Molecular detection and quantitation of the chemokine RANTES mRNA in neurological brain.

Accumulation of T-cells in the brains of patients with neurological disorders prompted a molecular analysis of brain tissue for expression of the chemokine RANTES, which is known to be a T-cell activator and chemoattractant. A fast, sensitive and reproducible technique was developed, based on the polymerase chain reaction and nonradioactive detection. The method could detect and quantitate RANTES in small amounts of brain tissue from all patients with multiple sclerosis, and in some patients with other neural or inflammatory diseases. The data indicate constitutive expression of RANTES in brain from some neurological disorders where its downregulation can have therapeutic benefits.

A single subtype of Epstein-Barr virus in members of multiple sclerosis clusters.

OBJECTIVES: Epidemiological studies strongly indicate an infectious involvement in multiple sclerosis (MS). Epstein-Barr virus (EBV), to which all multiple sclerosis patients are seropositive, is also interesting from an epidemiological point of view. We have reported a cluster of MS patients with 8 members from a small Danish community called Fjelsø. To further evaluate the role of EBV in MS we have investigated the distribution of EBV subtypes in cluster members and in control cohorts. MATERIALS AND METHODS: Blood mononuclear cells were isolated from cluster members, unrelated MS patients, healthy controls, including healthy schoolmates to the Fjelsø cluster patients and finally from persons with autoimmune diseases in order to investigate the number of 39 bp repeats in the EBNA 6-coding region in the EBV seropositive individuals. RESULTS: We observed a preponderance of the subtype with 3 39 bp repeats in the EBNA 6-coding region both in the MS patients and the healthy controls. In the Fjels cluster all 8 cluster members were harbouring this subtype, which is significantly different from the finding in healthy controls (n = 16), which include 8 schoolmates to the cluster members and 8 randomly selected healthy persons (Fischer's exact test P = 0.0047), and also compared to all non-clustered individuals studied (P = 0.017). CONCLUSION: Infection with the same subtype of EBV links together the 8 persons from the Fjelsø cluster who later developed MS. This finding adds to the possibility that development of MS is linked to infection with EBV.

Perivascular T cells express the pro-inflammatory chemokine RANTES mRNA in multiple sclerosis lesions.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS), characterized by accumulation of mononuclear cells. The pathogenesis of MS is complex and probably involves soluble immune mediators, particularly cytokines, and activated memory T cells, that are thought to migrate into the CNS. During lesion formation in MS, cytokines regulate cell functions, such as cell recruitment and migration. Because the chemokine RANTES play a role in both activating and recruiting leucocytes, particularly memory T cells into inflammatory sites, the authors have assessed RANTES mRNA levels at the site of lesions. Expression levels were analysed in brain samples and compared with neurological, infectious and other controls. RANTES was expressed by activated perivascular memory T cells, predominantly located at the edge of active plaques. While RANTES mRNA was detected in all 17 MS brains analysed, it was only found in six of the 14 control patients and generally at a lower expression level. In view of the regulatory and chemotactic properties of RANTES, these results imply that RANTES in MS lesions may play an important role in the activation and/or selective accumulation of memory T cells and, thereby, in the pathogenic events associated with MS.

The implications of Epstein-Barr virus in multiple sclerosis--a review.

The objective of this article is to bring together knowledge about Epstein-Barr virus (EBV) in relation to multiple sclerosis (MS) in order to evaluate its implications in this disease. All MS patients are EBV seropositive, but EBV is not normally detected in the brain. EBV can explain many of the epidemiological dogmas known in MS. In addition, other studies point towards the involvement of EBV in MS. Despite this, other co-actors seem also to be involved. We still need to know whether EBV may be an initiating factor in MS or whether it is a factor in the pathogenesis. Possible ways of EBV involvement are discussed: direct involvement, an autoimmune inducing factor or a transactivating factor. A current treatment study of MS patients with a specific herpes antiviral drug may add further information to the etiology and pathogenesis of MS.

Gamma delta T cell receptor repertoire in brain lesions of patients with multiple sclerosis.

The identification of activated T cells in the brains of patients with multiple sclerosis (MS) suggests that these cells are critical in the pathogenesis of this disease. Recently we have used the PCR method to analyse rearrangements of V alpha and V beta genes of the T cell receptor (TCR) in samples of MS and control brains. The results of these studies showed that TCR V gene usage in MS brains may be restricted and in particular that V beta genes may be preferentially rearranged in certain HLA haplotypes associated with susceptibility to MS. In view of the recent evidence that T lymphocytes bearing the gamma delta chains may have autoreactive potential, we have assessed whether or not such TCR-bearing lymphocytes were also present in chronic MS lesions. TCR V gamma and V delta were analysed by the PCR method using a panel of V gamma and V delta primers paired with C gamma or C delta primers in 12 MS brains, as well as in brain samples of ten normal post-mortem cases and three neurological controls. TCR V gamma-C gamma and V delta-C delta rearrangements were confirmed using Southern blotting and hybridisation of the PCR products with specific C gamma and C delta probes. Only one to four rearranged TCR V gamma and V delta transcripts were detected in each of the 23 brain samples obtained from 12 MS patients, with the majority of gamma delta T cells expressing the V gamma 2 and V delta 2 chains. In marked contrast, V gamma and V delta transcripts could only be found in one of the ten non-neurological control brains analysed. To assess the clonality of V gamma 2 and V delta 2 T cell receptor chains in the brain samples of MS patients, we have sequenced the junctional regions of the TCR V gamma-N-J gamma-C gamma and V delta-N-D delta-N-J delta-C delta segments amplified from brain tissues, CSF and spleens of two MS patients and from the spleen of two control subjects. The sequence analysis obtained so far shows no compelling evidence of an MS specific expansion of one or more clones expressing particular types of gamma delta T cell receptors. In contrast, a clonal expansion of a different population of TCR gamma delta-bearing T cells was found in the spleen of both an MS patient and one of the control individuals.(ABSTRACT TRUNCATED AT 400 WORDS)