Occurrence of T cells in the brain of Alzheimer's disease and other neurological diseases
Introduction
The brain is an immunologically unusual organ. A paucity of immune reaction in the brain was suggested by the early observation that the heterologous tissues transplanted into the brain survived much longer than those transplanted into the periphery Medawar, 1948, Barker and Billingham, 1977. In the classic model of immune privilege in the brain, the presence of the blood–brain barrier (BBB) was considered to prevent influx of both cellular and humoral elements of the immune system from the blood. The absence of obvious lymphatic vessels appeared to provide another anatomical basis for isolation of the brain from immune surveillance by T cells. Over the past decade, however, evidence has accumulated indicating that T cells are frequent visitors to the brain (Owens et al., 1994). The physical BBB utilizing tight endothelial junctions and glial endfeet blocks passive entry of large proteins but does not stop the active entry of living cells (Perry et al., 1997). Drainage of the cerebrospinal fluid and intracerebrally injected antigens to deep cervical lymph nodes has been proposed as a connection between the brain and the peripheral immune system Cserr and Knopf, 1992, Kida et al., 1995, Kida et al., 1998, Weller, 1998. The immunoreactivity of the brain may be viewed rather as an active state (Becher et al., 2000). The current concept focuses on the presence of immunosuppressive microenvironment, which is maintained in part by astrocytes- or neuron-derived factors such as transforming growth factor (TGF)-β, prostaglandins and neurotrophins Fabry et al., 1994, Hailer et al., 1998.
Despite such a suppressive environment for immune reactivity, inflammatory responses develop within the brain under a variety of pathological conditions. These include microbial infection Dietzschold, 1993, Schlüter et al., 1996, Rodrigeus et al., 1996, Deckert-Schluter et al., 1997, Griffin et al., 1998, multiple sclerosis (Raine, 1997) and autoimmune encephalitis, as well as a number of disorders such as cerebrovascular diseases (Becker, 1998) and Alzheimer's disease (AD) McGeer and McGeer, 1995, Neuroinflammation Working Group, 2000, Akiyama, 2000, Eikelenboom et al., 2000. It has been established that lesions of AD are decorated with multiple inflammatory mediators, among which complement proteins and their regulators have been studied most extensively. Microglia, the brain resident cells of the mononuclear phagocyte system, play a major role in the inflammatory processes of AD lesions, while astrocytes may also participate in these processes. Many investigators consider that immune components activated in the AD brain belong to the innate immune system. Despite the early reports on the presence of T cells in the brain parenchyma of AD Itagaki et al., 1988, Rogers et al., 1988, the significance of a small number of T cells that occur rather inconsistently has been questioned. The aim of this study is to re-evaluate the occurrence of T cells in the AD brain by semi-quantitative analysis of postmortem brain tissues. The phenotype of such T cells indicates that they are activated memory cells but are not fully differentiated effector cells.
Section snippets
Materials and methods
Brains from 60 cases were employed in this study. Cases included 21 patients with AD (ages 56–96, mean: 80.0), 2 with Down syndrome associated with AD (ages 49 and 64), 10 with dementia with Lewy bodies (DLB) associated with AD pathology (ages 67–91, mean: 77.5), 2 with DLB without AD pathology (pure form DLB) (ages 51 and 82), 3 with tangle dementia (ages 86, 92, and 102) (Bancher and Jellinger, 1994), 3 with grain dementia (ages 77, 80, and 93) (Braak and Braak,1989), 2 with fronto-temporal
Results
CD3 positive T cells were present in the brain parenchyma of all cases examined in this study. In the hippocampus, T cells were more frequent in many, if not all, AD cases (Fig. 2A) than in control cases (Fig. 2B). The parenchymal T cells were distributed unevenly. No spatial relationship to such AD lesions as the amyloid β-protein (Aβ) deposits and neurofibrillary tangles was evident, however. Fig. 3 illustrates the results of T cell count in the gray matter of the hippocampus. The number of T
Discussion
Lymphocytes migrate through the body to increase the chance of meeting the specific antigen. Despite the early concept of the immune privilege of the brain, it has now been established in experimental animals that the brain is continuously monitored by T cells Wekerle et al., 1986, Hickey et al., 1991. Such a notion could be applied to human brain, since we found at least some T cells in the brain parenchyma of all cases investigated in this study. T cells in the brain parenchyma are
Acknowledgements
This research was partially supported by grants from the Ministry of Health, Labor and Welfare of Japan (Brain Science).
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