Trends in Immunology
OpinionImmunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective
Section snippets
The anatomy of brain immune responses
Immune responses, immune cells and immune-specific tissues are organ specific; examples of this include skin-associated lymphoid tissue (SALT) [8], nasal-mucosa-associated lymphoid tissue (NALT) [9], gut-associated lymphoid tissue (GALT) [10] and the eye-specific immune responses [11]. Regional immune responses result from the need to maintain effective immune surveillance while preserving organ function 12, 13. Although these local lymphoid tissues are certainly important in generating quick
Why are adaptive immune responses not primed after parenchymal brain injections of viral vectors?
The lack of adaptive cellular immune responses to infectious particulate Ags injected into the naive brain can be most easily explained as a consequence of the absence of priming of naive T cells. This results from an anatomical or functional absence of afferent professional Ag-presenting cells (APCs) or dendritic cells (DCs) in the brain (Box 2). Lack of priming of naive T cells following the administration of infectious particulate Ags into the brain parenchyma could be a consequence of: (1)
Gene transfer into different brain compartments: an evolutionary and developmental perspective
The evolutionary appearance of the brain (in amphioxus and cyclostomes) pre-dates the appearance of the adaptive immune system in chondrichthyes by ∼50–100 million years 33, 34, 35 (Fig. 1; Table 1, Table 2). Thus, during its early phylogeny, the brain co-evolved with the phylogenetically older innate immune system. Innate immune mechanisms are present in all animals preceding the cartilaginous fishes 33, 34, 35, as well as in insects and plants [36]. Thus, during the early stages of brain
Does the brain's capacity for Ag presentation change during inflammation?
During brain inflammation, cells displaying immunocytochemical, molecular or functional characteristics of DCs become detectable within the brain parenchyma. The appearance of DCs in the brain parenchyma, in experimental allergic encephalomyelitis (EAE), delayed-type hypersensitivity (DTH) or brain infection, or following the administration of the DC growth factor Flt3 ligand 17, 30, 31, 32, 46, 47, 48, suggests three possible mechanisms. These are: (1) DCs enter the brain after the induction
Conclusion: clinical implications for the use of viruses as gene-therapy vectors for the treatment of brain diseases
This article proposes that the ‘immune privilege’ of the brain is a result of the co-evolution of the brain and the immune system (Fig. 1; Table 1, Table 2), maintained through phylogeny by constraints on the developmental programs (Table 3), as proposed by Gould and Lewontin [1]. This hypothesis is supported strongly by the parallel appearance of immune and nervous structures during ontogeny, following a time-course perfectly compatible with their evolutionary appearance.
The brain walks a
Acknowledgements
I wish to acknowledge the following for critical discussions of the ideas presented in this manuscript: M. Castro, C.A. Janeway, Jr, E. Bell, S. Ali, P. Walden and, especially, H. Lassmann, who has helped shape some of the ideas presented herein. I particularly wish to thank T. Southgate for his creative assistance in translating some of the essential ideas of this manuscript into its pictorial depiction in Fig. 1. I was supported by a Research Fellowship from The Lister Institute of Preventive
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2018, Clinical ImmunologyCitation Excerpt :Injection of an insoluble, particulate antigen into the skin (an organ that contains proper dendritic cells) will induce the stimulation of a systemic adaptive immune response. Careful injection of an identical antigen into the brain parenchyma will fail to induce a systemic adaptive immune response [8,35,75]. We assume that this difference is caused by the presence (skin) or absence (brain) of functional dendritic cells.