T-cell receptor Vβ gene usage in CSF lymphocytes in X-linked adrenoleukodystrophy

Abstract

X-linked adrenoleukodystrophy (ALD) is a peroxisomal disorder with impaired very-long-chain fatty acid (VLCFA) metabolism that produces a neurological disease with significant variability of clinical phenotypes even within kindred. The two most common forms are the cerebral form (CALD) with an important inflammatory reaction at the active edge of demyelinating lesions, resembling some aspects of multiple sclerosis pathology, and adrenomyeloneuropathy (AMN), which involves the spinal cord and in which the inflammatory reaction is mild or absent. One hypothesis is that the phenotypic variability is related to T cell-mediated immune mechanisms playing a primary role in the demyelinating pathogenic process of CALD. The present study aims to test the hypothesis that CSF of patients with the CALD form contains highly restricted T cell populations. The variable regions of the T cell receptor beta chains (TCR Vbeta) were studied in CSF from 29 ALD patients with different phenotypes. RNA was extracted and cDNA synthesized from CSF lymphocytes; TCR Vbeta gene segments were amplified from the cDNA by polymerase chain reaction (PCR) using 20 family-specific primers. PCR products were analyzed by Southern blot. Some amplified Vbeta products were sequenced. The majority of ALD patients (21/29), whatever their phenotype, exhibited oligoclonal T cell expansion. However the overexpression of some TCR Vbeta families was heterogeneous among the different patients without any preponderance of specific Vbeta families or any clustering according to clinical phenotype. In particular a dominant TCR Vbeta utilization was not found in patients with CALD.

Oligodendroglial impact on axonal function and survival – a hypothesis

“…Only few B cells were detected in post-mortem brains [27]. The analysis of cerebrospinal fluid (CSF) revealed in most patients with cerebral X-ALD oligoclonal T-cell expansion, similar to findings in MS patients [28,29].…”

Pathoetiology of multiple sclerosis: are we barking up the wrong tree?

“…While the author recognizes the fundamental differences between adrenoleukodystrophy and MS, this leukodystrophy and its variants are particularly instructive on a number of levels. The majority of adrenoleukodystrophy patients exhibit oligoclonal expansion of T cells [62], much like the oligoclonal T cell expansion found in MS brain [63]. Such T cell expansion in MS lesions is interpreted as a sign of antigen-specific activation, and therefore evidence of an autoimmune process [64]; this conclusion is undoubtedly correct.…”

Pathogenic CD8+ T cells in multiple sclerosis

“…The prominent inflammation in Pex5 mutants might be a sign that peroxisomes normally control lipid inflammatory mediators 70. Similarly, humans with X‐linked adrenoleukodystrophy, caused by mutations of the ABCD1 gene, which encodes a peroxisomal transporter, show infiltration by myelomonocytic and especially CD8 + T cells, which are expanded oligoclonally in the CSF 71. In addition, globoid cell leukodystrophy (Krabbe's disease; caused by galactocerebroside β‐galactosidase mutations72) is equally associated with lymphocyte infiltrates in the CNS.…”