The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis

doi:10.1016/S0165-5728(00)00233-2

Journal of Neuroimmunology

Volume 107, Issue 2, 24 July 2000, Pages 161-166

https://doi.org/10.1016/S0165-5728(00)00233-2 Get rights and content

Abstract

Autoreactive T cells are a component of the normal immune system. It has been proposed that some of these autoreactive T cells even have a protective function. Recent studies support this notion by demonstrating that (a) myelin basic-protein (MBP-) specific T cells show neuroprotective effects in vivo, and (b) activated antigen-specific human T cells and other immune cells produce bioactive brain-derived neurotrophic factor (BDNF) in vitro. Furthermore, BDNF is expressed in different types of inflammatory cells in brain lesions of patients with acute disseminated leukoencephalopathy or multiple sclerosis. We postulate that the neuroprotective effect of T cells and other immune cells observed in vivo is at least partially mediated by BDNF and other neurotrophic factors. The concept of neuroprotective autoimmunity has obvious implications for the therapy of multiple sclerosis and other neuroimmunological diseases.

Introduction

It has long been known that in health and disease, the immune system and the nervous system are closely linked at different levels. For example, when immune cells attack the nervous system, neuroimmunological diseases arise. Multiple sclerosis and its animal models provide the paradigm for such a deleterious interaction between cells of the immune and nervous system. Experimental autoimmune encephalomyelitis (EAE) can be induced by active immunization with CNS autoantigens [e.g., myelin basic protein (MBP)], or by the transfer of autoantigen-specific T cells into naı̈ve syngeneic recipients (Wekerle et al., 1994). Recently it was demonstrated that MBP-specific T cells may have — seemingly paradoxical — neuroprotective (side-)effects (Moalem et al., 1999, Schwartz et al., 1999). The mechanisms of the neuroprotective effects of T cells and other immune cells are presently unknown.

A different line of research has revealed that unexpectedly, T cells and other cells of the immune system are capable of producing neurotrophic factors (Torcia et al., 1996, Besser and Wank, 1999, Kerschensteiner et al., 1999). Here we propose that the two lines of investigation converge: The observed neuroprotective effects of immune cells may at least partially be mediated by their production and local secretion of neurotrophic factors. This concept would have far reaching consequences for the therapy of neuroimmunological diseases, especially multiple sclerosis.

Section snippets

Evidence for a neuroprotective effect of T cells and other immune cells

Autoimmune T cells have been shown to protect neurons from secondary degeneration after a partial crush injury of the optic nerve (Moalem et al., 1999). In a series of elegant experiments, T cells specific for MBP, ovalbumin (OVA), or a heatshock protein (hsp) peptide were activated with their respective antigens in vitro, and then injected intraperitoneally into rats immediately after unilateral optic nerve injury. Seven days after injury, the optic nerves were analysed immunohistochemically

Evidence for the production of neurotrophic factors by immune cells

Outside the nervous system, several types of immune cells and hematogenic precursor cells have been shown to express one or more neurotrophic factors. For example, nerve growth factor (NGF) is produced by B cells, which also express the trkA receptor and p75 NGF receptor (Torcia et al., 1996). Because neutralization of endogenous NGF caused apoptosis of memory B cells, it was concluded that NGF is an autocrine growth factor for memory B cells (Torcia et al., 1996). NGF has been detected also in

Expression of BDNF in multiple sclerosis lesions

We hypothesize that the neurotrophic effects of immune cells demonstrated in vivo (Moalem et al., 1999, Schwartz et al., 1999) are at least partially mediated by neurotrophic factors ‘imported’ into the CNS by activated immune cells (Besser and Wank, 1999, Kerschensteiner et al., 1999). Are the postulated neuroprotective effects of inflammation relevant to human disease? As a first step to answer this question, we searched for the expression of neurotrophins in inflammatory brain lesions of

Implications for therapy

According to current opinion, the treatment of multiple sclerosis has two major objectives, namely (a) suppression of the inflammatory process, and (b) restoration and protection of glial and neuronal function (Compston, 1994). The potential neuroprotective function of inflammatory cells is relevant to both these treatment goals.

Acknowledgements

Our project is supported by the Deutsche Forschungsgemeinschaft (SFB 217, C13), Hertie-Stiftung (GHS 339/95) and European Community (BMH4-CT96-0893: Immunoregulatory aspects of T cell autoimmunity in multiple sclerosis). The Institute for Clinical Neuroimmunology is supported by the Hermann and Lilly Schilling Foundation.

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Multiple sclerosis is an autoimmune demyelinating disease marked by the involvement of multiple pathophysiological pathways, including BDNF. BDNF (brain-derived neurotrophic factor) is one of the main neurotrophic factors in the adult brain. The amount of BDNF in the blood can be utilized as a surrogate for the central expression of this marker. Given contradicting reports, we set out to answer the question, “How do blood levels of BDNF differ in people with multiple sclerosis (PwMS) compared to controls?”
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At the same time, a large variety of neurotransmitters and trophic factors are present in the CNS that could have implications in MS. Neurotrophins, such as brain-derived neurotrophic factor (BDNF), for instance, regulate many processes such as axonal growth or synaptic plasticity in the CNS (Binder and Scharfman, 2004). Interestingly, not only neurons produce BDNF, but also T and B cells are capable of producing BDNF in active lesions in EAE or MS (Hohlfeld et al., 2000; Kerschensteiner et al., 1999). In the EAE, BDNF protects axons from degeneration, and glatiramer acetate, a well-established immunomodulating drug for MS, promotes BDNF production by lymphocytes and therefore promotes the neuroprotective effect of BDNF (Linker et al., 2010; Ziemssen et al., 2002).
Multiple sclerosis (MS) is an inflammatory demyelinating autoimmune disorder of the central nervous system (CNS) and one of the leading causes of neurological deficits and disability in young adults in western countries. Current medical treatment mainly influences disease progression via immunomodulatory or immunosuppressive actions. Indeed, MS research has been foremost focused on inflammation in the CNS, but more recent evidence suggests that chronic disability in MS is caused by neurodegeneration. Imaging studies show an early involvement of neurodegeneration as brain atrophy and gray matter lesions can be observed at disease onset. Thus, neuroprotective treatment strategies and the elucidation of the molecular mechanisms underlying neurodegeneration in MS have attracted the attention of the scientific community. Experimental autoimmune encephalomyelitis (EAE; the most commonly used animal model for MS), novel in-vivo imaging techniques such as two-photon microscopy and recently discovered molecular changes have offered new insights into the pathogenesis of neuroinflammation as well as neurodegeneration in MS. This review focuses on the interaction between components of the immune system and the neuronal compartment, as well as describing the most important molecular mechanisms that lead to axonal and neuronal degeneration in MS and EAE.
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Neurons are considered the major cellular source of BDNF, however recently it has been demonstrated that activated human T cells, B cells, and monocytes secrete bioactive BDNF in vitro and BDNF production by inflammatory cells is increased upon antigen stimulation (Kerschensteiner et al., 1999; Hohlfeld et al., 2000; Stadelmann et al., 2002; Kerschensteiner and Hohlfeld, 2003; Hohlfeld et al., 2006). Importantly, BDNF secreted by autoreactive immune T cells is bioactive, as it supports neuronal survival in vitro (Hohlfeld et al., 2000). These new findings suggest the possibility that TBX21-mediated suppression of Th1 inflammation linked with activation of neurotrophic factors are part of the mechanism terminating the relapse and the switch to clinical remission.
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The neuroprotective effect of inflammation: implications for the therapy of multiple sclerosis

Abstract

Introduction

Section snippets

Evidence for a neuroprotective effect of T cells and other immune cells

Evidence for the production of neurotrophic factors by immune cells

Expression of BDNF in multiple sclerosis lesions

Implications for therapy

Acknowledgements

Immunol. Today

J. Neuroimmunol.

Cell

Am. J. Pathol.

Trends Neurosci.

Trends Neurosci.

Trends Pharmacol. Sci.

Trends Neurosci.

Cell

J. Neuroimmunol.

Trends Neurosci.

Activated macrophages and microglia induce dopaminergic sprouting in the injured striatum and express brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor

J. Neurosci.

Clonally restricted production of the neurotrophins, brain-derived neurotrophic factor and neurotrophin-3 mRNA by human immune cells and Th1/Th2-polarized expression of their receptors

J. Immunol.

Future prospects for the management of multiple sclerosis

Ann. Neurol.

Expression of nerve growth factor and nerve growth factor receptor tyrosine kinase Trk in activated CD4-positive T-cell clones

Proc. Natl. Acad. Sci. USA

Axonal damage in acute multiple sclerosis lesions

Brain

Gene transfer into CD4+ T lymphocytes: Green fluorescent protein engineered, encephalitogenic T cells used to illuminate immune responses in the brain

Nature Med.

Adenoviral gene transfer of ciliary neurotrophic factor and brain-derived neurotrophic factor leads to long-term survival of axotomized motor neurons

Nature Med.

Regional distribution of brain-derived neurotrophic factor mRNA in the adult mouse brain

EMBO J.

Biotechnological agents for the immunotherapy of multiple sclerosis. Principles, problems and perspectives

Brain

Activated human T cells, B cells and monocytes produce brain-derived neurotrophic factor (BDNF) in vitro and in brain lesions: A neuroprotective role of inflammation?

J. Exp. Med.

Gene transfer into CD4⁺ T lymphocytes: Green fluorescent protein engineered, encephalitogenic T cells used to illuminate immune responses in the brain