CD1A and CD1E gene polymorphisms are associated with susceptibility to multiple sclerosis.

Multiple sclerosis (MS) is thought to be an autoimmune T-cell-mediated disease directed at myelin antigens of the central nervous system. Besides myelin proteins, lipid components of CNS are supposed to play a role as antigens for T cells in MS. CD1 is a family of MHC-like glycoproteins specialized in capturing and presenting a variety of microbial and self lipids and glycolipids to antigen-specific T cells. CD1-restricted T cells specific for gangliosides and sulfatide have been isolated from subjects with MS and in mice with experimental allergic encephalopathy. We genotyped exon 2 of CD1A and CD1E in 205 MS patients and 223 unrelated healthy controls and determined their association with the presence of anti-ganglioside and anti-sulfatide antibodies. CD1E 01-01 is associated with a reduced risk of MS (OR 0.54, p=0.001); CD1A 02-02 (OR 1.99, p=0.012) or CD1E 02-02 (OR 2.45, p=0.000) with an increased risk. The combination of the genotypes CD1A 02-02 and CD1E 02-02 is present in 90.7% of patients but in only 9.4% controls (OR 94.16, p= 0.000). CD1A and CD1E polymorphisms contribute to the polygenic susceptibility to MS. The functional effects of CD1 polymorphisms are unknown, however changes in CD1 alleles may affect numerous immunological functions.

Antibodies to ganglioside complexes in Guillain-Barré syndrome: clinical correlates, fine specificity and complement activation.

In the Schwann cells and neuronal plasma membranes the gangliosides are organized in clusters forming complexes of gangliosides in the microdomains termed lipid rafts. We investigated frequency, clinical correlates, fine specificity and pro-inflammatory properties of antibodies to ganglioside complexes (GSCs) in a Guillain Barre syndrome (GBS) population. In 63 patients with different GBS variants we performed an ELISA for antibodies to Campylobacter Jejuni (C. jejuni), gangliosides and GSCs. We studied the fine specificity of antibodies to GSCs by immunoabsorption study and performed a complement activation assay. Twenty-seven percent of patients had antibodies to GSCs and 71 percent had antibodies either to single gangliosides or to GSCs. Patients with antibodies to GSCs had more frequent involvement of cranial nerves but did not present more frequent antecedent respiratory, gastrointestinal or C. jejuni infection, did not have a preferential demyelinating or primary axonal GBS variant and did not develop greater disability at six months. The absorption study showed in 2 sera that antibodies to the complex GD1a/GD1b did not react with the gangliosides forming the complex or other single gangliosides, suggesting that antibodies to GSCs are targeted to new conformational glycoepitopes different from the ones displayed by the single gangliosides. Antibody anti-GSCs activated the complement more frequently than antibodies to single gangliosides. Complement activation indicates that antibodies to GSCs have high avidity, pro-inflammatory properties and may exert a pathogenic role in GBS.

T cell response in acute motor axonal neuropathy.

There is evidence that in the acute axonal motor neuropathy (AMAN) subtype of Guillain-Barré syndrome antibodies to gangliosides, produced through molecular mimicry by antecedent Campylobacter jejuni (C. jejuni) infection, attack gangliosides expressed in human peripheral nerve axolemma, inducing a primary axonal damage. The aim of this study is to investigate whether the T cell response has a role in AMAN pathogenesis. We isolated monocytes from 4 healthy subjects and 5 AMAN patients with antecedent C. jejuni infection and antibodies to GM1 and/or GD1a gangliosides. Immature dendritic cells expressing CD1 molecules cultured with autologous T cells were stimulated with 2 lipopolysaccharides (LPSs) extracted from C. jejuni strains containing GM1 and GD1a-like structures and with GM1 and GD1a. The T cell response to LPSs and to gangliosides was determined by measuring the release of IFN-gamma and TNF-alpha. We observed a T cell response to both LPSs in controls and AMAN patients, whereas only AMAN patients showed T cell reactivity to gangliosides GM1 and GD1a with a tight correlation between T cell reactivity to the ganglioside and individual antibody responses to the same ganglioside. T cells responding to gangliosides were CD1c-restricted CD8 positive and CD27 negative. These findings indicate a contribution of cellular immunity in the pathogenesis of AMAN. A possible role for ganglioside-reactive T cells might be to facilitate the production of antibodies against gangliosides.

Isolated shoulder palsy due to cortical infarction: localisation and electrophysiological correlates of recovery.

The corticospinal tract influences the distal musculature more than the proximal, and the mechanisms involved in recovery of proximal muscle strength after stroke are unclear. A 65 year old man developed right shoulder weakness due to infarction in the left precentral gyrus. MRI showed a 3 mm cortical-subcortical ischaemic lesion in the superior genu of the left precentral gyrus medially to the knob-like structure corresponding to the motor area of the hand. Two months after stroke, when the patient was able to abduct the right arm against gravity and seven months after stroke when the patient had almost completely recovered, maximal TMS of the contralateral and ipsilateral motor cortex during voluntary contraction did not evoke a MEP in the right deltoid either with a focal or a non-focal coil. Recovery of proximal muscles in these cases may be mediated by elements other than the fast corticospinal neurones responsible for MEP generation.

CD1a and CD1e allele frequencies in an Italian population from the Abruzzo region.

CD1 is a small family comprising 5 MHC-like genes located on chromosome 1 and encoding glycoproteins termed CD1a, CD1b, CD1c, CD1d and CD1e. They are expressed mainly on the surface of dendritic cells, monocytes and some thymocytes and are specialized in presenting lipid antigens to T lymphocytes. The structure is similar to that of MHC class I molecules with 3 globular domains and the Beta2-microglobulin. It has been shown that all five human CD1 genes exhibit a limited number of polymorphisms in the alpha1 domain whose effects are still unknown. CD1e results to be the most polymorphic isoform with six CD1e alleles (01, 02 in exon 2 and 03, 04, 05, 06 in ex3) described to date. At this moment, few investigations on the allele frequencies of the CD1 genes have been reported and all additional information improves our knowledge on this new class of antigen-presenting molecules. In order to study possible allelic variations of exon 2 of human CD1a and CD1e genes, we analyzed, by a sensitive technique, the sequence-based typing (SBT), 114 DNA samples from unrelated healthy Italian individuals from the Abruzzo region. Our experimental findings indicate that the allele frequency distribution of both CD1a and CD1e genes is in accordance with that observed in other geographic areas and did not identify any new allele, thus confirming a very low polymorphism.

Decreased integrin gene expression in patients with MS responding to interferon-beta treatment.

Interferon-beta (IFN-beta) ameliorates disease course in a subset of patients with MS. The reasons for heterogeneity of clinical responses, however, are unclear. We assessed possible effects of IFN-beta on the gene expression of the leukocyte adhesion molecules VLA-4 and LFA-1 during the first year of treatment of 50 patients with relapsing-remitting MS who showed differential clinical responses. We observed a significant reduction of VLA-4 (P=0.002) and LFA-1 (P=0.03) mRNA expression compared to baseline in first-year clinical responders (n=22). In contrast, first-year IFN-beta non-responders (n=28) had unchanged levels of VLA-4 and LFA-1. In vitro treatment of PBMC with IFN-beta indicated a direct effect on transcription of the integrins' genes. Transcriptional downmodulation of adhesion molecules during IFN-beta treatment may contribute to its mode of action in MS.

Inter-nerves and intra-nerve conduction heterogeneity in CMTX with Arg(15)Gln mutation.

OBJECTIVE: In X-linked Charcot-Marie-Tooth disease (CMTX), electrophysiological and histopathological studies have suggested either a demyelinating or an axonal polyneuropathy. We report a CMTX family with a striking heterogeneity of nerve conductions between and within nerves. METHODS: Two men and one woman have been studied by conduction velocities, sural nerve biopsy with morphometry (one man) and DNA analysis. RESULTS: In both men motor conduction velocities were slowed in the demyelinating range, conduction velocity differences among nerves in the same subject varied from 13 to 24 m/s, and distal median compound muscle action potential (CMAP) amplitudes were 3-5 times reduced compared to ulnar CMAPs. Abnormal area reduction or excessive temporal dispersion of proximal CMAP was present in at least two nerves in all patients. Sural nerve biopsy showed reduction of large myelinated fibres, cluster formations, occasional onion bulbs. Teased fibres study revealed short internodes for fibre diameter, enlarged Ranvier nodes but no evidence of segmental demyelination and remyelination. DNA analysis showed an Arg(15)Gln mutation in connexin32 gene in all patients. CONCLUSIONS: In this family conduction slowing and segmental conduction abnormalities, in absence of morphological evidence of de-remyelination, may be related to short internodes, widened Ranvier nodes and the specific effect of the mutation. The occurrence in some CMTX patients of a non uniform involvement between and within nerves, as in acquired demyelinating neuropathies, should be kept in mind to avoid misdiagnoses.

Acute motor conduction block neuropathy Another Guillain-Barré syndrome variant.

OBJECTIVE: To report two patients with an acute exclusively motor neuropathy with conduction blocks. METHODS: Serial electrophysiologic studies were carried out. RESULTS: Two patients developed symmetric proximal and distal weakness without sensory abnormalities after enteritis. Tendon reflexes were normal in one patient and brisk in the other. One patient had high titer immunoglobulin G to GD1a and GM1, and the other to GD1b, GD1a, and GM1 and a recent Campylobacter jejuni infection. Electrophysiology showed early partial motor conduction block in intermediate and distal nerve segments, normal sensory conductions even across the sites of conduction block, and normal somatosensory evoked potentials. Conduction blocks resolved in 2 to 5 weeks without excessive temporal dispersion of proximal motor responses. CONCLUSIONS: Acute motor neuropathy with normal or brisk tendon reflexes, conduction block, and fast recovery appears to be a variant of Guillain-Barré syndrome. Conduction block may result from immune-mediated conduction failure at the nodes of Ranvier without demyelination.