Dendritic cells and immune responses in the central nervous system.

Response from LowensteinThe letter by Pashenkov and Link identifies the aim of my article correctly [1xImmunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective. Lowenstein, P.R. Trends Immunol. 2002; 23: 23–30Abstract | Full Text | Full Text PDF | PubMed | Scopus (89)See all References[1]. My article suggests an evolutionary hypothesis to explain the lack of dendritic cells (DCs) in the brain, in terms of the evolutionary appearance of brain and immune structures, and the very late evolutionary appearance of the adaptive immune response and thus, DCs. Furthermore, this theory is supported by the fact that, as predicted, the developmental program that can be observed today mimics closely the evolutionary program, which can be inferred only from available records. A recently published review provides a further state-of-the-art, comprehensive overview of DCs in the central nervous system (CNS) [2xDendritic cells in the central nervous system. Aloisi, F. et al. : 371–387CrossrefSee all References[2].Pashenkov and Link propose that a virus previously sequestered in the brain parenchyma that is released into the cerebrospinal fluid (CSF) could lead to an antiviral immune response, with bystander damage to myelin in the brain. This is indeed possible, but a careful assessment of ‘bystander’ damage will need to monitor the specificity of the T cells invading the CNS. Any damage to myelin would not necessarily have to be due to a bystander mechanism. Indeed, the virus released into the CSF would activate the innate immune system per se. Such innate-immune activation combined with the presence of circulating myelin proteins, which are thought to be released normally at very low levels, could lead to an anti-myelin immune response [3xImmunology taught by viruses. Zinkernagel, R.M. Science. 1996; 271: 173–178Crossref | PubMedSee all References, 4xHow the immune system works to protect the host from infection: a personal view. Janeway, C.A. Jr. Proc. Natl. Acad. Sci. U. S. A. 2001; 98: 7461–7468Crossref | PubMed | Scopus (181)See all References, 5xInnate immune induction of the adaptive immune response. Medzhitov, R. and Janeway, C.A. Jr. Cold Spring Harbor Symp. Quant. Biol. 1999; 64: 429–435Crossref | PubMedSee all References].Why then, do DCs ‘appear’ in the brain during inflammation (reviewed in Ref. [1xImmunology of viral-vector-mediated gene transfer into the brain: an evolutionary and developmental perspective. Lowenstein, P.R. Trends Immunol. 2002; 23: 23–30Abstract | Full Text | Full Text PDF | PubMed | Scopus (89)See all References[1])? My article details all possible scenarios (whether their origin is endogenous or exogenous to the brain), and the letter by Pashenkov and Link identifies several pertinent molecular questions that will have to be addressed in the near future. Thus, although it will be crucial to identify the origin of the DCs and the mechanisms that lead them into the brain, even more importantly, we will need to reveal their fate – do they stay in the brain and undergo apoptosis as do many T cells in the brain [6xT-cell apoptosis in autoimmune diseases: termination of inflammation in the nervous system and other sites with specialized immune-defense mechanisms. Gold, R. et al. Trends Neurosci. 1997; 20: 399–404Abstract | Full Text | Full Text PDF | PubMed | Scopus (147)See all References[6] or are they able to leave the brain parenchyma proper to stimulate naive T cells in lymph nodes. Although it might be more straightforward to study the migration of DCs from the brain [7xDisproportionate recruitment of CD8? T cells into the central nervous system by professional antigen-presenting cells. Carson, M.J. et al. Am. J. Pathol. 1999; 154: 481–494Abstract | Full Text | Full Text PDF | PubMedSee all References[7], demonstrating the necessary and characteristic function of brain-parenchyma-derived DCs in vitro still poses formidable technical challenges that must be met. For example, any removal of DCs from the brain for their subsequent testing in vitro (i.e. to determine whether they are able to stimulate naive T cells) could easily lead to contamination with ventricular or meningeal DCs.Finally, Pashenkov and Link raise the interesting point of the release of myelin-basic-protein-like material into the CSF during multiple sclerosis, head trauma and stroke. This raises another important point touched upon in my article; namely, the existence of autoimmune myocarditis in a large percentage of patients with heart infarcts [8xExperimental autoimmune myocarditis produced by adoptive transfer of splenocytes after myocardial infarction. Maisel, A. et al. Circ. Res. 1998; 82: 458–463Crossref | PubMedSee all References, 9xCytotoxic T lymphocytes are activated following myocardial infarction and can recognize and kill healthy myocytes in vitro. Varda-Bloom, N. et al. J. Mol. Cell. Cardiol. 2000; 32: 2141–2149Abstract | Full Text PDF | PubMed | Scopus (77)See all References, 10xThe postcardiac injury syndromes. Khan, A.H. Clin. Cardiol. 1992; 15: 67–72Crossref | PubMedSee all References], but the complete absence of any autoimmune-disease consequences in patients suffering head trauma, stroke, brain tumors or brain surgery. Thus, even if potentially immunogenic epitopes are released into the brain in these circumstances, they do not appear to lead to priming of an immune response. The mechanisms underlying these phenomena might relate to the high concentration of immunosuppressants (e.g. transforming growth factor β) in the CSF and brain. The mechanisms that determine whether or not the injection of antigens and/or therapeutic gene-transfer vectors into the brain parenchyma or ventricular compartment will elicit immune priming and immune responses remain to be determined.