Inflammation in the nervous system: The human perspective

Abstract

Many basic aspects of brain inflammation, recently disclosed in experimental models, are reflected in the pathology of human inflammatory brain diseases. Examples include the key role of T lymphocytes in immune surveillance and in the regulation of the inflammatory response, the essential contributions of adhesion molecules, proinflammatory cytokines, chemokines, and proteases in the recruitment of inflammatory cells into the nervous tissue, the modulating effect of glia cells on the inflammatory process and the termination of T-cell-mediated inflammation by apoptotic cell death. Despite this progress in our understanding of the pathogenesis of brain inflammation, there are still major unresolved questions. Because of technical constraints, most of our knowledge on central nervous system inflammation so far relates to the role of a specific T-cell subset, the so-called T-helper-1 cells. Other T-cell subsets, in particular cytotoxic class I MHC-restricted T lymphocytes, however, appear to be of major importance in human disease. Furthermore, the detailed mechanisms, which are responsible for the profound differences in the patterns of tissue damage in different human inflammatory brain diseases, such as multiple sclerosis or various forms of virus encephalitis, are largely unresolved. We discuss the open questions to be addressed in the future, which, when answered, may help to design novel therapeutic strategies.

5-Aminoimidazole-4-Carboxamide Ribonucleoside: A Novel Immunomodulator with Therapeutic Efficacy in Experimental Autoimmune Encephalomyelitis

“…The Th1 CD4 ϩ T cells reactive to myelin produce the proinflammatory cytokines (IFN-␥ and TNF-␣) that are crucial in orchestrating an immunopathological cascade, mediating the damage to the myelin sheath and eventually the axon (4,34,35). In this study, we present data showing AICAR as a novel immunomodulatory agent with beneficial effects on EAE disease.…”

Phagocytosis of apoptotic inflammatory cells by microglia and its therapeutic implications: Termination of CNS autoimmune inflammation and modulation by interferon‐beta

“…Inactivation of inflammatory T-cells by apoptosis is a potent mechanism in the clearance of an autoimmune inflammatory infiltrate from the CNS leading to the elimination of bystander T-cells as well as autoantigenspecific T-cells (Gold et al, 1997;Bauer et al, 2001;Pender and Rist. 2001).…”

“…Apoptosis of T-lymphocytes also occurs in inflammatory human brain lesions, most prominently in the acute monophasic disease acute disseminated leukoencephalomyelitis (ADEM) (Bauer et al, 1999) and to a lesser extent in active MS lesions (Ozawa et al, 1994). The high degree of T-cell apoptosis in the inflamed rodent (EAE) and human CNS (ADEM) with approximately 30 -50% of all invading T-cells undergoing apoptosis highlights the importance of the local apoptotic destruction of these unwanted inflammatory cells in the termination of CNS inflammation (Gold et al, 1997;Bauer et al, 2001).…”

In Vitro Activation of CD8 Interphotoreceptor Retinoid-Binding Protein-Specific T Cells Requires not only Antigenic Stimulation but also Exogenous Growth Factors

“…Ϫ/Ϫ DBA/1 mice to myelin oligodendrocyte glycoprotein (MOG)-induced experimental allergic encephalomyelitis (EAE), and that depletion of CD8 T cells reduces demyelination, the major pathogenic process of the disease (12), that NOD mice backcrossed to MHC class I-deficient, ␤ 2 -microglobulin (␤ 2 m) gene knockout mice do not develop insulitis or diabetes (13)(14)(15), and that CD8 cells within the insulitis lesions are highly activated and contain abundant cytotoxic granules with granzyme B immunoreactivity (16). CD8 pathogenic T cells have also been shown to be more potent than CD4 T cells in causing disease progression (9).…”