Drug Development Research 19227-235 (1988)

Immune Actions in the Nervous System: A Brief Review With Special Emphasis on Alzheimer’s Disease Joseph Rogers and Judith Luber-Narod

L. J. Roberts Center, Institute for Biogerontology Research, Sun City, Arizona (J. R.) Department of Physiology, University of Massachusetts Medical School, Worcester (J. L. -N.)

ABSTRACT

Rogers, J. and J. Luber-Narod: Immune actions in the nervous system: A brief review with special emphasis on Alzheimer’s disease. Drug Dev. Res. 15:227-235, 1988.

The traditional dogma of brain immunologic privilege remains entrenched in the neurosci- ences. Thus the new discipline of neuroimmunology has often been understood as the study of effects of the nervous system on the immune system rather than vice versa. New data, however, are beginning to show potentially important interactions of the immune system in brain, especially in neurologic disease. These neuroimmune mechanisms appear to involve classic peripheral immune cells (e.g., T cells) as well as cells idiosyncratic to brain (e.g., glia).

Key words: neuroimmunology, T cells, blood-brain barrier, immune system, HLA-DR, la

INTRODUCTION

The nervous system has traditionally been held to be immunologically privileged. Perhaps for this reason, investigations into potential immune interactions in neurologic disorders such as Alzheimer’s disease have not been widely pursued. Consider, however, that the lesions of Alzheimer’s disease reflect focal concentrations of abnormal proteins, focal accumulations of scavenger cells, and focal areas of degeneration. Under such circumstances in the periphery, one would be willing to consider that perhaps these colocalized phenomena are interrelated as normal elements of an immune response. More convincing still would be the demonstration of immune system-related antigens on scavenger and other cells within the

Received final vcrsion August 2, 1988; accepted August 5 , 1988.

Address reprint requests to Joseph Rogers, L.J. Roberts Ccnter, lnstitute for Biogerontology Research, 13220 North 105th Avenue, P.O. Box 1278, Sun City, AZ 85372.

0 1988 Alan R. Liss, Inc.

228 Rogers and Luber-Nard

lesion or the presence of immunoglobulins and complement proteins. The thesis of this review is that evidence of the kind described above is beginning to emerge for Alzheimer’s disease and other neurologic disorders. Far from being immunologically privileged, the nervous system appears to have many of the elements of conventional peripheral immune responses as well as its own idiosyncratic complement of cells capable of immunclike actions.

INFLAMMATION IN THE NERVOUS SYSTEM

One of the tenets of brain immunologic privilege is that conventional, immunologically mediated inflammation is atypical of brain. Actually, this is something of an exaggeration, since brain inflammation does occur in a number of disease states, including acute viral infections, hereditary cerebral amyloidosis, head trauma, and numerous other conditions [Vinters, 19871. In addition, there is no reason to assume that all the characteristics of the peripheral immune response will find identical parallels in the nervous system. This is especially true given the gradual, long-term involvement that often obtains in such chronic neurodegenerative disorders as Alzheimer’s disease. Finally, if we define inflammation by criteria such as presence of immune cells, complement, antibody, and scavenger activity, then it becomes increasingly difficult to exclude even Alzheimer’s disease as lacking an inflam- matory response, since all these elements have been reported (see below).

THE BLOOD-BRAIN BARRIER

A second common argument for brain immunologic privilege is that there is a blood-brain barrier to entry of both pathogens and immune factors [Wekerle et al., 19861. However, the blood-brain barrier is known to be weak or nearly absent at several key sites even in young, normal animals. For example, the blood-brain barrier is almost nonexistent in the olfactory epithelium, permitting direct transport of pathogens and humoral factors to and through the olfactory bulb and tract [Balin et al., 19861. Areas of the temporal lobe, hypothalamus, and brainstem also have significant blood-brain barrier weaknesses [Balin et al., 1986; Schmidley, 19841. Moreover, several studies have demonstrated ultrastructural and functional [Nandy, 198 1; Wisniewski and Kozlowski, 19821 deterioration of the blood-brain barrier under a number of conditions, including head trauma and aging. Even if these weaknesses did not exist, several investigators have argued that the blood-brain barrier may actually serve as a necessary avenue for entrance into the nervous system of viable, activated immune elements [Germain, 19861. Finally, it has now bccn shown that activated T cells can attach to endothelial cells [Naparstek et al., 1984; Savion ct al., 1984; Wekerle et al., 19861, and/or pericytes [Vass et al., 19861 and penetrate the blood-brain barrier.

LYMPHATIC DRAINAGE

It has been stated that there is no complete lymphatic drainage of the central nervous system. Harling-Berg et al. [ 19871 have demonstrated that intraventricular injection of an antigen such as human serum albumin (HSA) into rats can result in high anti-HSA titers in cervical lymph nodes of the recipient animals. Some form of lymphatic drainage may therefore be operable for the anti-HSA antibody to be formed, an idea bolstered by the additional finding of systemic HSA after the intraventricular injection [Harling-Berg et al., 19871. Although it has not yet been shown that antibody-producing cells can return to the central nervous sytem, recent studies have clearly demonstrated that even young animals have a low but significant infiltration of lymphocytes into brain [Wekerle et al., 19861. In the normal elderly and to a greater extent in Alzheimer’s disease patients, we observe many cells with the size, morphology, and cell surface staining that characterizes lymphocytes. These include cells

Immune Actions in the Nervous System 229

immunoreactive for HLA-DR, T helper, and T cytotoxic/suppressor antigens [Luber-Narod and Rogers, in press; Rogers et al., 1986, 19881.

EXPRESSION OF IMMUNE-RELATED ANTIGENS

The fourth and perhaps most important basis for brain immunologic privilege is the purported paucity or lack of expression of major histocompatibility complex (MHC) and other immune-related antigens by cells of the nervous system [see Lampson et al., 1983; Hart and Fabre, 19811. Over the last few years, however, this view has been repeatedly refuted. In fact, we [Luber-Narod and Rogers, in press; Rogers et al., 1986, 19881 and others [Doherty, 1985; Hirsch et al., 1983; McCarron et al., 1985; Naparstek et al., 1984; Savion et al., 1984; Suzumura et al., 1986; Vass et al., 1986; Wekerle et al., 1986; Wong et al., 1984, 19851 can now demonstrate profuse MHC labeling of several different cell types in brain, including microglia, astrocytes, oligodendrocytes, pericytes, and endothelial cells. These data arc discussed more fully below.

Other, non-MHC immune-related antigens and processes have also been reported in the nervous system. These include CD4 sequences in murine brain mRNA [Tourvicille et al., 19861, T4 receptors in human forebrain (the binding site for HIV) [Lewin, 19861, expression of CD4, CD8, and CDl l antigens in human brain [Rogers et al., 1986. submitted], and expression of interleukin-2 (IL-2) receptors by human microglial cells in situ [Luber-Narod and Rogers, in press; Rogers et al., 1986, 19881.

HLA-DR AND IA EXPRESSION IN CULTURED BRAIN CELLS

The MHC class I1 antigens, generically referred to as Ia antigens but with species- specific nomenclature as well (e.g., HLA-DR in humans), occupy an especially important place in immunologic studies because of their necessary role in T-cell recognition, binding, and antigen presentation. Neuroglia in culture can be induced to express Ia antigen in response to gamma-interferon [DuBois et al., 1985; Hirayama et al., 1986; Hirsch et al., 1983; Wong et al., 19851. In fact, experiments using cultured central nervous system cells have demonstrated that Ia-positive astrocytes [Fontana et al., 19841 and oligodendrocytes [Cashman and Noronha, 19861 are capable of antigen presentation to activated T cells.

HLA-DR AND IA EXPRESSION IN SlTU BY NORMAL BRAIN CELLS

The occurrence of class I1 MHC and other immune-related antigens in situ in normal brain is not nearly so dear as in culture. Several papers report that there is no Ia expression by cells within the normal brain [Antoniou et al., 1987; Craggs and Webster, 1985; Hart and Fabre, 1981; Hume, 1985; Matsumoto et al., 1986; Natali et al., 1981; Traugott et al., 1986; Wong et al., 19851. Other authors have reported that Ia- or HLA-DR-positive glia are found in normal brain but are confined to the white matter [Acolla et al., 1984; de Tribolet et al., 1984; Hauser et al., 1983; Kim et al., 1985; Sobel et al., 1984; Traugott et at., 19861. Two groups have reported HLA-DR-positive cells in human gray matter [de Tribolet et al., 1984; Lampson and Hickey, 19861. The samples may not, however, be truly representative of normal tissue; they were derived from biopsy material immediately adjacent to metastic lesions. Similarly, the Ia induction in cultured glia following interferon exposure [DuBois et al., 1985; Hirayama et al., 1986; Hirsch et al., 1983; Wong et al., 19851 is more reminiscent of a disease state than the normal brain. We recently reported the presence of HLA-DR- positive glia in normal human gray and white matter [Luber-Narod and Rogers, 1986; Rogers et al., 1986, 19881, although the intensity of HLA-DR immunoreactivity and number of HLA-DR inmunopositive cells appeared to be much less in gray matter than in white matter.

230 Rogers and Luber-Narod

HLA-DR AND IA EXPRESSION IN NEUROLOGIC DISEASE

At least four neuropathologic conditions-myasthenia gravis, multiple sclerosis, exper- imental allergic encephalitis, and experimental allergic neuritis-are almost certain to involve nervous system immune responses. Increased HLA-DR expression, for example, has been demonstrated in brain tissue from multiple sclerosis patients: in addition to increased expression by endothelial cells, white matter glial cells also show increased HLA-DR during the acute phase of the disease [Traugott et al., 19841. This is mimicked in experimental allergic encephalitis, an animal model of multiple sclerosis [Antoniou et al., 1987; Matsumoto et al., 1986; Sobel et al., 1984; Traugott et al., 19861. During remissions of both experiniental allergic encephalitis and multiple sclerosis, the number of la- or HLA-DR-positive glia decreases. The density of HLA-DR-positive cells is greatest in multiple sclerosis plaques and decreases as one moves further away from these lesions. We have also shown that HLA-DR-positive cells form clusters that colocalize histochemically with amyloid plaques, the hallmark pathology of Alzheimer’s disease [Rogers et al., 1986, 19881. In addition, HLA-DR-positive glial cells have been demonstrated in the vicinity of metastatic tissue and gliomas of the central nervous system [Frank et al., 1986; Lampson and Hickey, 19861 and in human immunodeficiency virus (HIV)-infected brain cells [Koenig et al., 19861.

SPECIFIC GLIAL CELL TYPES THAT MAY EXPRESS MHC CLASS II ANTIGENS

Although several papers have suggested that cells found within the central nervous system may express Ia, the question of which cell types do so has not been definitively answered. The major contenders are astrocytes and microglia, with only two groups suggesting involvement of oligodendrocytes [Kim et al., 1985; Ting et al., 19811. Most groups who have identified Ia-positive cells as astrocytes have done so on morphologic grounds [Birnbaum et al., 1986; de Tribolet et al., 1984; Lampson and Hickey, 1986; Traugott et al., 1984, 19861 or have identified the antigens immunocytochemically on dissociated, cultured central nervous system cells that may or may not be typical of glial cells in vivo [Birnbaum, et al., 1986; de Tribolet et al., 1984; DuBois et al., 1985; Frank et al., 1986; Hirsch et al., 1983; Kim et al., 1985; Wong et al., 19851. de Tribolet and colleagues [de Tribolet et al., 1984; Frank et al., 1986) have used double staining with Ia antibody and glial fibrillary acidic protein (GFAP) (a marker for astrocytes) on central nervous system metastatic tissue to show conclusively that astrocytes (GFAP-positive cells) can express Ia. The authors do not, however, rule out expression of Ia by some niicroglial cells.

We [Luber-Narod and Rogers, in press; Rogers et al., 1986, 19881 and olhers [Antoniou et al., 1987; Craggs and Webster, 1985; Koenig et al., 1986; Matsumoto et al., 19861 have used such stains as acid phosphatase and nucleoside diphosphatase to mark cells of the macrophage/monocyte lineage, including microglia. These cells are also positive for HLA-DR or Ia markers.

It is most probable that both astrocytes and microglia can express type I1 MHC antigens. Antoniou et al. [I9871 note that most of the cells expressing Ia are microglia but that some astrocytes are involved. Our studies of human brain tissue [Luber-Narod and Rogers, in press; Rogers et al., 1986, 19881 also suggest a greater preponderance of HLA-DR-positive microglia than astrocytes, although this difference has not yet been quantified.

BRAIN GLlA AS ANTIGEN-PRESENTING CELLS

Tissue culture experiments indicate that astrocytes are capable of a number of immune-related functions, including production of and/or response to a number of lympho- kines (interferon, glial-stimulating factor, and interleukins- 1 and -3 ) [Fontana, 1982; Fontana

Immune Actions in the Nervous System 231

et al., 1984; Tedeschi et al., 1986; Frei et al., 19861 as well as presentation of foreign antigens to T cells in culture [Fontana et al., 19841.

Microglia have not yet been as intensively studied as astrocytes for antigen-presenting capability. Nonetheless, given their embryologic relationship to peripheral macrophages (which can function as antigen-presenting cells), it seems likely that microglia will have similar immunologic capabilities. In support of this hypothesis, we have begun to investigate other immune antigens in the nervous system and have found additional indications that microglia express antigens similar to those expressed by peripheral immune cells [Luber- Narod and Rogers, in press; Rogers et al., 1986, 19881. We can also demonstrate apposition of microglia with T cells in electron micrographs of Alzheimer’s disease cortex [Rogers et al., 19881, a physical juxtaposition that would be necessary for the process of antigen presentation.

BRAIN-IMMUNE INTERACTIONS IN ALZHEIMER’S DISEASE

Specific features of Alzheimer’s disease pathology suggest that an immune response is, or should be, taking place [Cavagnaro, 19861. There are focal accumulations of abnormal proteins (e.g., paired helical filaments, cerebrovascular and plaque amyloid, A68 protein) [Ball, 1978; Glenner and Wong, 1984; Kemper, 1984; Selkoe et al., 1982; Wolozin et al., 19861. There are focal lesions (e.g., neuritic plaques, neuron loss, granulovacuolar degener- ation) (Ball, 1978; Glenner and Wong, 1984; Kemper, 1984; Rogers and Morrison, 1985; Selkoe et al., 1982; Wolozin et al., 19861. There are focal aggregations of lytic scavenger cells (Berg, 1984; Kemper, 1984; Schechter et al., 19811, some of which can be shown to contain phagocytosed (or internally produced) amyloid [Kozlowski et al., 19811. As was mentioned above, the blood-brain barrier deteriorates with age [Nandy, 1981 ; Wisniewski and Koz- lowski, 19821; this alteration would apply with equal force to Alzheimer’s disease patients, who are themselves elderly and may even be exacerbated in dementia victims [Wisniewski and Kozlowski, 19821. Antibrain autoantibodies have been found in sera and cerebrospinal fluid of Alzheimer’s disease patients [McRae-Degueurce et al., this issue; Nandy and Nandy, 19861, as have complement proteins [Eikelenboom and Stam, 1982; Ishii and Haga, 19751. All these factors provide the potential for an immune response, provided immunocompetent cells with appropriate surface markers and binding sites are available.

Recent evidence from our laboratories strongly suggests, in fact, that in the brain in Alzheimer’s disease such cells are widely available [Luber-Narod and Rogers, in press; Rogers et al., 1986, 19881. The cell types include putative astrocytes, macrophages, activated T cells, endothelial cells and/or pericytes, and microglia. Astrocytes are unique to brain. Microglia more likely have a hematologic origin. However, the question of whether these cells are neural crest or mesodermally derived is actually relatively unimportant in the present context; the significant point is that these cells are in the brain (where they are, in fact, the most widespread and prolific cell type) and that they have many immune-related characteristics (e.g., presence of immune markers, lytic capabilities).

Microglia are probably closely related to macrophages [Oehmichen, 19801, making them an ideal candidate for carrying out a scavenger role in an immune context. In the periphery, macrophages play an important role in the immune response [Oehmichen, 19801. They bear MHC class I1 antigens and so are able to interact with T cells; our laboratory can now demonstrate that putative microglia and astrocytes in Alzheimer’s disease brain also bear these antigens [Luber-Narod and Rogers, in press; Rogers et al., 1986, 19881. Peripheral immune cells bear IL-2 receptors and so are able to respond proliferatively to IL-2 secretion by T cells at sites of lesions; our laboratory can now demonstrate that glial cells in the brain in Alzheimer’s disease also bear these receptors and, in addition, appear to proliferate at sites of Alzheimer’s disease lesions, particularly neuritic plaques [Rogers et al., 1986, 19881. Peripheral macrophages play a lytic, scavenger role in the immune response; microglia

232 Rogers and Luber-Nard

and astrocytes also play a Iytic, scavenger role [Berg, 1984; Kemper, 1984; Wisniewski et al., 19701. In a peripheral immune response, macrophages can be shown to process abnormal proteins or foreign antigens for presentation to T cells through a ternary complex with MHC structures [Gerrnain, 19861; similarly, in Alzheimer’s disease, microglia can be demonstrated to phagocytize (or contain) at least one abnormal protein, amyloid [Kozlowski et al., 19811, and they express the MHC necessary to form a ternary complex with abnormal proteins for antigen presentation. In this regard, it is intcresting that many immunologists believe a-helical and P-pleated sheet arrangements to be preferred configurations for formation of ternary complexes with MHC [Guillet et al., 19871; paired helical filaments and the amyloid of neuritic plaques are both congophilic because of their @-pleated sheet configurations [Glenner and Wong, 19841.

For these and other reasons, we have proposed [Rogers et al.. 1986, 19881 that brain microglia, astrocytes, and macrophages may participate in or help mediate immune system interactions with brain in Alzheimer’s discasc and that such a role is intrinsic to Alzheimer’s disease pathogenesis. This view is bolstered by our finding that class I1 MHC immunoreactive cells proliferate especially in gray matter of cortex in Alzheimer’s disease, the site of classic Alzheimer’s disease pathology, and that class I1 immunoreactive cells colocalize with virtually all neuritic plaques [Rogers et al., 1986, 19881.

The ability of the nervous system to influence the immune system provided the first seeds for neuroimmunology as a discipline. Now, as the dogma of brain immunologic privilege is gradually being overcome, it seems increasingly likely that such influence may work both ways: the immune system may have important interactions with the nervous system and, in particular, may provide a common pathogenic mechanism for a number of neurologic disorders such as Alzheimer’s disease.

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