Glial transforming growth factor (TGF)-β isotypes in multiple sclerosis: differential glial expression of TGF-β1, 2 and 3 isotypes in multiple sclerosis

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Abstract

We studied glial transforming growth factor (TGF)-β isotype expression in 14 cases of multiple sclerosis. Acute active lesions exhibited selective TGF-β2 immunoreactivity of lesion encircling ramified microglia. In contrast, astrocytes within chronic active white matter lesions expressed all three isotypes. Chronic active lesions which extended into cortex exhibited selective cortical astrocyte TGF-β2 expression. This isotype was also selectively expressed by astrocytes in apparently normal white matter. A similar pattern of glial TGF-β expression was seen in the pathological control, progressive multifocal leukoencephalopathy. The results suggest that TGF-β cytokines are locally expressed in demyelination and that the β2 isotype may be uniquely regulated.

Introduction

The transforming growth factor (TGF)-β family of cytokines are important modulatory molecules which influence: (1) cell proliferation, migration and maturation, (2) tissue repair and scarring, and (3) inflammatory and immune responses (Roberts and Sporn (1990), Roberts and Sporn (1992); Kulkarni et al., 1995; Sawada et al., 1995). Based upon experimental findings in the nervous system, they have been proposed to play a central position in organizing the brain's responses to varied insults (May and Finch, 1992; Finch et al., 1993; Krieglstein et al., 1995). There are three highly homologous isoforms of TGF-β in mammals: TGF-β1, 2, and 3. Despite their structural similarities these isoforms differ in respect to their expression, regulation and function (Roberts and Sporn (1990), Roberts and Sporn (1992); Geiser et al., 1993; Kulkarni et al., 1995; Sawada et al., 1995). Survey studies have described normal neonatal and adult rodent brain TGF-β message and protein cellular distributions (Sawada et al., 1995; Krieglstein et al., 1995; Unsicker et al., 1991; Pelton et al., 1991). In addition, studies in vitro have supported glial TGF-β synthesis and provided some evidence of particular isotype patterns of synthesis by astrocytes and microglia (Danielpour et al., 1989; Constam et al., 1992; daCunha and Vitkovic, 1992).

To date, there have been limited studies of the expression of this cytokine family in the lesions of either experimental allergic encephalomyelitis (EAE) or multiple sclerosis (MS) (Racke et al., 1992; Santambrogio et al., 1993; Woodroofe and Cuzner, 1993; Cannella and Raine, 1995; Johns et al., 1991). Recent studies on the cytokine profiles of T cell lines from patients with MS, on the impact of TGF-β cytokines on encephalogenic T cells harvested from patients with MS and rodents with EAE, and on clinical/pathological findings in EAE provide evidence of their ability to influence the demyelinating diseases (Johns et al., 1991; Kuruvilla et al., 1991; Racke et al. (1991), Racke et al. (1992); Weinberg et al., 1992; Santambrogio et al., 1993; Johns and Sriram, 1993; Mokhtarian et al., 1994; Link et al. (1994a), Link et al. (1994b), Link et al. (1994c), Link et al. (1995); Correale et al., 1995).

We therefore undertook the present, comparative descriptive immunohistochemical, study of the differential glial expression of the TGF-β isotypes, TGF-β 1, 2 and 3, in acute, chronic active and chronic inactive MS lesions (Cannella and Raine, 1995). In addition to internal comparisons within the MS cases, the MS results are compared to those seen in age matched normal control brains and in a pathological control, progressive multifocal leukoencephalopathy (PML), a virally induced demyelinating disease (Esiri and Kennedy, 1992). These studies extend our investigations into the patterns of glial TGF-β isotype expression in pathological processes characterized by reactive astrocytosis, microglial activation and the deposition of soluble components of the immune system (Peress and Perillo, 1995).

Section snippets

Materials and methods

In recent reports, we established that glass affixed sections of tissues fixed in 10% neutral buffered formalin followed by paraffin embedment were preferable to 4% paraformaldehyde fixed, quick frozen or non-fixed, quick frozen sections for demonstrating TGF-β immunoreactivity with the well characterized and highly specific rabbit polyclonal antibodies used in this study (Peress and Perillo (1994), Peress and Perillo (1995)).

Formalin fixed, paraffin embedded blocks of MS lesions were obtained

Multiple sclerosis

Multiple acute active lesions were studied from the single case with acute lesions. These lesions consisted of pale, edematous, centrally demyelinated regions encircled by cellular edges. The cellular edges were composed of an inner aspect rich in swollen macrophages (LCA and HAM 56 positive cells) encircled by a process rich glial boarder containing predominantly ramified LCA positive microglial croglial cells and some soma-rich GFAP positive astrocytes. Perivascular leukocytes, lymphocytes

Discussion

Despite evidence that TGF-β cytokines are important in the pathogenesis of immune mediated demyelination (Johns et al., 1991; Kuruvilla et al., 1991; Racke et al. (1991), Racke et al. (1992); Weinberg et al., 1992; Santambrogio et al., 1993; Johns and Sriram, 1993; Woodroofe and Cuzner, 1993; Mokhtarian et al., 1994; Link et al. (1994a), Link et al. (1994b), Link et al. (1994c), Link et al. (1995); Cannella and Raine, 1995; Correale et al., 1995), there have been only limited studies directed

Acknowledgements

This research was supported by Veterans Administration Merit Grant Funding.

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