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Early viral proteins as autoantigens: The evidence from JC virus T-antigen
166
LESION-INDUCED CHANGES OF ASTROCYTE MORPHOLOGYAND PROTEIN EXPRESSION IN RAT OPTIC NERVE G. Stoll and H.W. Muller Molecular Neurobiology and Neuroimmunology Laboratory, Department of Neurology, University of Dusseldorf, West Germany Crushing r a t optic nerve (ON) induces a sequence of d i s t i n c t changes in a s t r o g l i a l morphology and the expression of specific proteins. At the molecular level one of the most prominent effects following ON injury was the rapid disappearance of apolipoprotein E (apo E) from GFAP-positive a s t r o g l i a l cell bodies within 3 days post crush as revealed by immunocytochemical methods (Stoll and Muller, Neurosci. Lett. 72,1986,233). Simultaneously typical reactive astrocyte morphology was expressed and maintained for several weeks in degenerating ON. During this period of time no s i g n i f i c a n t myelin phagocytosis and degradation could be observed. However, between 6 to 8 weeks a f t e r lesion the morphology of the GFAP-positive astrocytes was markedly altered by retraction of processes and rounding of the cell body. Numerous i n t r a c e l l u l a r vesicles and myelin inclusions appearing indicating phagocytic a c t i v i t y . Despite these morphological changes into "giant phagocytes" the a s t r o g l i a l marker GFAP ( g l i a l f i b r i l l a r y acid protein) was continuously expressed within these c e l l s . When acquiring phagocytic properties, however, the astrocytes a d d i t i o n a l l y expressed macrophagespecific antigens. Our results demonstrate molecular, physiological and structural properties shared by astrocytes in the injured ON and macrophages of the immune system indicating s i g n i f i c a n t a s t r o g l i a l p l a s t i c i t y in response to central nervous system i n j u r y .
EARLY VIRAL PROTEINS AS AUTOANTIGENS: THE EVIDENCE FROM JC VIRUS T-ANTIGEN
G.
L. Stoner*, C. F. Rvschkewitsch*, D. L. WalLer**, D. Softer*, and H. deF. Webster*
*NINCDS, National Institutes of Health, Bethesda, MD 20892 **Dept. of Medical Microbiology, University of Wisconsin Medical School Madison, WI 53706
In multiple sclerosis the target antigen in the CNS could be a normal component of the ollgodendrocyte or myelin. Alternatlvel~. p a r t l a l reactivation of a latent viral infection might leaO to expression of an early v i r a l protein tEVP) without virus replication. If an EVP becomes the target ot an immune response, i t could mimic an autoantlgen. An EVP mechanism would explain both the pattern of recurrence and the absence of Vlrlons from leslons. Although JC vlrus is not known to latentIy In+ect the brain~ i t occaslonally reactivates in the kidney, anO in progressive multlfocal leukoenceph-
167
alopathy (PML) i t infects ollgodendrocytes. PolyomavirusT-antlgens are early DNA-blndlng nuclear protelns whlch can become targets of the immune response at the cell surface. We have developed a doublelabel method for slmultaneous detectlon of JCV T-ant*gen and capsld protelns ,n PML braln. In many cells T-antlgen Is expressed in the nucleus wlthout detectable capsld antlgens. Somecells stain for both antlgens, and others appear to express only capsld proteins. These results suggest that JCV react,vation is frequently arrested for a time at the early ant*gen stage. Thus, JCV T-antlgen might provide a target for a c y t o l y t l c immune response In the absence of v l r a l r e p l i c a t i o n . JCV Is unllkely to be unique in this regard.
GLIA CELLS AS IMMUNOREGULATORY ELEMENTS OBSERVATIONS ON THE UP-AND DOWN-REGULATING ACTIVITIES OF ASTROCYTE CLONES Deming Sun and Hartmut Wekerle Max-Planck-Gesellschaft, Clinical Research Unit for Multiple Sclerosis, D-8700 Wurzburg, F.R.G. The discovery of antigen-presenting capacity of astrocytes indicates that astrocytes are important cell component in the immune responses of the central nerve system. The successful isolation of a series of astrocyte clones recently in our laboratory made us possible to observe the functional heterogeneity of astrocytes on the clonal levels. The experimental results demonstrated that while some of the astrocyte clones (represented by clone Flo) are potential antigen-presenting c e l l s , in terms of MHC class I I antigen expression induced by exogeneous IFN-y and t h e i r accessory functions in antigen-specific and lectin-mediated T cell p r o l i f e r a t i o n s , other clones (e.g. clone BlO) had d i s t i n c t i v e suppressive a c t i v i t i e s . The suppressive a c t i v i t y of astrocyte clones was radiosensitive, but resistant to the indomethacin treatment, and i t appears to be c e l l - c y c l e related: Con A repose of thymocytes was much more sensitive than the IL2dependent T cell p r o l i f e r a t i o n to the suppressive a c t i v i t y of astrocytes. The results indicated that astrocytes are able to function both as upand down-regulating effector cells in the immune responses.
LESION-INDUCED CHANGES OF ASTROCYTE MORPHOLOGYAND PROTEIN EXPRESSION IN RAT OPTIC NERVE G. Stoll and H.W. Muller Molecular Neurobiology and Neuroimmunology Laboratory, Department of Neurology, University of Dusseldorf, West Germany Crushing r a t optic nerve (ON) induces a sequence of d i s t i n c t changes in a s t r o g l i a l morphology and the expression of specific proteins. At the molecular level one of the most prominent effects following ON injury was the rapid disappearance of apolipoprotein E (apo E) from GFAP-positive a s t r o g l i a l cell bodies within 3 days post crush as revealed by immunocytochemical methods (Stoll and Muller, Neurosci. Lett. 72,1986,233). Simultaneously typical reactive astrocyte morphology was expressed and maintained for several weeks in degenerating ON. During this period of time no s i g n i f i c a n t myelin phagocytosis and degradation could be observed. However, between 6 to 8 weeks a f t e r lesion the morphology of the GFAP-positive astrocytes was markedly altered by retraction of processes and rounding of the cell body. Numerous i n t r a c e l l u l a r vesicles and myelin inclusions appearing indicating phagocytic a c t i v i t y . Despite these morphological changes into "giant phagocytes" the a s t r o g l i a l marker GFAP ( g l i a l f i b r i l l a r y acid protein) was continuously expressed within these c e l l s . When acquiring phagocytic properties, however, the astrocytes a d d i t i o n a l l y expressed macrophagespecific antigens. Our results demonstrate molecular, physiological and structural properties shared by astrocytes in the injured ON and macrophages of the immune system indicating s i g n i f i c a n t a s t r o g l i a l p l a s t i c i t y in response to central nervous system i n j u r y .
EARLY VIRAL PROTEINS AS AUTOANTIGENS: THE EVIDENCE FROM JC VIRUS T-ANTIGEN
G.
L. Stoner*, C. F. Rvschkewitsch*, D. L. WalLer**, D. Softer*, and H. deF. Webster*
*NINCDS, National Institutes of Health, Bethesda, MD 20892 **Dept. of Medical Microbiology, University of Wisconsin Medical School Madison, WI 53706
In multiple sclerosis the target antigen in the CNS could be a normal component of the ollgodendrocyte or myelin. Alternatlvel~. p a r t l a l reactivation of a latent viral infection might leaO to expression of an early v i r a l protein tEVP) without virus replication. If an EVP becomes the target ot an immune response, i t could mimic an autoantlgen. An EVP mechanism would explain both the pattern of recurrence and the absence of Vlrlons from leslons. Although JC vlrus is not known to latentIy In+ect the brain~ i t occaslonally reactivates in the kidney, anO in progressive multlfocal leukoenceph-
167
alopathy (PML) i t infects ollgodendrocytes. PolyomavirusT-antlgens are early DNA-blndlng nuclear protelns whlch can become targets of the immune response at the cell surface. We have developed a doublelabel method for slmultaneous detectlon of JCV T-ant*gen and capsld protelns ,n PML braln. In many cells T-antlgen Is expressed in the nucleus wlthout detectable capsld antlgens. Somecells stain for both antlgens, and others appear to express only capsld proteins. These results suggest that JCV react,vation is frequently arrested for a time at the early ant*gen stage. Thus, JCV T-antlgen might provide a target for a c y t o l y t l c immune response In the absence of v l r a l r e p l i c a t i o n . JCV Is unllkely to be unique in this regard.
GLIA CELLS AS IMMUNOREGULATORY ELEMENTS OBSERVATIONS ON THE UP-AND DOWN-REGULATING ACTIVITIES OF ASTROCYTE CLONES Deming Sun and Hartmut Wekerle Max-Planck-Gesellschaft, Clinical Research Unit for Multiple Sclerosis, D-8700 Wurzburg, F.R.G. The discovery of antigen-presenting capacity of astrocytes indicates that astrocytes are important cell component in the immune responses of the central nerve system. The successful isolation of a series of astrocyte clones recently in our laboratory made us possible to observe the functional heterogeneity of astrocytes on the clonal levels. The experimental results demonstrated that while some of the astrocyte clones (represented by clone Flo) are potential antigen-presenting c e l l s , in terms of MHC class I I antigen expression induced by exogeneous IFN-y and t h e i r accessory functions in antigen-specific and lectin-mediated T cell p r o l i f e r a t i o n s , other clones (e.g. clone BlO) had d i s t i n c t i v e suppressive a c t i v i t i e s . The suppressive a c t i v i t y of astrocyte clones was radiosensitive, but resistant to the indomethacin treatment, and i t appears to be c e l l - c y c l e related: Con A repose of thymocytes was much more sensitive than the IL2dependent T cell p r o l i f e r a t i o n to the suppressive a c t i v i t y of astrocytes. The results indicated that astrocytes are able to function both as upand down-regulating effector cells in the immune responses.