Innate and adaptive immune responses in neurodegeneration and repair

Abstract

Emerging evidence suggests important roles of the innate and adaptive immune responses in the central nervous system (CNS) in neurodegenerative diseases. In this special review issue, five leading researchers discuss the evidence for the beneficial as well as the detrimental impact of the immune system in the CNS in disorders including Alzheimer's disease, multiple sclerosis and CNS injury. Several common pathological mechanisms emerge indicating that these pathways could provide important targets for manipulating the immune reposes in neurodegenerative disorders. The articles highlight the role of the traditional resident immune cell of the CNS - the microglia - as well as the role of other glia astrocytes and oligodendrocytes in immune responses and their interplay with other immune cells including, mast cells, T cells and B cells. Future research should lead to new discoveries which highlight targets for therapeutic interventions which may be applicable to a range of neurodegenerative diseases.

Introduction

The central nervous system (CNS) is considered to be immune privileged, implying that non-self antigens that gain access into the CNS are unable to invoke an adaptive immune response. Such shielding of the CNS from the adaptive immune response is aided by the cerebrospinal fluid–blood barrier, blood–brain barrier and blood–spinal cord barrier. In addition, the expression of immune regulatory molecules by cells of the CNS down-regulates T cell function and together with low levels of MHC molecules act to limit immune activation and immune-mediated damage in the CNS. Although the idea of immune privilege was first discussed over 70 years ago^1,2 by Sir Peter Medawar, who was awarded the Nobel Prize with Sir Frank Macfarlane Burnet in 1960 for the discovery of acquired immune tolerance, it is clear that immune privilege is not absolute because immune reactions do, and indeed must, take place to control infections in the CNS.

In recent years the role of the innate and adaptive immune responses in neurodegeneration has become a major focus of neuroimmunologists, not least because of the increasing ageing community. The average life expectancy now extends late into the eighth decade in the Western world, and the prevalence of most neurodegenerative disorders increases dramatically with advancing age. In 2000 the worldwide number of persons with dementia was estimated at 25 million³ and this did not include individuals with neurodegenerative diseases not associated with cognitive decline, such as traumatic brain injury. Although the immune system is crucial for shaping the brain during development, both the nervous and immune systems change with age, implying that loss of regulation of immune responses in the healthy brain is a contributing factor to neurodegeneration. Table 1 illustrates both innate and adaptive immune responses reported to be associated with the damage as well as repair processes in many neurodegenerative disorders. The major challenge in this area is to understand why and how the immune system is activated and the precise roles of the innate and adaptive immune responses in these diseases. Such an understanding will be a key to developing therapeutics targeting the relevant component of the immune system.⁴ In this special review issue, five leading researchers in the field of neuroimmunology relating to neurodegeneration discuss their latest findings and provide an insight into our current understanding of these processes in the CNS.

Table 1.

Innate and adaptive immune responses in neurodegenerative diseases

Disease	Innate immunity	Adaptive immunity	References
ALS	Activated microglia and astrocytes. Increase in complement components. Increased TLR, CD14, RAGE and HMGB1 on reactive glia	Alterations in peripheral levels of CD4+, CD8+ T cells. CD8+ T cells in spinal cord	5
Alzheimer's disease	Expression of cytokines, chemokines and complement in amyloid plaques. Aβ induces innate immune expression in vitro. Microglia aid Aβ clearance	Activation of adaptive immune system against Aβ peptide to aid clearance as a therapeutic approach	6
Epilepsy	Activation of microglia and astrocytes. Up-regulation of CCL3 and CCL4 genes in CNS	Pathogenic role of autoantibodies. CD8+ T cells	7
Multiple sclerosis	NK cells, microglial activation, TLR expression, complement in lesions. Phagocytosis of neuronal debris by macrophages and microglia	Antibodies and T cells to CNS antigens. CD4+ and CD8+ T cells close to neurons	8,9
Neoplastic and PNND	Microglia activation and expression of immune regulatory molecules	Antibodies to neuronal antigens. Elevated numbers of Treg cells, memory T cells and B cells	10,11
NMO	Astrocyte damage, microglia activation, chemokine and cytokine expression	Pathogenic antibodies to AQP4. T cells to AQP4 induce disease in mice	12
Infections	Microglia activation, astrocytosis, increase in innate receptors, complement deposition	Antibodies, T cells, B cells	4
Parkinson's disease	TLR2, TLR5 and CD14 in CNS. Activated NK cells. Microglia and astroglia activation. CD14 and TLR4 in substantia nigra of MPTP animal model	CD4+ T cells infiltrate in CNS	13
Stroke	Up-regulation of TLRs on endothelium, neurons and glia	Bias towards Th2 responses	14
Toxins	Heavy metals induce microglia activation	Autoantibody production, increases in serum IgG and IgE, polyclonal activation of B and T lymphocytes	15,16
Traumatic brain injury	MyD88 involvement in inflammation following TBI, independently of TLR2/4. Induction of pro-inflammatory cytokines	CD4+ and CD8+ T cell infiltration	17

Aβ, amyloid-beta; ALS, amyotrophic lateral sclerosis; CNS, central nervous system; HMGB1, High-mobility group protein B1; MPTP, 1-methyl 4-phenyl 1,2,3,6-tetrahydropyridine; NK, natural killer; NMO, Neuromyelitis optica, PNND, paraneoplastic neurological disorders; RAGE, Receptor for Advanced Glycation Endproducts; TBI, traumatic brain injury; Th2, T helper type 2; TLR, toll-like receptor; Treg cells, regulatory T cells.

A balancing act in the CNS

As with many aspects of the adaptive and innate immune systems, whether these responses are beneficial or detrimental in these neurological conditions depends on the magnitude of the response and the degree to which the responses are regulated in the CNS. During viral infections, immune responses are deemed to be beneficial because infectious virus is eliminated. However, when CNS cells are damaged during the process of viral eradication the responses are clearly detrimental. The immune response is also essential for pruning of neurons by microglia during development, removal of debris and apoptotic cells – all essential for normal homeostasis within the CNS – which must be delicately balanced to prevent unsolicited bystander damage. This balance in part is controlled by regulatory T and B cells as well as by particular subsets of regulatory innate immune cells.

On the one hand, control of adaptive immune function is known to decline with age, raising the possibility that immune control of infections becomes compromised with increasing age. By contrast, during ageing the microglia take on a more inflammatory phenotype referred to as primed, reactive or sensitized. Such sensitization may lead to increased and prolonged activation in the CNS, for example after peripheral infection. The consequence of ageing is therefore increased vulnerability to infections as well as the phenomenon of sickness behaviour and cognitive deficits¹⁸ arising from enhanced activation of the innate immune system.

In this mini-review series on immune responses in neurodegenerative diseases we have collated articles that argue for a beneficial effect of the immune system in CNS injury and neurodegenerative disorders as well as detrimental effects. Manipulating the responses of both the adaptive and innate arms of the immune responses clearly holds great promise for novel therapeutic approaches for neurodegenerative diseases. However, as discussed below and in the mini-reviews, several questions remain to be addressed.

Effector and regulatory T cell networks

A specific subset of T cells is essential in suppressing autoimmunity and maintaining immune homeostasis. Already in the early 1980s the term suppressor T cell was used, yet this terminology fell out of favour in the 1990s. These cells, ‘re-branded’ as regulatory T (Treg) cells have now been extensively characterized, revealing a plethora of markers and functions. Emerging evidence shows that Treg cells are not only important for maintaining immune balance in the periphery but also contribute to self-tolerance and immune privilege in the CNS. However, when an efficient immune response is needed to protect the brain after injury, for example, over-presence of Treg cells may actually contribute to continuous neurodegeneration after CNS injury by inhibiting protective effector T cell responses. In this series, compelling evidence is presented by Jonathan Kipnis for the differing roles of Treg cells in CNS injury and how cautious one should be in designing future therapeutics that are based on manipulation of Treg cells.

Mast cells

Mast cells were identified more than 130 years ago by Paul Ehrlich and are potent effector cells of the innate immune system. Similar to T cells and microglia, discussed above, mast cells are involved in tissue degeneration as well as repair. In multiple sclerosis (MS), mast cell proteases have been shown to degrade specific myelin proteins, suggesting that these cells are involved in the demyelination process. These cells have been shown to aggravate CNS damage in models of brain ischaemia and haemorrhage, impacting on blood–brain barrier damage, and promoting inflammatory responses. In the third review in this series Stephen Skaper points out that mast cells may well provide an under-appreciated peripheral immune signalling link to the brain in an inflammatory setting, by engaging in cross-talk with microglia and astrocytes.

Microglia–T cell interactions

Communication between the immune system and the CNS is exemplified by cross-talk between neurons and microglia reported to be essential for maintaining homeostasis in the CNS. Microglia express numerous cell surface proteins, enabling them to interact with and modulate the activity of neighbouring cells. Several lines of evidence indicate that the maintenance of microglia in a quiescent state relies to some extent on interaction between specific ligand–receptor pairs, for example CD200–CD200R. While microglia are actively modulated by neurons in the healthy brain, disruption of this cross-talk due to infection, ageing and stress may lead to aberrant immune responses in which neurons are vulnerable to excessive neuroinflammation. For example recent evidence indicates that co-incubation of microglia with T helper type 1 cells markedly increases their activation.

Under normal conditions, small numbers of activated T cells gain entry to the brain and are involved in immune surveillance; however infiltration of significant numbers of T cells occurs in disease and following injury. As discussed above, peripheral viral infections may lead to sickness behaviour and cognitive dysfunction. This finding may be relevant to the observation that peripheral infections lead to a deterioration in cognition in patients with Alzheimer's disease. The review by Lynch et al. addresses the modulatory effect of T cells on microglia and the impact of infiltration of T cells into the brain with a focus on Alzheimer's disease, and considers how this might provide a novel therapeutic strategy for Alzheimer's disease and other neurodegenerative disorders.

Oligodendrocyte–microglia cross-talk

As stressed above cell–cell communication is essential in the cross-talk between the immune system and cells of the CNS in normal physiology and in disease. In the paper by Laura Peferoen and colleagues the cross-talk between oligodendrocytes and microglia is reviewed. Oligodendrocytes are essential for the propagation of action potentials along axons and also serve to support neurons by producing neurotrophic factors. In general oligodendrocytes are thought to be the victims in demyelinating diseases such as MS, yet in this paper the immune function of oligodendrocytes is also revealed. These cells express immune receptors and respond to immune activation in the CNS. This paper also reviews the evidence that stress and damage to oligodendrocytes triggers activation of the innate immune system through production of heat-shock proteins such as HSPB5.^9,19 While induction of HSPB5 protects cells from apoptosis, when released by oligodendrocytes in MS it leads to clustering of microglia to form what is termed pre-active MS lesions,²⁰ triggering a cascade of protective and regenerative responses in microglia. The paper discusses how oligodendrocytes may become stressed and the consequences of such microglial activation that triggers progression of disease.

Towards therapeutic modulation of microglia

Polarization of macrophages and microglia into pro-inflammatory and anti-inflammatory phenotypes may underlie their differing functional properties in vitro. Although simplistic, the ability to polarize macrophages and microglia into different phenotypes is thought to hold great promise for modulating responses in neurodegenerative diseases. Extrapolating findings from in vitro studies to disease in vivo is more problematic. For example, intermediate phenotypes are observed in diseased tissues,²¹ indicating that an overlapping spectrum is more realistic and that such quantitative and qualitative differences will occur in the spectrum of neurodegenerative disorders.

One idea to manipulate microglia in vivo is through the transfer of mesenchymal stem cells. In many neurodegenerative diseases the efficacy of therapeutic approaches using stem cells was thought to act by replacing the degenerating cells. More recently studies reveal that stem cells have immune regulatory roles. For example, mesenchymal stem cells were shown to modulate the immune response and protect the CNS mainly through the release of soluble factors;²² in particular, they induce a shift to a neuroprotective phenotype in microglia.²³ Whether such modulation can be applied to neurodegenerative disease, in particular to MS, is the focus of Dr Giunti's paper.

Perspective and questions

The field of immune responses in the CNS has developed in leaps and bounds since the first congress on Neuroimmunology in 1982. Nevertheless, it is surprising that some questions asked in the 1980s are still being asked today. Aside from those questions posed in the mini-reviews we have added a few extra questions and thoughts on the important questions in Neuroimmunology today.

1. What are the targets in autoimmune-mediated neurodegenerative diseases?

2. How relevant are experimental animals to human neurodegenerative diseases?

3. Can T cells be manipulated to become beneficial?

4. Can modulating the innate immune system be a new approach to the treatment of neurodegenerative diseases?

5. What are the molecular mechanisms involved in immune cell–neuron interaction?

6. Is there a common pathway?

In summary, emerging evidence indicates that neurodegenerative diseases may share common pathological mechanisms involving the interplay of innate resident immune cells in the CNS, components of the adaptive immune response, which breach the CNS barriers, together with neurons and glia. The link between the changes in immune responses with ageing and the increased incidence of neurodegenerative diseases in the ageing population could provide important insights into this interplay. Many questions still need to be answered and future research in this field should result in exciting new discoveries that might be relevant to neurodegenerative diseases in general and highlight targets for novel therapeutic strategies.