Expression of major histocompatibility complex class II antigen on amoeboid microglial cells in early postnatal rat brain following intraperitoneal injections of lipopolysaccharide

In rats given two single intraperitoneal injections of lipopolysaccharide (LPS) at 1 and 4 days of age and killed at 7 days of age, 11.5–12% of amoeboid microglial cells (AMC) in the supraventricular corpus callosum were induced to express major histocompatibility complex (MHC) class II antigen, as detected with monoclonal antibody OX-6. The MHC class II antigen induced was colocalized with MHC class I antigen and type 3 complement receptors on the same cells. The expression of MHC class II antigen on the plasma membrane of AMC was confirmed in immunoelectron microscopy. Although OX-6-positive AMC often assumed a perivascular position, the majority of them, however, were far removed from the blood vessels. The cytoplasmic processes of the perivascular OX-6-positive AMC appeared to rest directly on the vascular lamina, and in some section profiles they were in contact with a large surface area of the outer wall of small blood vessels. It is concluded from this study that although MHC class II antigen is not constitutively present on AMC, it is, however, inducible under stimulation with LPS. It is, therefore, suggested that the OX-6-positive AMC, especially the perivascular AMC, may have the potentiality to function as antigen-presenting cells in the developing brain when challenged by LPS.     

Immunocytochemical localization of CR3 complement receptors with OX-42 in amoeboid microglia in postnatal rats

Summary The present study described the labelling of amoeboid microglial cells in the postnatal rat brain with OX-42, an antibody that recognizes type 3 complement receptors CR3 in mononuclear phagocytes. Of the diverse morphological forms of amoeboid microglia present in the corpus callosum in early postnatal (2–5 days) rats, cells with a round regular outline, or showing short stout processes, were the most intensely stained. When traced from the main cell colony into the borderline zone with the cortex, the immunoreactivity of amoeboid microglia that assumed a ramified form was drastically reduced. Examination of materials from the late postnatal (8–12 days) age group showed that the majority of the OX-42 positive cells in the corpus callosum became oval, elongated and ramified. Immunoelectron microscopy confirmed the above observations, and also showed that the immunoreactivity in the round amoeboid microglia was localized in their plasma membrane, surface projections and invaginations, as well as in some of the subsurface vacuoles. The immunoreactivity was reduced in the oval cells, and diminished in the elongated or ramified form. It is proposed that the presence of CR3 membrane receptors in amoeboid microglial cells is related to their active role in endocytosis. These, however, diminish with the growth of the brain.     

Insulin-like growth factor I and II expression and modulation in amoeboid microglial cells by lipopolysaccharide and retinoic acid

Insulin-like growth factors I and II are known to regulate the development of the CNS. We examined the developmental changes in insulin-like growth factor I and insulin-like growth factor II expression in the postnatal rat corpus callosum. Insulin-like growth factor I and insulin-like growth factor II mRNA expression increased at 3 days as compared with 1 day whereas the protein expression increased up to 7 days. Insulin-like growth factor I and insulin-like growth factor II immunoexpression was specifically localized in round cells confirmed by double immunofluorescence with OX-42 to be the amoeboid microglial cells. Insulin-like growth factor I expression was observed up to 7 days in amoeboid microglial cells while insulin-like growth factor II expression was detected in 1-3 day old rats. Exposure of primary rat microglial cell cultures to lipopolysaccharide increased insulin-like growth factor I and insulin-like growth factor II mRNA and protein expression significantly along with their immunoexpression in microglial cells. The lipopolysaccharide-induced increase in insulin-like growth factor I and insulin-like growth factor II mRNA and protein expression was significantly decreased with all-trans-retinoic acid. We conclude that insulin-like growth factor I and insulin-like growth factor II expression in amoeboid microglial cells in the developing brain is related to their activation. Once the activation is inhibited, either by transformation of the amoeboid microglial cells into ramified microglia regarded as resting cells or as shown by the effect of all-trans-retinoic acid administration, insulin-like growth factor I and insulin-like growth factor II mRNA and protein expression is downregulated.     

Induction of microglial immunomolecules by anterogradely degenerating mossy fibres in the rat hippocampal formation

Degeneration of myelinated axonal connections is generally held to provide a strong stimulus for microglial expression of major histocompatibility complex (MHC) class II antigen. The present study demonstrates that strong microglial reactions also are induced by axonal and terminal degeneration of the unmyelinated hippocampal mossy fibres. After destruction of denate granule cells by focal injections of colchicine (or transection of the mossy fibres) in adult rats, immunocytochemical analysis of the mossy fibre terminal fields in the dentate hilus and regio inferior of hippocampus proper (CA3) revealed profound changes in microglial cells with increased expression of the complement receptor type 3 and induction of MHC class I antigen, leukocyte common antigen, lymphocyte function-associated antigen-1 and MHC class II antigen. The microglial reaction, first detectable 4 days after the lesion, became maximal during the third postlesional week, and had almost vanished 6 weeks after the lesion.From recent studies we know that anterograde degeneration of myelinated Schaffer-collaterals from CA3 to regio superior of hippocampus proper and myelinated entorhinal perforant path fibres to fascia dentata is accompanied by microglial expression of MHC class I antigen, but not class II. Together with the present findings, this demonstrates that myelin debris is neither necessary nor sufficient to induce expression of microglial MHC class II antigen within the hippocampus.     

Expression of induced nitric oxide synthase in amoeboid microglia in postnatal rats following an exposure to hypoxia

The present study showed the expression of induced nitric oxide synthase (iNOS) immunoreactivity in amoeboid microglia following an exposure to transient hypoxia in postnatal rats. iNOS immunoreactivity was expressed mainly in the amoeboid microglia in corpus callosum and subependymal regions of the ventricles within 3 h after hypoxia. The expression declined after 5 h, and became undetectable after 15 h and in longer surviving rats. The immunoreactivity of these cells with OX-42, which is a marker for microglia cells and detects complement type three receptors (CR3), was comparable in the rats exposed to hypoxia and the control rats. Immunoglobulin G (IgG) immunoreactivity was observed in the amoeboid microglia up to 3 h after hypoxia but it was undetectable in longer surviving rats and in the control rats. The iNOS expression in the amoeboid mircoglial cells may be related to the host defense and maintenance of structural integrity of the highly vulnerable periventricular white matter after hypoxia. The immunostaining of amoeboid microglial cells with IgG following hypoxia indicates leakage of plasma immunoglobulin from the blood vessels and its removal by the amoeboid microglial cells.     

Antigen presentation and tumor cytotoxicity by interferon-gamma-treated microglial cells

In this study microglial cells isolated from brain cell cultures of newborn mice were characterized and investigated for morphology, their responses to growth factors and their functional properties. The microglial cells were phagocytic, contained nonspecific esterase activity and expressed Fc (IgG1/2b) and type-3 complement receptors. Scanning electron microscopy revealed that in analogy to brain tissue two types of microglial cells are present in the cultures: the ameboid and the ramified type which both display similar appearance by transmission electron microscopy. Interleukin 3 and the granulocyte-macrophage colony-stimulating factor were potent growth factors for the cultured microglial cells. The cells were negative for class II antigens (Ia) of the major histocompatibility antigen complex. However, upon treatment with interferon-gamma (IFN-gamma) microglial cells became Ia+ and functioned as antigen-presenting cells when tested on ovalbumin-specific Ia-restricted helper T cells. Furthermore, microglial cells exposed to IFN-gamma and endotoxin developed tumor cell cytotoxicity and produced tumor necrosis factor alpha. Taken together, microglial cells share the characteristics of cells of the macrophage lineage.     

Sleep deprivation inhibits expression of NADPH-d and NOS while activating microglia and astroglia in the rat hippocampus

This study investigated the expression of nitric oxide (NO)-synthesizing enzymes and the glial reaction in the rat hippocampal formation following sleep deprivation for 5 days. Nicotinamide adenine dinucleotide phosphate-diaphorase (NADPH-d) reactivity was markedly reduced in the hippocampal CA1, CA2 and CA3 sectors as well as in the dentate gyrus, suggesting a suppression of NO production in these areas. Microglial cells were hypertrophic and showed an up-regulation of complement type 3 receptors as determined by antibody OX-42. However, expression of major histocompatibility complex class I and II antigens, and antigen of monocyte/macrophage lineage marked by OX-18, OX-6 and ED1, respectively, was undetected. Astrocytes also displayed hypertrophied processes with enhanced glial fibrillary acidic protein (GFAP) immunoreactivity. Western blots of hippocampal tissues corroborated the above-mentioned morphological findings in that expression of NO-synthase (NOS) was decreased while that of OX-42 and GFAP was increased in the sleep-deprived rats. Since NO is thought to be involved in memory consolidation processes in the hippocampus during sleep, the inhibition of NADPH-d and NOS reactivities may account for the memory decline after long-term sleep deprivation. The concomitant reactions in microglia and astrocytes suggest the involvement of these cells in the deleterious effect of prolonged sleep deprivation.     

Phenotypical characterization of the cells invading pancreatic islets of diabetic BB/OK rats: effect of interleukin 2 receptor-targeted immunotherapy

We investigated immunohistochemically the phenotypes of mononucleated cells invading pancreatic islets of diabetic BB/OK rats in comparison to the diabetes-resistant parental strain, and 12 and 120 days after a temporary treatment (10 days) with a monoclonal antibody (1 mg/kg b.w.) directed against interleukin 2 receptor (IL 2R) combined with a subtherapeutic dose of cyclosporin A (1.5 mg/kg b.w.). Using a panel of monoclonal antibodies (OX-19, OX-8, W3/25, KI-M2R, OX-6, OX-17, ART-18) and the alkaline phosphatase anti-alkaline phosphatase system to visualize the bound primary antibodies, we observed an even distribution of mononucleated cells across the endocrine pancreas at a "background" level when obtained from diabetes-resistant parental rat strain. Diabetic BB/OK rats, characterized by a moderate hyperglycemia and a marked decrease of pancreatic insulin content, displayed a remarkable accumulation of mononucleated cells in the endocrine pancreas. Morphometric studies revealed an increase of all phenotypes investigated, nearly all mononucleated cells expressed class II histocompatibility antigens (OX-6+, OX-17+) and the number of cells expressing the IL 2R (ART-18+) was markedly enhanced. Sixty-seven percent of the immunotherapeutically treated BB/OK rats normalized plasma glucose and enhanced pancreatic insulin content. The successfully treated animals are characterized by a decrease of cells invading pancreatic islets (OX-19+, OX-8+, W3/25+, KI-M2R+), a decrease of class II histocompatibility antigen and IL 2R expression. The number of IL 2R cells is also diminished in the endocrine pancreas of unsuccessfully treated BB rats.     

Increased expression of transferrin receptors and iron in amoeboid microglial cells in postnatal rats following an exposure to hypoxia

This study was aimed to ascertain the effects of hypoxia on regulation of iron in the brain of newborn rats. At 3 h and 1 day after hypoxic exposure transferrin receptor expression as detected immunohistochemically with the antibody OX-26, and the iron content as shown by Perls' staining of amoeboid microglial cells was markedly increased. The induced changes, however, were not evident at 10 min and in longer surviving rats killed at 3 and 7 days. It is suggested that the upregulation of transferrin receptor expression coupled with iron uptake by amoeboid microglial cells in the periventricular regions is a protective mechanism to facilitate the sequestration of excess iron that may have been released either from the iron-rich oligodendrocytes, or accumulated due to a disruption of its normal transportation following the hypoxic insult. This would help protect the brain from harmful effects of iron.     

Morphological differentiation of microglial cells in culture: involvement of insoluble factors derived from astrocytes

It is believed that ramified resting microglial cells in the brain are differentiated from macrophage-like ameboid cells, although the mechanism for the differentiation is not fully understood. In the present study, we investigated whether the differentiation of microglial cells is observable in mixed brain cell culture prepared from newborn rat forebrains. In confluent mixed brain cell culture, both ramified and ameboid microglial cells were simultaneously present. The ramified cells were located in or under the astrocyte monolayer, while the ameboid cells were over the layer as revealed by confocal laser scan microscopy. The majority of ramified cells appeared after the astrocyte layer was completely formed and they downregulated the expression of the major histocompatibility complex antigen. Fibronectin was detected around ramified microglial cells, and laminin was also present in the astrocyte monolayer in mixed brain cell culture, while both proteins were not distributed near ameboid cells over the monolayer. When purified microglial cells were cultured on astrocyte-derived extracellular matrix in serum-free medium, they ramified. These results show that the differentiation of microglial cells is observable in culture and that astrocytes may play pivotal roles in the differentiation mainly by secreting insoluble factors.     

Primary cortical glial reaction versus secondary thalamic glial response in the excitotoxically injured young brain: microglial/macrophage response and major histocompatibility complex class I and II expression

The excitatory amino acid analog, N-methyl-D-aspartate, was injected intracortically into nine-day-old rats. Resulting axon-sparing lesions in the developing sensorimotor cortex, which secondarily affect thalamic neurons that become deprived of cortical targets, provide an experimental model for the study of the glial response in distantly affected areas. The microglial/macrophage response was studied using tomato lectin histochemistry and major histocompatibility complex I and II immunocytochemistry. Blood-brain barrier integrity was evaluated. In the cortical lesion site, where blood-brain barrier breakdown occurs, the rapid microglial response was restricted to the degenerating area. Microglial changes were first seen at 4 h post-injection, peaking at days 3-5. Reactive microglia changed morphology, increased tomato lectin binding and expressed major histocompatibility complex I. Additionally, some cells expressed major histocompatibility complex II. In the secondarily affected thalamus, the microglial response was not as pronounced as in the cortex, was first seen at 10 h post-injection and peaked at days 3-5. Reactive microglia showed a bushy morphology, were intensely lectin positive and expressed major histocompatibility complex I. The exceptional response of the nine-day-old brain to cortical lesions makes this model an interesting tool for studying the implications of microglial major histocompatibility factor expression in still enigmatic processes such as wound healing and plasticity.     

Nicotinamide and 3-Aminobenzamide Reduce Interferon-γ -Induced Class II MHC (HLA-DR and -DP) Molecule Expression on Cultured Human Endothelial Cells and Fibroblasts

We investigated the effects of nicotinamide and 3-aminobenzamide, known as inhibitors of poly(ADP-ribose) synthetase, on the expression of interferon-γ (IFN-γ) -induced class I and II major histocompatibility complex (MHC) molecules on the surface of cultured human umbilical vein endothelial cells (HUVEC) and human dermal fibroblasts (HDF). Indirect immunofluorescent staining on HUVEC and HDF was performed using monoclonal antibodies against class I MHC (HLA-A, B, C) and class II MHC (HLA-DR, HLA-DP and HLA-DQ) molecules, and then the expression of these molecules was determined using a fluorescence flow cytometry. Human recombinant IFN-γ (100 U/ml) increased the expression of HLA-A, B, C molecules, and induced the expression of HLA-DR molecules and, to a lesser extent, of HLA-DP on both HUVEC and HDF. HLA-DQ molecules were not induced by IFN-γ on either cell type. Nicotinamide and 3-aminobenzamide in the concentration great-er than or equal to 1 mM reduced the IFN-γ -induced expression of HLA-DR and HLA-DP on both HUVEC and HDF, whereas neither agent in the concentration of up to 10 mM affected the IFN-γ -induced increase in HLA-A, B, C molecule expression. These data suggest that nicotinamide and 3-aminobenzamide suppress antigen presenting function of class II MHC positive endothelial cells and fibroblasts at the site of tissue inflammation.     

Response of amoeboid and differentiating ramified microglia to glucocorticoids in postnatal rats: a lectin histochemical and ultrastructural study.

After glucocorticoid injection(s), the number of amoeboid microglial cells (AMC) in the corpus callosum labelled by lectin was markedly reduced when compared with the corresponding control rats. In rats killed at the age of 7 days, all the labeled cells differentiated to become ramified microglia. Ultrastructurally, the AMC in glucocorticoid-injected rats were extremely vacuolated and showed increased lipid droplets. Furthermore, the cells displayed varied lectin labelling patterns especially at both the trans saccules of the Golgi apparatus and lysosomes. In differentiating ramified microglia, massive cellular debris and lectin-stained vesicles or vacuoles were observed; some of the latter appeared to fuse with the plasma membrane. The most striking feature after glucocorticoid (GCC) treatment was the complete diminution of lectin labelling at the Golgi saccules in some differentiating ramified microglia. The present results have demonstrated different effects of glucocorticoids on AMC and differentiating ramified microglia. The differential response of AMC and differentiating ramified microglia to the immunosuppressive drugs may be attributed to the fact that these cells in the postnatal brains subserve different functions or that they are at different differentiation stages. In other words, the sensitivity of microglial cells to the immunosuppressive drugs is dependent upon the stage of cell maturation/differentiation.     

Major histocompatibility complex molecules on glial cells

While glial cells of the central nervous system do not constitutively express class I or II major histocompatibility complex (MHC) molecules, astrocytes and microglial cells can be induced by a variety of factors to express these antigens. Oligodendrocytes have inducible class I but not class II elements. There are considerable differences in regulation of MHC antigen expression between glial cells from rodent and human brains, both in situ and in vitro. The consequence of glial cell MHC expression for immune interactions in the CNS is discussed in the context of glial cell antigen presentation capacity and neural cell susceptibility to cell-mediated immune effector mechanisms.     

Differential immune responses to fetal intracameral spinal cord and cortex cerebri grafts

While the central nervous system (CNS) has been characterized as an immunologically privileged site, there are also several reports describing immunological reactions within the CNS. A certain degree of immunological privilege has also been ascribed to the anterior chamber of the eye. We have used the intraocular transplantation model to study immunological reactions in transplants of embryonic neural tissue. Outbred SpragueDawley rats and inbred Fisher rats were used. Pieces of rat parietal cortex or the cervical spinal cord were prepared from embryonic day 14 and implanted into the eye chambers of adult rats of the same strain. Following intraocular maturation, grafts were analysed using antibodies against: major histocompatibility complex (MHC) class I, MHC class II; rat antigens CD4, CD8, CD11b; T-cell receptor; rat antigen ED1; and glial fibrillary acidic protein. Using this set of markers for immunological reactions, transplants were scored on a blind basis. We found no significant differences in immunological scores between transplants obtained from different litters of fetuses of the outbred animals. Grafting in the outbred strain led to increased numbers of immunologically reactive cells in the grafts. This was not seen in grafts in the inbred strain. Spinal cord transplants led to a significantly higher degree of cytotoxic immunity-related cells expressing MHC class II as well as CD4-positive cells. There was a positive correlation between ED1 negativity and well-developed ramified microglia. From these results we conclude also that well-developed intraocular CNS tissue grafts do contain cellular evidence of immunological events and that different areas of the CNS may provoke different degrees of response. Reactive microglial proliferation appears to be one of the most sensitive ways to monitor the immunological condition of grafted CNS tissue.     

Microglia/macrophages responses to kainate-induced injury in the rat retina

The present study was aimed to elucidate how retinal microglia/macrophages would respond to neuronal death after intravitreal kainate injection. An increased expression of the complement receptor type 3 (CR3) and an induction of the major histocompatibility complex (MHC) class II and ED-1 antigens were mainly observed in the inner retina after kainate injection. Prominent cell death revealed by Fluoro Jade B (FJB) staining and ultrastructural examination appeared at the inner border of the inner nuclear layer (INL) at 1 day post-injection. Interestingly, some immunoreactive cells appeared at the outer segment of photoreceptor layer (OSPRL) at different time intervals. Our quantitative analysis further showed that CR3 immunoreactivity was drastically increased peaking at 7 days but subsided thereafter. MHC class II and ED-1 immunoreactivities showed a moderate but steady increase peaking at 3 days and declined thereafter. Double labeling study further revealed that retinal microglia/macrophages expressed concurrently CR3 and ED-1 antigens (OX-42+/ED-1+) or MHC class II molecules (OX-42+/OX-6+) and remained branched in shape at early stage of kainate challenge. By electron microscopy, microglia/macrophages with CR3 immunoreactivity displayed abundant cytoplasm containing a few vesicles and phagosomes. Other cells ultrastructurally similar to Müller cells or astrocytes could also engulf exogenous substances. In conclusion, retinal microglia/macrophages responded vigorously to kainate-induced neuronal cell death that may also trigger the recruitment of macrophages from neighboring tissues and induce the phagocytotic activity of cells other than retinal microglia/macrophages.     

Accessory cells of the lung. II. Ia+ pulmonary dendritic cells display cell surface antigen heterogeneity

In earlier studies, we had determined that class II (Ia) major histocompatibility complex (MHC) antigen expression in the normal rat lung was limited to dendritic cells and type II alveolar cells. In order to characterize the Ia+ pulmonary dendritic cells of the lung parenchyma, Lewis rat lungs were dissected free of their major airways, enzymatically digested, and serially subjected to density centrifugation on bovine serum albumin, overnight adherence, and immunopanning with a murine anti-rat monoclonal antibody (anti-OX-6) that reacts specifically with class II (Ia) MHC antigens. The purified Ia+ pulmonary cells displayed the morphologic and functional features of dendritic accessory cells, including extended cell processes, absence of nonspecific esterase staining, minimal phagocytosis of latex beads, rapid clustering with T lymphocytes, and co-stimulation of T-cell mitogen responses. Detailed immunophenotyping by cytofluorimetry and immunohistology showed that the purified dendritic cells were Ia (OX-6)+, CD45R (OX-1)+, CD45Rb (OX-22)-, ICAM-1+, and OX-43-. As many as 50% of the cells bound heat-aggregated IgG, while a smaller percentage expressed the CD43 sialophorin antigens (W3/13) expressed by a variety of blood-derived cells, and/or the OX-41 and RMA macrophage antigens. We conclude that Ia+ dendritic cells of lung are heterogeneous with respect to their expression of surface membrane differentiation antigens and may prove to be functionally distinct with respect to their accessory activities.     

Association of some cell surface antigens of lymphoid cells and cell surface differentiation antigens with early rat pregnancy

Monoclonal antibodies and the immunoperoxidase technique were used to localize some cell surface antigens of rat lymphoid cells and cell surface differentiation antigens on cryostat sections of early rat pregnancies. The W3/13 leucocyte sialoglycoprotein was detected almost constantly on trophoblast. The immunoglobulins were more associated with mother's rather than with embryo-derived tissues. We were unable to detect considerable amounts of class I and class II major histocompatibility complex-derived antigens on trophoblast and adjacent decidual cells. The Ia+ cells of the lymphocyte type were occasionally detected in the sites exhibiting presence of immunoglobulins. The Thy-1 cell surface differentiation antigen was detected on the cells producing Thy-1+ material among decidual cells. Depletion of Thy-1 was followed by the regression of decidualized tissue. The OX-2 antigen, known as minor glycoprotein of rat thymocytes, was detected on trophoblast cells and endothelia of decidual vessels, the latter exhibiting also class I major histocompatibility complex-derived antigens. The non-pregnant uterine tissues, as well as the oviduct epithelium were also investigated. The possible role of some of these antigens in the maintenance of the 'immunologically privileged' stage of trophoblast, and in the control of the rearrangement of maternal tissues surrounding the embryo, is discussed.     

MHC-positive, ramified macrophages in the normal and injured rat peripheral nervous system

Summary Resident endoneurial macrophages form a prominent, but little recognized component of the PNS. We have studied immunocytochemically the distribution, morphology and immunophenotype of endoneurial macrophages in several normal peripheral nerves of the rat. In addition, we investigated the macrophage response following crush injury of the sciatic nerve.Resident endoneurial macrophages had a ramified morphology with processes oriented parallel to the long axis of nerve fibres. They were positive for several monocyte/macrophage markers such as ED1, ED2 and the recently-described MUC 101 and MUC 102 antibodies. They furthermore expressed the complement type three receptor, the CD4 antigen and MHC class I and II molecules. These results were consistent in all the peripheral nerves studied. In addition, 1000 rad of -irradiation led to a strong reduction in the number of MHC class II-positive ramified cells in the peripheral nerves similar to that observed in other peripheral organs such as the heart. A considerable percentage of resident macrophages in the PNS and/or their precursor cells are therefore radiosensitive and could be related to the lineage of dendritic cells.Following crush injury, ED1-3-, OX-42-, MUC 101- and MUC 102-positive round macrophages were observed from 24 h postlesion onward at the site of trauma. In the distal part, they were observed to form strings of round, foamy macrophages probably involved in myelin phagocytosis. In contrast, the number of MHC class II-positive resident macrophages was only slightly increased at the site of trauma and in the distal part. These cells transformed from a ramified to a round morphology, but did not appear as typical strings of foamy macrophages.These results demonstrate that the PNS is provided with a resident macrophage population analogous in many respects to microglial cells in the CNS. These constitutively MHC class II-positive PNS microglial-like cells could act as the major antigen-presenting cells in the peripheral nerve. They may thus constitute a local immune defense system of the PNS with a function similar to that of microglial cells in the CNS.On leave of absence from the Institute of Neurology, University of Verona, Italy.     

Patterns of MHC antigenic modulation in cyclosporine-induced autoimmunity. Implications for pathogenesis

To explore the role of aberrant MHC expression in the pathogenesis of cyclosporine-induced autoimmunity (CSIA), we examined the patterns of major histocompatibility complex (MHC) class I and II antigenic modulation during disease induction and the relationship between MHC modulation and tissue injury. Disease was induced consistently in rats but never in mice. Unlike rats, mice were resistant to downmodulation by cyclosporine of class II antigen expression in the thymic medulla. In rats with CSIA, MHC class I and II antigen expression was induced on all target epithelia, frequently before mononuclear infiltration or tissue injury, consistent with a role for MHC antigens in selecting cells for injury. Much increased numbers of strongly class II-positive interstitial dendritic cells were present throughout the body, even in tissues not involved by CSIA. Thus, class II expression alone is insufficient to lead to cell injury in CSIA.