Multiple sclerosis: basic immunology

A 24-year-old male presented with a 4 year history of a crusted erythematous papular eruption of the scalp and external auditory meati and a 12 month history of painful perianal ulceration. A diagnosis of Langerhans cell histiocytosis was made and confirmed by skin histology. Extensive investigation revealed no systemic involvement. Rapid improvement occurred after intravenous 2-chlorodeoxyadenosine but relapse of perianal lesions occurred within 5 months. Local radiotherapy to the perianal region resulted in a complete remission sustained over 12 months.     

Multiple sclerosis in Fife

Patients in Fife with multiple sclerosis were identified from three sources: a postal questionnaire to all general practices in Fife, hospital discharge data, rehabilitation service database. A total of 508 patients were identified in a population of 354,273 giving a crude prevalence rate of 143/100,000. The Standardised Prevalence Rate was 178/100,000. The sex ratio was 2.43 females to males. The prevalence was higher than identified in southern parts of the United Kingdom and similar to northern Scotland. A total of 200 (40%) cases were identified as having relapsing-remitting disease and of these 151 were ambulant, making them eligible for treatment with interferon beta-lb under current licensing criteria. Only 90 (60%) of the 151 currently eligible for the drug were under the care of a specialist and almost half the practices felt that they would change their referring habits. These factors may have implications for the workload of specialist clinics.     

Multiple sclerosis: variations on a theme

Paediatric intensive care has developed into a highly specialized and labour-intensive clinical activity. The provision of adequate numbers of properly staffed children's intensive care beds within the UK, and the lack of national planning and coordination are both problematic. This article examines these problems and discusses current thinking on the provision of paediatric intensive care services.     

Multiple sclerosis and the neurogenic bladder

Allosteric regulators of alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors include 2,3-benzodiazepines such as GYKI 52466 and GYKI 53655 and the chaotropic anion thiocyanate that inhibit, and benzothiadiazines such as cyclothiazide that potentiate AMPA receptor currents. Here we sought to determine whether the allosteric regulators modulate AMPA receptors at a common or distinct allosteric sites by comparing their actions on AMPA- and kainate-evoked currents in cultured rat hippocampal neurons and Xenopus oocytes expressing recombinant AMPA receptor subunits. GYKI 52466 and thiocyanate blocked AMPA-evoked currents in a concentration-dependent manner (IC50 values, 8.2 microM and 1.1 mM, respectively); in contrast, kainate-evoked currents were blocked by GYKI 52466, but were potentiated by high concentrations of thiocyanate (> or = 3 mM). Thiocyanate enhanced the rate of desensitization and slowed recovery from desensitization of AMPA-evoked currents, whereas GYKI 52466 failed to affect desensitization. Among neurons in the hippocampal cultures, there was cell-to-cell variability in the sensitivity to block of AMPA-evoked currents by thiocyanate that was correlated with the degree of potentiation by cyclothiazide. Moreover, cyclothiazide caused a parallel rightward shift in the concentration-response curve for thiocyanate block, and slowed the onset of thiocyanate block to a rate that was similar to that of cyclothiazide dissociation. Together, these observations suggest that thiocyanate and cyclothiazide act at non-distinct allosteric sites. GYKI 52466 blocked AMPA receptor responses to a similar extent, irrespective of the degree of cyclothiazide potentiation. Moreover, the kinetics of GYKI 53655 block in the presence of cyclothiazide were not consistent with a competitive interaction. As is the case for cyclothiazide, SCN- exhibited greater affinity for flip than for flop AMPA receptor splice variants. In particular, GluR1flip/GluR2flip was especially sensitive to thiocyanate block. We conclude that thiocyanate, a flip-preferring allosteric modulator like cyclothiazide, appears to act by enhancing desensitization at a site that may overlap the site where cyclothiazide reduces desensitization, whereas 2,3-benzodiazepines act at a distinct site and the block does not involve a modification of desensitization.     

Soluble ICAM-1, demyelination, and inflammation in multiple sclerosis and acute optic neuritis

We measured sICAM-1 in paired samples of serum and cerebrospinal fluid (CSF) from patients with an attack of multiple sclerosis (MS) (n = 50) and patients with acute monosymptomatic optic neuritis (ON) as a possible first attack of MS were also included (n = 25). Based on calculations of extended indices we found evidence of intrathecal synthesis of sICAM-1 both in patients with clinically definite MS and in patients with idiopathic ON compared to neurological control subjects. The amount of intrathecally synthesized sICAM-1 correlated significantly to the CSF leukocyte count and to the concentration of myelin basic protein in the CSF. The serum concentrations of sICAM-1 were not increased in patients with demyelinating disease compared to the neurological control subjects.     

Determinant spreading associated with demyelination in a nonhuman primate model of multiple sclerosis

Definition of the immune process that causes demyelination in multiple sclerosis is essential to determine the feasibility of Ag-directed immunotherapy. Using the nonhuman primate, Callithrix jacchus jacchus (common marmoset), we show that immunization with myelin basic protein and proteolipid protein determinants results in clinical disease with significant demyelination. Demyelination was associated with spreading to myelin oligodendrocyte glycoprotein (MOG) determinants that generated anti-MOG serum Abs and Ig deposition in central nervous system white matter lesions. These data associate intermolecular "determinant spreading" with clinical autoimmune disease in primates and raise important issues for the pathogenesis and treatment of multiple sclerosis.     

Multiple sclerosis and measles: a study of cellular sensitization

Lymphocyte sensitization to measles has been studied in comparable groups of multiple sclerosis, other neurologic disease and normal subjects. The macrophage electrophoretic mobility test has been used. No difference between the three groups has been found, though there is a small group of children with obscure neurological disease which might well be multiple sclerosis and which fails to mount an adequate response to measles. The role of measles (and other banal infections) in aetiopathogenesis of multiple sclerosis is briefly discussed.     

Multiple sclerosis: use of MRI in evaluating new therapies

11q23 translocations (t(11q23)) are recurring cytogenetic abnormalities in both acute myeloid leukemia (AML) and acute lymphoblastic leukemia, involving the same gene, ALL1 (or MLL). Mixed lineage antigen expression has been reported in these leukemias, but its frequency and clinical significance are unknown. We immunophenotyped leukemia cells from 19 adult de novo AML patients with t(11q23) by multiparameter flow cytometry. Translocations included t(6;11)(q27;q23), t(9;11)(p22;q23), t(9;11;19)(p22;q23;q13.3), t(2;11)(11;17)(q37;q11q23;q11), t(11;17)(q23;q25), t(11;19)(q23;p13.1), t(11;19)(q23;p13.3) and t(11;22)(q23;q11). FAB types were M4 and M5. The committed stem cell and myeloid antigens HLADr, CD4dim, CD11b, CD13, CD15, CD32, CD33, CD38 and CD64 were each expressed in 80-100% of cases, and the early stem cell and lymphoid antigens CD34, CD56, CD3, CD2 and CD7 in 42, 39, 16, 5 and 5%, respectively. Antigen expression frequencies did not differ from those in 443 adequately karyotyped M4 and M5 cases without t(11q23). Fifteen patients (79%) attained complete remission (CR); median CR duration and survival were 10.0 and 15.1 months. CR duration and survival did not correlate with antigen expression. In particular, patients with t(9;11) survived longer than those with other t(11q23) (median not reached vs 7.6 months; P = 0.048), but antigen expression did not differ in the two groups. Thus frequencies of lymphoid antigen expression are similar in AML with t(11q23) and in other FAB M4 and M5 cases, treatment outcome does not differ in t(11q23) cases with and without lymphoid antigen expression, and better outcome of patients with t(9;11) compared to other t(11q23) does not correlate with differences in antigen expression. Mixed lineage antigen expression is not a distinctive feature of AML with t(11q23).     

Multiple sclerosis and the HLA-D region: linkage and association studies

Inheritance patterns of multiple sclerosis (MS) in multiplex families suggest a complex aetiology involving environmental and genetically determined components. The association between the HLA class II DR15, DQ6, Dw2 haplotype and MS has been well documented in patients with ancestral origins in Northern Europe. Conversely, linkage analysis of this region in multiplex families, derived from a population base, has generated negative results. Thus, given the Dw2 specificity association, evidence implicating this locus in disease susceptibility appears contradictory. We have collected and determined the HLA-DR and -DQ haplotypes of 115 sibling pairs with multiple sclerosis, and confirm a significant association with the Dw2-associated haplotype, both in index cases and their affected siblings compared with controls. However, using a sibling pair linkage analysis that restricts haplotype sharing probabilities to defined genetic models, we have not observed linkage of this region to susceptibility in MS. We discuss the basis for association and linkage and conclude that the DR15, DQ6, Dw2 haplotype does represent a susceptibility locus but its contribution to the pathogenesis is small; although it may interact epistatically with other susceptibility genes, this haplotype is not necessary for disease expression.     

Spontaneous and induced remyelination in multiple sclerosis and the Theiler's virus model of central nervous system demyelination

Remyelination in the central nervous system, originally thought to occur rarely, if ever, is now an established phenomena in multiple sclerosis patients. However, the extent of myelin repair is incomplete and limited. Experimental models of central nervous system demyelination provide an opportunity to study the cellular and molecular events involved in remyelination. These models may provide some clue to why remyelination in multiple sclerosis is incomplete as well as suggest potential methods to stimulate central nervous system repair. In this review we examine the morphological aspects of central nervous system remyelination and discuss both spontaneous and induced remyelination in multiple sclerosis and experimental models of central nervous system demyelination. We give special emphasis to the Theiler's virus model of central nervous system demyelination and its usefulness to identify therapeutic agents to promote remyelination. The role of immunoglobulins in promoting remyelination in both the Theiler's model system and in multiple sclerosis is discussed. Finally, we examine the potential physiological role of demyelination and remyelination and its relationship with clinical manifestations of central nervous system disease.     

Multiple sclerosis of the spinal cord: magnetic resonance appearance

OBJECTIVE: To determine the MR appearance of spinal cord multiple sclerosis (MS) plaques in patients presenting with myelopathy by using a high-field (1.5 T) imager. MATERIALS AND METHODS: We studied 119 patients who underwent high-field (1.5 T) MR studies of the spinal cord for evaluation of myelopathy. All 119 patients were thought to have possible findings of spinal cord MS at the time of the MRI interpretation. RESULTS: Sixty-four plaques were studied in 47 patients with clinically definite MS and adequate quality MRI. Of these patients 68% had a single spinal cord plaque, 19% had two plaques, and 13% had three or more plaques. Sixty-two percent of the plaques occurred in the cervical spinal cord and most frequently involved the posterior (41%) and lateral (25%) aspects of the spinal cord. None of the 64 lesions involved the entire thickness of the spinal cord. The lesion length varied from 2 to 60 mm, with 84% of the lesions < 15 mm in length. The spinal cord diameter was unchanged in 84% of plaques, enlarged at the level of the lesion in 14%, and atrophic in 2%. Just over half (55%) of the plaques enhanced with intravenously administered gadolinium. Of the patients who received synchronous head and spinal cord examinations on the same day, 24% had normal findings on the MR study of the head. Follow-up spinal cord studies were available in nine patients. New lesions developed in two patients, while previously described lesions resolved. In three patients only new lesions developed. In four patients no change occurred in the existing number of cord plaques. CONCLUSION: Spinal cord demyelinating plaques present as well-circumscribed foci of increased T2 signal that asymmetrically involve the spinal cord parenchyma. Knowledge of their usual appearance may prevent unnecessary biopsy. An MR examination of the head may confirm the imaging suggestion of spinal cord demyelinating disease, because up to 76% of patients have abnormal intracranial findings. In the remaining 24% of cases in which the clinical diagnosis is not certain and MR findings in the head are negative, a follow-up spinal cord study is recommended, because these lesions evolve and change over time.     

Multiple sclerosis: the role of puberty and the pineal gland in its pathogenesis

Epidemiological studies demonstrate that the incidence of multiple sclerosis (MS) is age-dependent being rare prior to age 10, unusual prior to age 15, with a peak in the mid 20s. It has been suggested that the manifestation of MS is dependent upon having passed through the pubertal period. In the present communication, I propose that critical changes in pineal melatonin secretion, which occur in temporal relationship to the onset of puberty, are intimately related to the timing of onset of the clinical manifestations of MS. Specifically, it is suggested that the fall in melatonin secretion during the prepubertal period, which may disrupt pineal-mediated immunomodulation, may stimulate either the reactivation of the infective agent or increase the susceptibility to infection during the pubertal period. Similarly, the rapid fall in melatonin secretion just prior to delivery may account for the frequent occurrence of relapse in MS patients during the postpartum period. In contrast, pregnancy, which is associated with high melatonin concentrations, is often accompanied by remission of symptoms. Thus, the presence of high melatonin levels may provide a protective effect, while a decline in melatonin secretion may increase the risk for the development and exacerbation of the disease. The melatonin hypothesis of MS may explain other epidemiological and clinical phenomena associated with the disease such as the low incidence of MS in the black African and American populations, the inverse correlation with sun light and geomagnetic field exposure, the occurrence of relapses in relation to seasonal changes and fluctuations in mood, and the association of MS with affective illness and malignant disease. Therapeutically, this hypothesis implies that application of bright light therapy or the use of other major synchronizers of circadian rhythms such as sleep deprivation or application of external weak magnetic fields may be beneficial in the treatment and/or prophylaxis of relapses in the disease.     

Immunohistochemical and genetic evidence of myeloperoxidase involvement in multiple sclerosis

The influence of sampling time on the frequencies of micronuclei, centromere-positive micronuclei and chromosome nondisjunction was investigated in binucleated lymphocytes following treatment with a known clastogen (mitomycin C) or an aneuploidy-inducing agent (vincristine sulfate). Cytochalasin B (6 micrograms/ml) was added 44 h after mitogen stimulation and cultures were harvested 12, 28, 36 and 48 h thereafter. Micronucleated cells and micronuclei were significantly induced by the two treatments at all sampling times. Furthermore, in situ hybridization with an 'all centromeres' probe showed that vincristine-induced micronuclei were prevalently centromere-positive whereas in mitomycin C-treated cultures only a minor fraction of induced micronuclei contained the hybridization signals. Chromosome nondisjunction rates, as measured by in situ hybridization with chromosome 7- and 11-specific alphoid probes, significantly increased following vincristine treatment. Chromosome nondisjunction and total micronucleus frequencies were found to increase with time both in controls and in mutagen-treated cultures, whereas the percentage of centromere-positive micronuclei in the different treatments was not influenced by the sampling time. Our data suggest that even in the presence of 6 micrograms/ml cytochalasin B, the abnormal segregation of binucleated cells may contribute to the baseline level of micronuclei and influence the results obtained. The introduction of a short cytochalasin B treatment (between 12 and 28 h) in the cytokinesis-blocked micronucleus assay may avoid the cytochalasin B effect on micronucleus frequencies.     

The neuregulin, glial growth factor 2, diminishes autoimmune demyelination and enhances remyelination in a chronic relapsing model for multiple sclerosis

Glial growth factor 2 (GGF2) is a neuronal signal that promotes the proliferation and survival of the oligodendrocyte, the myelinating cell of the central nervous system (CNS). The present study examined whether recombinant human GGF2 (rhGGF2) could effect clinical recovery and repair to damaged myelin in chronic relapsing experimental autoimmune encephalomyelitis (EAE) in the mouse, a major animal model for the human demyelinating disease, multiple sclerosis. Mice with EAE were treated with rhGGF2 during both the acute and relapsing phases. Clinically, GGF2 treatment delayed signs, decreased severity, and resulted in statistically significant reductions in relapse rate. rhGGF2-treated groups displayed CNS lesions with more remyelination than in controls. This correlated with increased mRNA expression of myelin basic protein exon 2, a marker for remyelination, and with an increase in the CNS of the regulatory cytokine, interleukin 10, at both the RNA and protein levels. Thus, a beneficial effect of a neurotrophic growth factor has been demonstrated on the clinical, pathologic, and molecular manifestations of autoimmune demyelination, an effect that was associated with increased expression of a T helper 2 cytokine. rhGGF2 treatment may represent a novel approach to the treatment of multiple sclerosis.     

Multiple sclerosis, the great masquerader: an atypical ocular presentation

BACKGROUND: Multiple sclerosis (MS) is the most common chronic disease of the central nervous system and is pleomorphic in it presentations. The optic pathways are frequently involved, and the classic ocular abnormality is optic neuritis. METHODS: A case is presented of a 23-year-old woman in whom optic neuropathy developed and multiple sclerosis was diagnosed by neuroradioimaging, in spite of her lack of awareness of vision loss. RESULTS: The demyelinating lesions in MS may develop anywhere in the visual system and produce a variety of visual defects. Magnetic resonance imaging (MRI) is the most sensitive method for demonstrating these lesions. CONCLUSION: The cause of MS is unknown, but current opinion holds that autoimmunity--perhaps induced by viral infection--is likely to be implicated in its etiopathogenesis. Currently, no method for prevention of MS is known.