Neurons Control Brain Immunity: Neurotrophins As Regulators Of Antigen-Presentation In Microglial Cells

June 08, 1998

Antigen presentation in the context of major histocompatibility complex (MHC) molecules is a seminal step in the initiation of specific immune responses. These proteins lack in the healthy brain rendering it a partially "immune privileged site". The reasons for this immunological peculiarity of the brain are thus far unknown. Recent work from Hartmut Wekerle's department at the Max Planck Institute of Neurobiology (in Martinsried/Germany) published in the PNAS (Neumann H., Misgeld T. et al., PNAS, 1998, 95 [10]: 5779-5784) shows that neurons might be a key player in this regulatory process by down-regulating MHC class II molecules in neighbouring microglial cells. The data suggest that neurotrophins acting via their p75 receptor are involved in this process, demonstrating an immunological function for these signalling molecules.

MHC class II antigens are dimeric glycoproteins, which are loaded with pathogen derived antigenic peptides within so called antigen-presenting cells (APCs). The exposure of MHC-antigen complexes on the surface of APCs and their recognition by T cell antigen receptors is one of the initiating events of a specific immune response. Astonishingly these important immune molecules that can be found constitutively in most tissues of the body lack in the normal central nervous system. Only under pathological conditions they are induced, most prominently in microglial cells that represent the major APC of the brain. Not only inflammatory lesions to the brain can initiate this state of increased "immune responsiveness" but also neurodegenerative conditions of many kinds.

Using explant cultures of neuronal tissue and a confocal laser scanning microscopy based image quantification approach, Harald Neumann, Thomas Misgeld, Kenji Matsumoro and Hartmut Wekerle from the Max Planck Institute of Neurobiology at Martinsried/Germany were able to shed some light on the processes underlying the specific regulation of antigen presentation in the brain (PNAS, 1998, 95 [10]: 5779-5784). In hippocampal slice cultures, MHC class II antigens lacked under unstimulated conditions and were barely inducible by the strong pro-inflammatory cytokine interferon gamma.

In contrast, after pharmacological interference with normal neuronal action potential generation, e.g. by paralysing neurons with the neurotoxin tetrodotoxin, the ability of interferon-gamma to induce MHC class II antigens in surrounding microglia cells was strongly increased. External application of the neurotransmitter glutamate was able to counteract this effect of action potential blockage.

Experiments on microglial cells in isolated culture confirmed that these pharmacological interventions act by modulation of neuronal activity rather than direct action on microglial cells, as both, inhibitors of neuronal signalling as well as glutamate, did not show any activity in the absence of neuronal cells.

Further experiments addressed the question which nerve cell derived mediator could be involved in the activity-related down-regulation of microglial immune responsiveness. Neurotrophins were strong candidates, as their release is enhanced by neuronal activity. Indeed, neurotrophins, including nerve growth factor (NGF), brain derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) were found to reverse the inducibility of MHC class II molecules in microglia after action potential blockage in tissue cultures. As demonstrated by blocking experiments with antibodies against the p75 neurotrophin receptor, this specific receptor molecule is involved in down-regulating the MHC class II loci. Further experiments confirmed that at least NGF, but to a lesser degree also NT-3, can directly inhibit MHC class II expression in isolated microglia cells via the p75 receptor.

The data presented by Harald Neumann and colleagues fit into an emerging model of activity controlled immune regulation in brain tissue. Previous reports from this group showed that also in neurons themselves and in a second major group of glial cells, the astroglia, neuronal activity down-regulates antigen presentation. This may explain why diverse damage to neuronal cells, including primary neurodegenerative processes like Alzheimer's disease, can be accompanied by secondary immune pathology in the surrounding brain parenchyma. These results raise the question in how far immunological mechanisms might be involved in maintenance and progression of neurodegenerative disease and whether interference with ongoing immune responses might modulate their natural history. The involvement of neurotrophic factors and their receptors gives a clue to an attractive site of possible experimental intervention.


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