Viruses disrupt functions of human lymphocytes. II. Measles virus suppresses antibody production by acting on B lymphocytes.

Measles virus infection is associated with suppression of immune functions both in vivo and in vitro. The virus infects T lymphocytes, B lymphocytes, and monocytes, but does not produce cytolysis. One consequence of infection in vitro is the failure of T and B lymphocyte mixtures to cooperate in secreting Ig in a PWM-driven system. Here we report that this defect in Ig secretion resides in the infected B lymphocyte, but not in the T lymphocyte or monocyte. Further, NK cells are not involved, since neither their depletion nor reconstitution abrogates suppression of B cell function. Proliferation of B cells in the early culture period is suppressed, suggesting that measles virus suppresses B cell development at the activation or proliferation stages, but does not affect terminal differentiation into Ig secreting cells.

Human histocompatibility determinants and virus antigens: effect of measles virus infection on HLA expression.

Histocompatibility antigens on the surface of human lymphoblastoid cells were quantified by a microadsorption technique. During the course of measles virus infection, no quantitative or qualitations in surface HLA antigens were observed. In contrast, infection with poliovirus type 1 or vesicular stomatitis virus, or treatment with puromycin (50 microgram/ml) resulted in a significant decrease in surface HLA. These experiments suggest that an inhibition of host protein synthesis rather than the insertion of virus-specificied antigens into the membrane results in a net decrease in amounts of this cell surface antigen. The HLA antigens also appear to be both functionally and structurally distinct from measles virus surface antigens. Pretreatment of cells with HLA-directed antibody did not prevent the infection of these cells by measles virus, thus HLA antigens appear unrelated to the measles virus receptor site on the plasma membrane. Electron microscopic studies revealed that measles virus maturation occurs at membrane sites devoid of demonstrable HLA. Furthermore, HLA antigens could not be detected on the surfaces of mature infectious virions.

Host immunoglobulin G and complement deposits in the choroid plexus during spontaneous immune complex disease.

Hybrid (NZB x W)F(1) mice spontaneously develop antibodies to nuclear antigens (ANA) and DNA (ADNA) and are an animal model of human systemic lupus erythematosus. Immunofluorescent and electron microscopic observations of the choroid plexus and renal glomeruli of (NZB x W)F(1) mice reveal deposits of host immunoglobulin G (IgG) and the third complement component which appear shortly after the development of ANA and ADNA in the circulation. Additionally, enhancement of ADNA responses accelerates the appearance and severity of IgG deposits in the choroid plexus. The choroid plexus may be a favored site for the deposition of immune complexes and the neuropsychiatric findings in patients with systemic lupus erythematosus and some patients with acute or chronic infections may be related in part to immune complex disease of the choroid plexus.

Virus-induced alterations in homeostasis: alteration in differentiated functions of infected cells in vivo.

The noncytopathic lymphocytic choriomeningitis virus displays a tropism for the anterior lobe of the murine pituitary gland. Virus replicates in cells that make growth hormone. This results in a diminished synthesis of growth hormone with a concomitant clinical picture of retarded growth and hypoglycemia. However, there is no morphologic evidence of either cell necrosis or inflammation in the anterior lobe of the pituitary. Hence, during infection in vivo, a noncytopathic virus may turn off the "differentiation" or "luxury" function of a cell while not killing that cell (loss of vital function). This is turn can disrupt homeostasis and cause disease. This model illustrates a novel way whereby viruses may cause disease.

Reduced nerve blood flow in hexachlorophene neuropathy: relationship to elevated endoneurial fluid pressure.

To test the hypothesis that increased endoneurial fluid pressure (EFP) causes a reduction in nerve blood flow (NBF) in the vasa nervorum, we adapted a noninvasive method for measurement of nerve blood flow which was originally developed for measurement of local cerebral blood flow. This technique measures tissue distribution to the radioisotope, 14C-iodoantipyrine, and was used to compare NBF in sciatic nerves of rats with increased EFP induced by feeding them hexachlorophene (HCP), a neurotoxin which causes edema exclusively to the nervous system and confined to the myelin sheath. Elevation of interstitial fluid pressure in peripheral nerves from control values of 2.0 +/- 1.0 cm H2O to over approximately 6 cm H2O was associated with a statistically significant reduction in nerve blood flow from 14.8 +/- 5.9 to 7.8 +/- 2.5 ml/100 g of tissue/minute (min). These results support the hypothesis that increased endoneurial fluid pressure exacerbates the neuropathy by diminishing local blood flow.

Localization of cytomegalovirus proteins and genome during fulminant central nervous system infection in an AIDS patient.

Approximately one-half of autopsied acquired immune deficiency syndrome (AIDS) patients demonstrate probable human cytomegalovirus (CMV) infection of the central nervous system (CNS). Because CMV in brain tissue or cerebrospinal fluid is difficult to culture, we used antisera, and radioactive probes to diagnose CMV infection in the brain of an autopsied AIDS patient, who died of a fulminant CNS and systemic infection with CMV, suggesting a complete seeding of the ependymal regions possibly followed by a uniform ventriculofugal spread of the virus deep into the parenchyma. Cytomegalic cells were observed in optic nerve, retina, ependymal and subependymal regions of the brain and in the motor (but not sensory) root-CNS junctions. Immunocytochemistry demonstrated viral antigen predominantly in cytomegalic cells, which also stained positively for glial fibrillary acidic protein, S-100, or neuron-specific enolase, but not a common leukocyte antigen. Virions were visible in these cells examined by electron microscopy. No viral replication was observed in pineocytes, pituicytes or the choroid plexus. Morphologically normal cells that were CMV antigen-negative proved to be infected after in situ hybridization with well-defined human CMV DNA fragments. Hence, morphologically normal glia and neurons show restricted replication of CMV, indicating that such cells may be latently infected.

Effects of regional spinal X-irradiation on demyelinating disease caused by Theiler's virus, mouse hepatitis virus or experimental allergic encephalomyelitis.

The effects of X-irradiation on the course of chronic demyelinating disease were examined in mice with experimental allergic encephalitis (EAE), mouse hepatitis virus (MHV) or Theiler's virus (DAV) infection. One month after the induction of EAE or 2-16 months after inoculation of DAV, exposure of the cervical spinal cord to 20 Gy X-rays caused local exacerbation of disease activity but spinal irradiation did not affect MHV-induced demyelination. In EAE, there was a significant increase in the number of inflammatory cells in the irradiated part of the cord. Mice infected with DAV showed locally increased demyelination and axonal degeneration but no change in the titer of infectious virus within the cord. Thus in DAV infection, as in EAE, the exacerbation of disease seemed to be due to vascular or immunological factors rather than viral reactivation.

Selective localization of wild type and mutant mouse hepatitis virus (JHM strain) antigens in CNS tissue by fluorescence, light and electron microscopy.

Demyelination may be induced by several different pathogenetic mechanisms. We have been utilizing mouse hepatitis virus (MHV) to study virus-induced demyelination in the central nervous system (CNS). To learn whether the different disease phenotypes in 4-week-old mice, caused by wild type (a model for fatal encephalomyelitis) or mutant ts8 (a model for primary demyelination), is due to an altered cellular tropism, we have developed an immunolabeling technique to evaluate critically the localization of MHV antigens in the unique cells of the CNS. Using mouse derived L-cells and primary neuronal cells in vitro, we determined an appropriate fixative (4% paraformaldehyde and 0.5% glutaraldehyde) that both preserved MHV antigenicity and cell structure. These studies in vitro showed the presence of MHV antigens on the surface of cells. Utilizing immunoperoxidase labeling as developed, we studied the localization of MHV antigens in vivo. MHV antigens associated with wild type (wt) virus were localized in neuronal cells as well as oligodendrocytes, which might account for the encephalomyelitis and primary demyelination, respectively. In contrast, MHV antigens associated with ts8 were localized rarely in neurons but commonly in oligodendrocytes. This might account for the uncommon occurrence of fatal encephalomyelitis, but the frequent presence of primary demyelination. Of interest was the finding of viral antigens during MHV infection in the cytoplasmic processes of oligodendrocytes surrounding intact myelin sheaths. We conclude that the different disease phenotypes caused by wt and mutant ts8 reflect differences in the cellular tropism of the two viruses for cells in the CNS.

Immunohistochemistry as an aid in the diagnosis of Hirschsprung's disease.

The interpretation of rectal suction mucosal biopsies taken for the purpose of ruling out Hirschsprung's disease (HD) can be especially difficult in neonatal patients because of ganglion cell (GC) immaturity. Acetylcholinesterase histochemistry on frozen sections can be helpful but requires experience and may be complicated by excessive mucosal hemorrhage. The authors retrospectively have studied 27 patients, including 11 patients with HD, on whom conventionally fixed and embedded tissue was available, using an immunoperoxidase system directed against neuron-specific enolase (NSE) and S100 protein. NSE immunostaining produced intense staining of GC perikarya, greatly facilitating recognition of small immature forms. S100 immunostaining also highlighted GC as prominent negative stained cells surrounded by the positivity of Schwann cells. Both stains were helpful in demonstrating the overall pattern of microinnervation and its relationship to possible GC. The authors conclude that NSE and S100 immunostaining may facilitate interpretation of rectal mucosal biopsies when Hirschsprung's disease is being considered as a possibility.

Pathology of dendrites in subacute spongiform virus encephalopathies.

The spongiform changes in the cerebral cortex of scrapie mice and of chimpanzees afflicted with experimental kuru and Creutzfeldt-Jakob disease were examined by electron microscopy. The pathognomonic findings consisted of swelling and vacuolation of neurons, particularly of dendrites. Fusion of swollen cells and processes occurred. The changes were associated with alterations of plasma membranes. Curled fragments of membranes accumulated at points of cell fusion and at the margin of vacuoles within dendrites. The abnormal membranes were wider and more osmiophilic than normal plasma membranes. These findings as well as other data on the nature of the atypical viruses of scrapies, kuru, and Creutzfeldt-Jakob disease indicate that the infectious agents are closely associated with membranes and that alterations of neuronal membranes initiate the spongiform degeneration of neurons.

Pathology of multiple sclerosis.

MS has certain salient morphologic features that distinguish it from other disorders of white matter and that may represent points of departure for investigation.