as in most cases GBS follows an infection with pathogens known to induce immunosuppression. Such infections may be followed by breakdown of immune tolerance and induction of an immune attack on peripheral nerves. Mounting of the immune-mediated assault might be triggered either by the same infective pathogen or by secondary infection. Clearance of the infection and resumption of a normal immune response and tolerance eventually terminate the immune-mediated damage to the peripheral nerves and enable recovery. This hypothesis assumes that the entire sequence of events that culminates in GBS is due to transient exogenous factors and excludes a significant role for inherent host susceptibility, which explains the monophasic nature of the disorder.

Increased severity over generations of Charcot-Marie-Tooth disease type 1A.

BACKGROUND: Charcot-Marie-Tooth type 1A (CMT1A) is an autosomal dominant polyneuropathy due to a 1.5 Mb tandem duplication in chromosome 17p11.2, containing the PMP22 gene. This mutation is not modified during inheritance. OBJECTIVES: We set forth to test the hypothesis that in a subgroup of CMT1A patients there is clinical anticipation, namely an increase in disease severity over generations. METHODS: Thirty-nine CMT1A mutation-positive patients in 16 families and 23 parent-offspring pairs were evaluated. This included 14 families with 2 generations and 2 families with 3 generations. Age of presentation was assessed by interviewing the patients and clinical severity was measured using the CMT neuropathy score (CMTNS). RESULTS: In 21/23 parent-child pairs and 14/16 families, there was an earlier age of presentation in children of genetically affected parents. The mean age of onset in the progeny was 12.61 years compared to 41.22 years in the parent generation, (p < 0.001). Mean severity in the younger generation was slightly higher than that of the parent generation. When corrected for the age difference, the trend for a worse phenotype in the younger generation became statistically significant (p < 0.02,Wilcoxon signed rank test). CONCLUSIONS: Our findings suggest that in a subgroup of CMT1A patients there is an increase in clinical severity over generations. The mechanism responsible for this observation remains unknown. Our findings should be validated on a larger cohort of CMT1A families.

Co-morbidity of Emery-Dreifuss muscular dystrophy and a congenital myasthenic syndrome possibly affecting the phenotype in a large Bedouin kindred.

Emery-Dreifuss muscular dystrophy (EDMD) is an X-linked humero-peroneal muscular dystrophy associated with contractures and cardiomyopathy. In a 90 member family, we found 11 affected male individuals, three of whom displayed areflexia and neurogenic electromyographic changes. Muscle biopsy performed in one case demonstrated type grouping suggestive of a neurogenic disorder. These three individuals and another family member, who suffers from mild, static limb weakness but is clinically and genetically unaffected by EDMD showed an abnormal incremental response of over 100% to tetanic stimulation. In contrast, one affected family member showed myopathic features on needle electromyography and no definite pathology in repetitive stimulation studies. The diagnosis of EDMD was established by demonstrating a 1712_1713insTGGGC mutation in the emerin gene. This family apparently expresses co-morbidity of EDMD with an exceptionally mild form of pre-synaptic congenital myasthenic syndrome resembling the Lambert-Eaton myasthenic syndrome (LEMS). The superimposed pre-synaptic disorder may have contributed to the development of the neurogenic features demonstrated in these patients.

Hereditary inclusion body myopathy: the Middle Eastern genetic cluster.

BACKGROUND: Recessively inherited hereditary inclusion body myopathy (HIBM) with quadriceps sparing was initially described only in Jews originating from the region of Persia. The recent identification of the gene responsible for this myopathy and the common "Persian Jewish mutation" (M712T) enabled the re-evaluation of atypical phenotypes and the epidemiology of HIBM in various communities in the Middle East. OBJECTIVE: To test for the M712T mutation in the DNA from HIBM patients in the Middle East. METHODS: DNA from all suspected HIBM patients was tested for the M712T mutation. Unaffected members of families with genetically proven HIBM were studied too. In the majority of families, haplotype construction with markers spanning the 700-kb region of the HIBM gene was performed. RESULTS: One hundred twenty-nine HIBM patients of 55 families (Middle Eastern Jews, Karaites, and Arab Muslims of Palestinian and Bedouin origin) were homozygous for the M712T mutation, and all carried the same haplotype. Five clinically unaffected subjects were also homozygous for the common mutation and haplotype, including two older adults (ages 50 and 68 years). Atypical features with this same mutation were marked quadriceps weakness in five patients, proximal weakness only in two patients, facial weakness in three patients, and a muscle biopsy showing perivascular inflammation in one patient. CONCLUSIONS: The phenotypic spectrum of recessive HIBM is wider than previously described, and the diagnostic criteria for this myopathy must be changed. The Middle Eastern cluster is the result of a founder mutation, with incomplete penetrance, that is approximately 1,300 years old and is not limited to Jews.

Ganglioside agglutination immunoassay for rapid detection of autoantibodies in immune-mediated neuropathy.

Elevated levels of serum autoantibodies directed against gangliosides are closely associated with acute and chronic autoimmune neuropathies. An agglutination immunoassay using polystyrene microparticles coated with a total extract of brain gangliosides was used to test patient sera for the presence of anti-ganglioside antibodies. Results were compared with those obtained by ELISA for anti-GM1 and anti-GQ1b ganglioside antibodies. Eight of the twelve sera from patients with multifocal motor neuropathy and seven of the thirteen sera from patients with Guillain-Barré syndrome were positive for the presence of anti-ganglioside antibodies by the ganglioside agglutination immunoassay. The assay compared favorably with the ELISA system in sensitivity and specificity, while requiring a fraction of the time and cost to perform. The new assay can serve as a rapid and effective method for detecting or screening for anti-ganglioside antibodies in patients with acute or chronic immune-mediated neuropathies. It would be particularly useful for detecting antibodies that react with multiple gangliosides, or with minor or as yet uncharacterized gangliosides.

Thiamine-responsive acute neurological disorders in nonalcoholic patients.

Wernicke's encephalopathy (WE) is most commonly associated with alcoholism, although other causes have also been implicated. In the years 1994-1997, 9 patients with no history of alcohol abuse presented with acute signs of ophthalmoplegia or nystagmus and ataxia which resolved within 48 h after intravenous thiamine. There were 7 women and 2 men aged 17-57 (7 below the age of 30). Precipitating events included vomiting 2, drastic weight-reducing diet 2, renal colic in a postpartum woman 1, colonic surgery 2 and chronic hemodialysis 1. In 2 patients there was no obvious precipitating event but their history was suggestive of a genetic predisposition. Mental changes were slight or absent in all patients and all of them made good functional recovery. These cases suggest that the diagnosis of WE should be considered more often in nonalcoholics in various clinical settings.

Infection and the etiology and pathogenesis of multiple sclerosis.

Multiple sclerosis (MS) currently defies clinical and scientific definitions, and carries a prognosis that remains practically unchanged despite many years of intensive research. Although the prevailing dogma is that MS is an immune-mediated condition, it fulfills none of the criteria of an autoimmune disease. On the other hand, there is enough significant data to suggest that infectious agents(s) could be involved in either direct damage to the white matter or induce inflammatory responses that secondarily affect the brain. Our goal here is to review the data supporting the possibility that infection has a critical role in the disease, examine the list of potential candidates that have been suggested, and outline an approach regarding the potential role of infectious agents in the etiology and pathogenesis of MS.

Multiple sclerosis--in need of a critical reappraisal.

Multiple sclerosis (MS) is a disease that currently defies clinical and scientific definitions. Despite intensive clinical and basic research, very little is known about its possible cause(s) or pathogenesis, and the course and prognosis of MS practically remain unchanged. The aim of the present article is to outline some of the reasons for the constant failure to improve the therapy of MS. It also attempts to offer several guidelines which may enable a fresh and different approach to this devastating condition.

Lipopolysaccharides of a Campylobacter coli isolate from a patient with Guillain-Barré syndrome display ganglioside mimicry.

Campylobacter coli was isolated from a patient with severe, axonal type Guillain-Barré syndrome (GBS). The patient's serum was tested by ELISA for glycolipid antibodies and showed a high titer of IgG antibodies to asialo-GM1 (GA1) and GD3. Campylobacter coli lipopolysaccharide (LPS) was extracted and analyzed by ELISA, immunoblot binding and blocking studies, and found to avidly bind cholera toxin and peanut agglutinin. The LPS from the patient's isolate also induced anti-GA1 antibodies in a rat model. These findings suggest that the LPS from this bacterial isolate contains a ganglioside-like epitope, which most likely resembles GA1. Thus, it appears that ganglioside cross-reactivity is not unique to Campylobacter jejuni and seems to occur in all bacterial isolates from GBS cases so far analyzed.

Oral administration of a dual analog of two myasthenogenic T cell epitopes down-regulates experimental autoimmune myasthenia gravis in mice.

Myasthenia gravis (MG) and experimental autoimmune MG (EAMG) are T cell-regulated, antibody-mediated autoimmune diseases. The major autoantigen in MG is the nicotinic acetylcholine receptor (AChR). Two peptides, representing sequences of the human AChR alpha-subunit, p195-212 and p259-271, were previously shown to be immunodominant T cell epitopes in MG patients as well as, respectively, in SJL and BALB/c mice. A dual analog (termed Lys-262-Ala-207) composed of the tandemly arranged two single amino acid analogs of p195-212 and p259-271 was shown to inhibit, in vitro and in vivo, MG-associated autoimmune responses. Furthermore, the dual analog could down-regulate myasthenogenic manifestations in mice with EAMG that was induced by inoculation of a pathogenic T cell line. In the present study, the ability of the dual analog to treat EAMG induced in susceptible C57BL/6 mice by native Torpedo AChR was evaluated. Mice that were diagnosed to have clinical symptoms of EAMG were treated with the dual analog by oral administration, 500 microg per mouse three times a week for 5-8 weeks. Treatment with the dual analog down-regulated the clinical manifestations of the ongoing disease as assessed by the clinical score, grip strength (measured by a grip strength meter), and electromyography. The effects on the clinical EAMG correlated with a reduced production of anti-AChR antibody as well as a decrease in the secretion of interleukin-2 and, more dramatically, interferon-gamma, in response to AChR triggering. Thus, the dual analog is an efficient immunomodulator of EAMG in mice and might be of specific therapeutic potential for MG.

Murine typhus presenting as subacute meningoencephalitis.

Murine typhus is a febrile systemic illness, presenting with headache and undulating fever. Neurological involvement is considered a rare complication. During 1994 and 1995, 34 patients admitted to our hospital were diagnosed as having murine typhus. Five of these patients presented with a syndrome of subacute "aseptic" meningitis or meningoencephalitis. Three had bilateral papilloedema and 2 had focal neurological signs. None had a rash or other systemic findings suggestive of rickettsial disease. The diagnosis was based on serum and cerebrospinal fluid serology and on prompt response to doxycycline therapy. These cases suggest that neurological involvement in murine typhus is more common than previously suspected and that murine typhus should be included in the differential diagnosis of subacute meningitis in endemic areas.

Single amino acid analogs of a myasthenogenic peptide modulate specific T cell responses and prevent the induction of experimental autoimmune myasthenia gravis.

Peptide p259-271 of the human acetylcholine receptor alpha-subunit, preferentially stimulates T cells of patients with myasthenia gravis (MG) and is an immunodominant epitope for T cells of BALB/c mice. A p259-271 specific T cell line of BALB/c origin was established and was shown to induce experimental MG in naive mice. Seven analogs of p259-271 were synthesized, and two of them were found to inhibit the p259-271 specific proliferative responses of the line and of p259-271 primed lymph node cells. Moreover, the most efficient inhibitor, analog 262Lys, prevented the MG related manifestations in mice inoculated with the line, and might be of potential value for the treatment of MG.