Expression of major histocompatibility complex antigens on inflammatory peripheral nerve lesions

The expression of major histocompatibility complex (MHC) antigens by cells of the rat peripheral nervous system (PNS) was studied using a model of peripheral nerve transplantation. Monoclonal antibodies to polymorphic determinants of MHC class I and class II (Ia) molecules were used to determine donor or recipient origin of MHC antigen-bearing cells in nerve allografts. The expression of class I and class II antigens by PNS parenchymal cells was modified during varying alloimmune conditions. Baseline, constitutive expression of class I antigens on endothelial and perivascular cells and class II antigens on interstitial cells were identified. Decreased MHC antigen expression was noted following in vitro culture of nerve allografts prior to implantation. After transplantation, enhanced donor-derived MHC antigen expression was demonstrated by both cultured and untreated allograft endothelial, perivascular and interstitial cells in a pattern which was distinct from isografts. This data supports a concept of perivascular monocytic and/or parenchymal cell (Schwann cell or resident macrophage-like cell) activity as the resident antigen-presenting cell for PNS immune processes.     

Rat and human Schwann cells in vitro can synthesize and express MHC molecules

The expression of MHC class I and II molecules on cultured rat and human Schwann cells (SCs) was studied to determine whether these molecules could be synthesized by SCs in the absence of T cells. Normal rat and human SCs in vitro expressed low levels of class I MHC, but this was markedly increased by incubation with interferon gamma (IFN-gamma). Untreated SCs of rat or human origin did not express detectable class II MHC molecules, but after 48 hours incubation with IFN-gamma 100 U/ml, 20% of rat SCs and 90% of human SCs were class II positive. Immunoelectron microscopy confirmed the surface expression of MHC molecules on SCs and demonstrated class II MHC within endocytotic vesicles. These findings provide further evidence for an immunological role for SCs as antigen presenting cells or as targets for cytotoxic T cells.     

Up-regulation of major histocompatibility complex class II antigen expression in the central nervous system of dogs with spontaneous canine distemper virus encephalitis

Major histocompatibility complex class II (MHC II) and canine distemper virus (CDV) antigen expression were compared by immunohistochemistry in the cerebellar white matter of ten dogs with naturally occurring canine distemper encephalitis. In addition, infiltrating mononuclear cells were characterized by employing poly- and monoclonal antibodies directed against human CD3, canine MHC II, CD5, B cell antigen and CDV-specific nucleoprotein. Positive antigen-antibody reaction was visualized by the avidin-biotin-peroxidase complex method on frozen sections. Histologically, neuropathological changes were categorized into acute, subacute, and chronic. In control brains, MHC II expression was weak and predominantly detected on resident microglia of the white matter and on endothelial, perivascular and intravascular cells. In CDV antigen-positive brains, MHC II was mainly found on microglia and to a lesser extent on endothelial, meningeal, choroid plexus epithelial, ependymal and intravascular cells. In addition, virtually all of the perivascular cells expressed MHC II antigen. CDV antigen was demonstrated most frequently in astrocytes. Of the perivascular lymphocytes, the majority were CD3-positive cells, followed by B cells. Only a small proportion of perivascular cells expressed the CD5 antigen. In addition, B cells and CD3 and CD5 antigen-positive cells were found occasionally in subacute and frequently in chronic demyelinating plaques. In acute encephalitis, CDV antigen exhibited a multifocal or diffuse distribution, and MHC II was moderately up-regulated throughout the white matter and accentuated in CDV antigen-positive plaques. In subacute encephalitis, moderate multifocal CDV antigen and moderate to strong diffuse MHC II-specific staining, especially prominent in CDV antigen-positive lesions, were observed. In chronic encephalitis, CDV antigen expression was restricted to single astrocytes at the edge of the lesions or was absent, while MHC II expression, especially prominent on microglia, was strongly up-regulated throughout the white matter, most pronounced in demyelinated plaques. In summary, in acute and subacute lesions without perivascular cuffs, MHC II expression correlated with the presence of CDV antigen. In contrast, in chronic lesions, MHC II expression on microglial cells was the most prominent despite a few CDV antigen-positive astrocytes, indicating that nonviral antigens may play an important role as triggering molecules for the process of demyelination. Received: 13 September 1995 / Revised: 26 February 1996 / Accepted: 1 April 1996     

Interactions between CD4+ T-cells and rat Schwann cells in vitro. 1. Antigen presentation by Lewis rat Schwann cells to P2-specific CD4+ T-cell lines.

Interactions between CD4+ P2-specific T-cell lines and Schwann cells were examined in vitro by scanning electron microscopy (SEM) and T-cell proliferation studies. CD4+ T-cell lines clustered around and attached to Schwann cells which expressed Major histocompatibility complex (MHC) class II molecules. Only those P2-specific T-cell lines capable of inducing experimental allergic neuritis (EAN) when injected into adult Lewis rats clustered around the Schwann cells. T-cell lines responsive to P2 but not able to induce EAN did not cluster around Schwann cells. The addition of exogenous P2 protein inhibited in a dose-dependent way clustering and proliferation of the P2-specific T-cell lines. Cytoplasmic P2 was detected in Schwann cells by immunofluorescent labelling and the results of proliferation assays in this study suggest that endogenous P2 protein was processed by the Schwann cells and presented to T-cell lines in association with MHC class II molecules. The clustering and proliferation of class II-restricted CD4+ P2-specific T-cell lines in the presence of Schwann cells provides evidence for a role for Schwann cells as facultative antigen presenting cells, processing and presenting 'self' endogenous antigen to CD4+ T-cell lines capable of inducing EAN.     

Mouse Schwann cells activate MHC class I and II restricted T-cell responses,but require external peptide processing for MHC class II presentation

Schwann cells are the myelinating glia cells of the peripheral nervous system (PNS). In inflammatory neuropathies like the Guillain-Barré syndrome (GBS) Schwann cells become target of an autoimmune response, but may also modulate local inflammation. Here, we tested the functional relevance of Schwann cell derived MHC expression in an in vitro coculture system. Mouse Schwann cells activated proliferation of ovalbumin specific CD8+ T cells when ovalbumin protein or MHC class I restricted ovalbumin peptide (Ova_257–264 SIINFEKL) was added and after transfection with an ovalbumin coding vector. Schwann cells activated proliferation of ovalbumin specific CD4+ T cells in the presence of MHC class II restricted ovalbumin peptide (Ova_323–339 ISQAVHAAHAEINEAGR). CD4+ T-cell proliferation was not activated by ovalbumin protein or transfection with an ovalbumin coding vector. This indicates that Schwann cells express functionally active MHC class I and II molecules. In this study, however, Schwann cells lacked the ability to process exogenous antigen or cross-present endogenous antigen into the MHC class II presentation pathway. Thus, antigen presentation may be a pathological function of Schwann cells exacerbating nerve damage in inflammatory neuropathies.     

Characterization of perivascular cells in astrocytic tumours and peritumoral oedematous brain

Perivascular cells (PVCs) form an immunophenotypically defined population that plays an important scavenging role in the perivascular fluid drainage pathways in the rat brain: such cells may also act as antigen-presenting cells. The present study tests the hypotheses that (a) PVCs in human brain are distinct from microglia and haematogenous macrophages, and (b) PVCs within astrocytic tumours and peritumoral oedematous brain tissue react in a similar way to PVCs in the rat brain. Parafin sections of formalin-fixed tissue from 10 astrocytomas. 10 anaplastic astrocytomas, 10 glioblastoma multiforme. peritumoral oedematous brain and from normal human brain were examined immuno-cytochemically using antibodies HLA-DR P-chain for MHC class II antigen, PGMl and MAC 387 directed against macrophage components, MT1 for T lymphocytes and GFAP for astrocytes. No PVCs, microglia or macrophages were labelled by these techniques in paraffin sections of normal brain. Microglia. Macrophages recently derived from haematogenous monocytes and PVCs were labelled by immunocytochemistry in all tumours but were more numerous in glioblastomas than in astrocytomas or anaplastic astrocytomas. Perivascular cells were distinguished by their perivascular position, their expression of MHC class II antigen and were labelled by PGM1 antibody but not by MAC 387 antibody. Microglia and monocyte/macrophages, remote from blood vessels, on the other hand, were strongly labelled by MAC 387, moderately by PGMl and showed weak expression of MHC class II antigen. A similar pattern of staining was seen in peritumoral oedematous tissue. These findings suggest that PVCs form a defined population of resident cells in the human brain and that they are distinct from microglia, monocytes and macrophages. Furthermore. upregulation of MHC class II and PGM1 expression on PVCs in tumours and oedematous brain, suggest that they play a similar scavenging role in the human brain to that seen in the rat brain.     

MHC class II-positive perivascular microglial cells mediate resistance to Cryptococcus neoformans brain infection

Acquired resistance to the CNS pathogen Cryptococcus neoformans is mediated by CD4(+) T lymphocytes primed by exposure to antigen in the context of major histocompatibility class II (MHC II) molecules. In mouse brain, parenchymal and perivascular microglial cells may express interferon-gamma (IFN-gamma)-inducible MHC class II marker and thus interact with CD4(+) T cells. Primed effector T cells are retained in the infected CNS if antigen is encountered in proper MHC context and may deliver signals that potentiate microglia to enhanced fungistasis. Vaccinated C57BL6/J mice resist an ordinarily lethal C. neoformans rechallenge, but identically treated congenic Abeta(o/o) mice (MHC class II-deficient; CD4(+) T-cell-deficient) do not. Nor can Abeta(o/o) mice be adoptively immunized by infusion of lymphocytes from vaccinated C57BL6/J donors, as are severe combined immunodeficient (SCID) mice (MHC class II-intact, lymphocyte-deficient). Chimeric (C57BL/6J:Abeta(o/o)) mice with class II expression likely on perivascular microglia only were, like SCID mice, capable of adoptive immunization against C. neoformans brain infection. To the contrary, chimeric mice with class II expression likely only on parenchymal microglia were not capable of effective adoptive immunization against C. neoformans brain infection. Therefore, in order to mediate resistance to infection, primed CD4(+) T cells must interact with the replenishable perivascular microglial subset that lies in close proximity to cerebral vasculature. Although T cells may supply help in the form of inflammatory cytokines to parenchymal microglia, expression of class II on these cells appears unnecessary for antifungal activity.     

The endoneurial response to microsurgically removed epi- and perineurium

The purpose of the study was to examine the response of the endoneurium of the rat sciatic nerve after removal of the epi- and perineurium. For this purpose, segments (4-5 mm long) of the whole epi- and perineurium around the rat sciatic nerve were microsurgically removed (the peel-off area) and the endoneurium was left intact. The post-operative changes were followed up to 5 weeks post-operatively (PO) by histo- and immunohistochemical studies. Additionally, neuromorphometric analyses considering the number of Schwann cells, axons, macrophages and endothelial cells were examined in the peel-off area. The results showed that at the operative area the central part of the endoneurium (65% of the total area of the endoneurium) remained morphologically intact, but the outer part of the endoneurium (35% of the total area) reacted strongly and showed Wallerian type of degeneration. The number of axons and Schwann cells decreased 3 days PO. However, after 2 weeks the number of Schwann cells increased markedly and the highest number was noted 5 weeks PO. A great number of capillaries were observed in the outer part 1 week PO. A rapid invasion of macrophages was noted at the outer part of the endoneurium immediately after the operation. During the regeneration the endoneurial fibroblasts in the peripheral zone started to form minifascicle-like formations, which resulted in a distinct dense outer part of the endoneurium. This dense outer zone was preserved up to 5 weeks PO and participated in the formation of a new perineurium-like structure, but no distinct new perineurium was formed. At the border zone, areas beside the normal epi- and perineurium proliferation of preserved perineurial cells were noted, which fused to the outer part of the dense endoneurium. On focal areas, an attachment of the operated area to the adjoining muscle was observed. This study shows for the first time that despite the microsurgical removal of epi- and perineurium, the inner part of the endoneurium stays intact, but in the outer part of the endoneurium marked reactive changes ensue, probably to protect the injured peripheral nerve.     

Perivascular cells act as scavengers in the cerebral perivascular spaces and remain distinct from pericytes,microglia and macrophages

Summary Perivascular cells in the rat brain are an immunophenotypically defined group of cells which can be identified by their expression of the ED2 antigen. The present study investigates the role of perivascular cells as scavengers in the perivascular spaces of the rat brain and the relationship of these cells to microglia, macrophages, pericytes and smooth muscle cells. Particulate matter (Indian ink) was injected selectively into the perivascular spaces of the left caudoputamen of 59 rats. Animals were killed by cardiac perfusion of formalin or glutaraldehyde 2 h-2 years after ink injection. Cerebral hemispheres were examined histologically and immuno-cytochemically using the ED2 antibody for perivascular cells, ED1 for microglia and macrophages and OX-6 directed against la antigen [major histocompatibility complex (MHC) class II]. ED2⁺ perivascular cells ingested Indian ink in the perivascular spaces and expressed MHC class II antigen. Reactive microglia and macrophages in the perivascular parenchyma expressed ED1, but no ED2⁺ cells were seen outside the perivascular spaces. Transmission electron microscopy distinguished perivascular cells, which ingested carbon particles, from pericytes, which did not. The results of this study suggest that perivascular cells remain distinct from pericytes, microglia and macrophages and that they play a major role as scavengers in the perivascular spaces of the rat brain. This role reflects the improtance of perivascular spaces as drainage pathways for soluble and insoluble material from the brain.Supported in part by the Vehara Memorial Foundation, Japan (S.K) and by the David Gibson Fund, Wessex Neurological Centre Research Trust, Wessex Medical Trust and the Sino-British fellowship trust (E.-T.Z.)     

The ordered array of perivascular macrophages is disrupted by IL-1-induced inflammation in the rabbit retina

In this study we have shown that an antibody to CD18 identified a population of cells in the rabbit retina that resembled the perivascular macrophage found in other regions of the central nervous system. In the normal retina these cells possessed a ramified morphology and presented in an ordered array on the vitreal surface in association with the epiretinal vessels. Approximately 50% of the perivascular macrophages constitutively expressed MHC class II. In response to interleukin-1β (IL-1β)-induced inflammation, these cells became activated, as evidenced by a change from a ramified to an ameboid morphology and increased expression of MHC class II, and migrated away from the vessels. These changes were first detected around 3 h post-intraocular challenge coincident with the onset of inflammation. At the peak of the inflammatory response (∼24 h post-challenge), many activated perivascular macrophages were no longer associated with the vessels and formed long “cords” of MHC class II+ cells associated with underlying deposits of fibrin. In eyes challenged with heat-inactivated IL-1, no change in the morphology or distribution of the perivascular macrophage was noted. At 3 weeks post-challenge with IL-1, the number and distribution of the perivascular macrophages were restored to baseline values, although with a reduced cell size. Since these changes closely resemble those that occur in non-lymphoid dendritic cells in the skin, heart, and/or kidney following activation with cytokines or bacterial products, the results suggest that the perivascular macrophage represents the dendritic cell of the retina and may thus play an important role in immune surveillance in the eye and maintenance of the blood-retina barrier. © 1996 Wiley-Liss, Inc.     

Ultrastructural location of major histocompatibility complex (MHC) class II positive perivascular cells in histologically normal human brain.

The expression of major histocompatibility complex (MHC) class I and II antigens was studied in surgical and postmortem brain biopsy tissue using light and electron microscopic immunocytochemistry. In addition, monoclonal antibodies directed against human macrophages (EBM11) and alpha-smooth muscle actin were applied. It is shown that blood vessel-associated MHC class II immunoreactivity in histologically normal human brain can be localized to a distinct class of cells, termed perivascular cells, which share macrophage but not smooth muscle cell antigen. This immunophenotype, the location in the perivascular space as well as the morphology, frequency and tissue distribution distinguish perivascular cells from pericytes and intraparenchymal microglia. It is suggested that MHC class II positive perivascular cells are a normal constituent of the human cerebral microvasculature. The potential role of these cells in immunological reactions occurring at the blood-brain interface is discussed.     

Rat Schwann cells produce interleukin-1

There is increasing evidence that Schwann cells of peripheral nerves may be able to function as accessory cells, interacting with the immune system in T cell-mediated immune responses, by expression of the major histocompatibility complex (MHC) class II molecules. In addition to MHC class II-associated presentation of antigen to T lymphocytes, the release of a co-stimulatory factor, interleukin-1 (IL-1), is an essential function of accessory cells for T cell activation. In this study, we investigated if Schwann cells were able to produce IL-1. Purified cultures of neonatal and adult rat Schwann cells were incubated with various stimulatory agents. Supernatants and cell lysates were collected from these cultures and IL-1 activity was assayed. Both neonatal and adult rat Schwann cells produced IL-1 activity in response to bacterial antigens and the IL-1 activity was often higher in the cell lysate than in the supernatant. When stimulated neonatal or adult rat Schwann cells were examined with antibody against IL-1, strong immunolabelling was seen intracellularly, but no IL-1 was detected on the cell surface. Since IL-1 plays an important role in the initiation of immune responses, these observations support the view that Schwann cells may function as antigen-presenting cells, thereby taking part in neuroimmunological responses within peripheral nerves.     

Major histocompatibility antigens and lymphocyte subsets during experimental allergic neuritis in the Lewis rat

Summary Major histocompatibility antigens were identified in frozen sections of normal Lewis rat peripheral nerve tissue with monoclonal antibodies and an avidin-biotin-peroxidase complex system. Class I antigen is normally required for cytotoxic/suppressor T lymphocyte function and class II antigen for activation of helper T lymphocytes. In the sciatic nerves class I antigen was expressed diffusely by most endoneurial and perineurial cells but class II antigen only by a minority. In the cauda equina class I antigen was expressed by all arachnoid and some endoneurial cells, while class II antigen was expressed by a smaller proportion of arachnoid cells in the endoneurium of spinal roots and interstitial cells surrounding dorsal root ganglion neurons. The endothelium of endoneurial, perineurial and meningeal vessels uniformly expressed class I but not class II antigen. Experimental allergic neuritis was induced in Lewis rats by immunisation with bovine intradural root myelin. Early lesions consisted of multifocal infiltration of the nerve roots by cells expressing leucocyte common antigen. Surrounding endoneurial cells showed markedly increased expression of major histocompatibility antigens. In inflammatory lesions about 10% of the cells were stained with pan T cell antibodies. T lymphocyte subsets were identified with antibody W3/25 for helper cells and MRC OX-8 for cytotoxic/suppressor cells. The W3/25 positive cells were usually slightly in excess of OX-8 positive cells and their relative proportions did not alter during the disease. The presence of class I antigen on normal endothelium and its increased expression on endoneurial cells in the early phase of inflammation suggest an important role for class I restricted lymphocytes in the pathogenesis of the early stages of experimental allergic neuritis.     

Interactions between CD4+ T-cells and rat Schwann cells in vitro: 2. Cytotoxic effects of P2-specific CD4+ T-cell lines on Lewis rat Schwann cells

The cytotoxic effects of CD4+ P₂-specific T-cell lines on Schwann cells were examined in vitro with ⁵¹Cr-release cytotoxicity assays. Only those P₂-specific T-cell lines capable of inducing EAN when injected back into adult Lewis rats were cytotoxic to the Schwann cells. The addition of exogenous P₂ protein was not necessary for the cytotoxic effect. The monoclonal antibody (mAb) OX6 directed against Major histocompatibility complex (MHC) class II molecules blocked cytotoxicity, indicating an essential role for MHC class II molecules in this interaction between CD4+ T-cell lines and Schwann cells.     

The effects of West Nile virus on major histocompatibility complex class I and II molecule expression by Lewis rat Schwann cells in vitro

The expression of major histocompatibility complex (MHC) class I and II molecules by Lewis rat Schwann cells after infection with West Nile virus (WNV) in vitro was examined by fluorescence microscopy and flow cytometry. WNV enhanced the expression of MHC class I molecules and induced the expression of MHC class II molecules by Schwann cells. Irradiated medium from WNV-infected Schwann cell cultures upregulated class I molecule expression on dissociated Schwann cell cultures but did not induce the expression of class II molecules. This finding has implications for virally triggered autoimmune diseases of nervous tissue.     

The distribution and abundance of MHC and ICAM-1 on Schwann cells in vitro

Schwann cells, the myelin forming glial cells of peripheral nerves, have been implicated as having an immunoregulatory role in inflammatory demyelinating neuropathies (IDNs) such as Guillain Barré syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP). We employed rat IFN-γ, a cytokine released by macrophages and CD4⁺ T-cells during inflammatory demyelination of the peripheral nervous system, to examine the distribution and abundance of MHC class I, MHC class II and ICAM-1 on Lewis rat Schwann cells and fibroblasts in vitro. MHC class I, class II and ICAM-1 molecules were immunolabelled with 30 nm colloidal gold and observed by scanning electron microscopy. Incubation with IFN-γ for 24 and 72 h, resulted in the clustering of MHC class I and ICAM-1 on Schwann cells and fibroblasts with MHC class II randomly distributed as single particles. MHC class I and ICAM-1 were upregulated after 24 h incubation in the presence of IFN-γ, whereas MHC class II was upregulated after 72 h. The difference in the rate of upregulation may indicate differences in the recycling and/or synthesis of these molecules. Changes in distribution such as clustering, in conjunction with the upregulation of these molecules, suggest a role for Schwann cells in the restimulation of specifically primed CD4⁺ T-cells in IDNs.     

TNF alpha, IFN gamma and IL-2 mRNA expression in CIDP sural nerve biopsies

Proinflammatory cytokines contribute to the regulation of the disease process in inflammatory neuropathies. Cellular localisation of cytokine expression in CIDP nerve biopsies should provide further insight into the pathogenic mechanisms of the disease and the individual cells involved. In this study in situ hybridisation was used to determine the exact localisation and identity of cells that express TNF alpha, IFN gamma and IL-2 mRNA within the CIDP nerve. Paraffin embedded and frozen sural nerve biopsies from three acute phase CIDP patients were used for the study. Sections of these samples were probed with digoxigenin labelled oligoprobes for TNF alpha, IFN gamma and IL-2. The results demonstrate localisation of cytokine expression to the inner rim of the perineurium, epineurial and endoneurial blood vessels and infiltrating inflammatory cells. In addition strong staining for TNF alpha. mRNA was widespread in the endoneurium in areas consistent with/suggestive of Schwann cells. Expression of cytokines in the perineurium and endoneurial blood vessels may have pertinent implications with respect to the breakdown of the blood nerve barrier associated with CIDP. In the very least the potential for an immunomodulatory role may be ascribed to these cells.     

Class II antigen expression and inflammatory cells in the Guillain-Barré syndrome

Monoclonal antibodies to T-lymphocyte subsets and Class II molecules (Ia) have been used to characterize the inflammatory infiltrate in nerve tissue biopsied from 2 patients in the acute phase of Guillain-Barré syndrome; the findings were compared with those in control nerve specimens. Normal control nerve was treated in the same way. In normal nerves, Class II molecules are expressed on endothelial cells and on occasional mononuclear and perineurial cells. In Guillain-Barré nerves the inflammatory infiltrate consisted mainly of Class II-positive cells of the monocyte-macrophage lineage and of lesser numbers of T4 and T8 lymphoid cells. T4 cells predominated in perivascular collections. In the more severely affected patient, there was a marked increase of Class II molecules expressed on endothelial cells, perineurial cells, and most Schwann cells. Schwann cells associated with unmyelinated fibers and the Schwann cell processes of denervated Büngner bands all expressed Class II molecules. These histological changes were less marked in the more mildly affected patient. It is suggested that the expression of Class II molecules on the myelin forming cell, the Schwann cell, has important implications for the pathogenesis of the demyelination that occurs in Guillain-Barré syndrome.     

Endothelial cell class II major histocompatibility complex molecule expression in stereotactic brain biopsies of patients with acute inflammatory/demyelinating conditions

To determine if central nervous system (CNS) microvessel endothelial cells express class II major histocompatibility complex (MHC) molecules in early demyelinating lesions in humans, cerebral white matter (WM) biopsies from patients with acute inflammatory/demyelinating conditions, including 4 with multiple sclerosis (MS), were immunostained for class II MHC and other antigens. Eight of 9 biopsies showed focal MHC class II-positive endothelial cells; there were none in the CNS of 1 of the MS patients at autopsy. There were more vessels with class II-positive endothelial cells in areas with intact WM and gliosis than in areas with active demyelination or control WM; class II-positive endothelial cells in small venules and capillaries were adjacent to transmigrating and perivascular CD4-positive cells. By immunoelectron microscopy, class II molecules were localized to vesicles in endothelial cell cytoplasm, suggesting the potential for antigen processing. Perivascular cells, parenchymal microglia, mononuclear cells and the perinuclear cytoplasm but not the processes of astrocytes were also class II-positive. These data indicate that in acute CNS inflammatory/demyelinating lesions, endothelial cells focally and apparently transiently express class II MHC molecules. This expression implies potential antigen-specific interactions, immunoregulatory or signalling functions in endothelial cells, or it may render them susceptible to CD4-positive cell-mediated cytotoxicity. Thus, class II-positive endothelial cells may have pivotal immunologic roles in initial stages of T cell responses in human CNS WM, particularly in acute MS lesions.     

Differential expression of MHC class II molecules by microglia and neoplastic astroglia: relevance for the escape of astrocytoma cells from immune surveillance

There is increasing evidence that microglia serve as antigen presenters in the human CNS. Although the occurrence of MHC class II immunoreactive cells has been reported in astrocytic gliomas, the relative contribution of microglia to this cell population has not been studied in detail. Using computer-assisted image analysis, we have investigated the expression of MHC class II molecules and of the microglia/macrophage markers Ki-M1P, RCA-1, KP1 and iba1 , in 97 astrocytic gliomas comprising all WHO grades to answer the question whether there is a correlation between tumour grade and the number of MHC class II positive microglia/macrophage profiles. Microglia expressing MHC class II were common in astrocytomas and anaplastic astrocytomas but rare in pilocytic tumours although there was significant variation within each group. MHC class II immunoreactivity was reduced in highly cellular areas of glioblastomas where large numbers of cells expressing macrophage markers were still present. Thus, there was no simple relationship between tumour grade and microglial/macrophage MHC class II expression. In addition, up to 55% of astrocytic gliomas contained MHC class II immunoreactive tumour cells. Microglia but not tumour cells were found to express the BB1/B7 costimulator. We conclude that microglia in astrocytic gliomas are well equipped to function as antigen presenting cells. Yet, neoplastic astroglia appear to acquire the capacity to downregulate microglial MHC class II expression and, at the same time, may induce T-cell clonal anergy through aberrant expression of MHC class II molecules.