Toxic effector molecules in the pathogenesis of immune-mediated disorders of the central nervous system
A growing body of evidence supports the notion that inflammatory reactions in the central nervous system (CNS) are not only restricted to established immune mediated disorders, such as multiple sclerosis, but also contribute to the pathogenesis of Alzheimer’s disease and other types of neurodegenerative disorders. The biological roles of toxic mediators, such as nitric oxide, reactive oxygen species, as well as complement and proteases in the genesis of inflammatory reactions in the CNS are reviewed within the context of demyelination and neuronal damage.
The central nervous system (CNS) has lonb been regarded as a site of immunologic privilege in the past. This concept was based on the assumptions that (i) an anatomically tight interface between neural parenchyma and blood vessel wall, the so called blood-brain barrier (BBB), forms a strict separation between the nervous system and the systemic immune compartment, and that(ii) other immunologic mechanisms such as the expression of major histocompatibility complex (MHC) molecules, T cell surveillance, and lymphatic drainage are not operating in the brain. During recent years evidence has been accumulated suggesting that these notions ae no longer justified. We know that immune mediators present in the nervous system are recruited from the systemic lymphoid organs, and that endogenous cells of the nervous system, such as astrocytes and microglia, play key roles in regulationg immunologic processes in situ. The model in which an aberrant immune response as a causative mechanism in neurologic diseases has been extensively studied is known as experimental autoimmune encephalomyelitis (EAE). While it reproduces essential aspects of the pathogenesis of human multiple sclerosis (MS) (Swanborg, 1995), it was also intrumental in recognizing basic features of the immune system’s organization (Wekerle et al., 1994).
EAE is an inflammatory disorder of the CNS. It can be actively induced by immunization with various CNS proteins, or adoptively transferred by injection of activated encephalitogenic T cells specific for these antigens in susceptible rodents (Swanborg, 1995; Wekerle, 1993). The histomorphologic hallmark of EAE, and of MS, is the presence of perivascular inflammatory infiltrates, mainly consisting of T cells and macrophages, the latter being regarded as the most important effector cells in immune-mediated demyelination (Lassmann et all., 1991; Raine, 1992). Once activated in the periphery. circulating T cells need to cross the BBB in order to initiate a local immunoinflammatory response within the nervous system, This mechanism of transsendothelial migration is a multistep process occurring in an ordered sequential fashion, involving a complex interaction of various molecules. such as adhesion molecules, cytokines, and chemokines (Bianchi et al,. 1997; Hartung, 1994). Once in the nervous sytem, T lymphocytes undergo local reactivation and clonal expansion if they encounter a microglial cell that displays antigenic epitopes in the context of major histocompatibility complex (MHC) class II molecules and the simultaneous delivery of additional costimulatory signals (Hartung and Rieckmann, 1997). These CD4+ T cells can differentiate into two types of effector T cells: (a) inflammatory T cells (TH1) that activate macrophages/microglia to increased phagocytic activity and synthesis of inflammatory mediators by releasing the pro-inflammatory cytokines tumor necrosis factor-α (TNF-α) and interferon-γ (IFN-γ); (b) helper T cells (TH2) that activate specific B cells to produce antibodies, but also syntesize down-regulatory, anti-inflammatory cytokines, such as transforming growth factor-ß, Interleukin-4 (IL-4)and IL-10.
As mentioned before, macrophages and microglia cells play a pivotal role in the inflammatory response within CNS: These cells act as antigen presenting cells and are of critical importance in the amplification and effector convert into potent effector cells of the immunologic response, activated by release of pro-inflammatory cytokines and highly toxic mediators such as nitric oxide, reactive oxygen species, and proteases (Fig. 1). Given their microbicidal properties, release of these mediators is of paramount importance in host defense, however they are also toxic to host cells. Thus, tight regulation of macrophage activity by inflammatory T cells allows the specific deploymet of this effective intrumentarium, minimizing the expense of tissue damage.
KeywordsMultiple Sclerosis Experimental Autoimmune Encephalomyelitis Myelin Basic Protein Myelin Oligodendrocyte Glycoprotein Multiple Sclerosis Plaque
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