Immunosuppression and eye disease. First Vail lecture.

Several viral, fungal, and protozoal diseases of the eye are significantly associated with immunologic deficiencies. Of the viral agents, cytomegaly and herpes simplex and zoster cause a discrete necrotizing retinopathy that has the characteristics of vascular occlusion. Measles may result in a delayed retinopathy that is predominantly macular and associated with subacute progressive encephalopathy. Of the fungal agents, Candida and Aspergillus are apt to involve the eye, beginning as choroidal lesions with extension forward to involve the pigment epithelium and retina secondarily. Mucor and Cryptococcus are less common. Toxoplasmosis is the one ocular protozoal disease whose incidence is increased by immunosuppression, and, like the viral diseases, is characterized by a discrete necrotizing retinopathy and probably results from activation of dormant organisms in the retina. Autoimmunity undoubtedly plays an important role in eye disease but its ocular pathogenesis is obscure.

Pathogenesis of subacute spongiform encephalopathies.

The subacute spongiform encephalopathies include scrapie of sheep, transmissible mink encephalopathy, and kuru and Creutzfeldt-Jakob disease of man. These diseases are caused by filterable infectious agents with unique physical properties. The usual sources of infection in nature are not completely known. Epidemiological evidence suggests that the agents may enter the body through breaks in the skin and mucous membranes. Experimental studies of scrapie after subcutaneous inoculation demonstrated early replication of the agent in lymphoid tissues and later appearance in other organs; as the amount of agent in the central nervous system (CNS) increased, it decreased in or disappeared from lymphoid tissues. In preliminary studies of kuru and Creutzfeldt-Jakob disease, the infectious agents were regularly recovered from the brains of clinically-ill patients and experimental animals but only occasionally from organs outside the CNS. It remains to be seen if early events in the pathogenesis of the two human diseases, before the appearance of clinical signs, are similar to those in scrapie.

Multiple sclerosis. A hypothesis on the aetiology.

Based on personal experience with multiple sclerosis a hypothesis is set out concerning a possible viral origin for M.S, a protective immunological defense mechanism for sequestration of the virus, the processes involved in the occasional failure of this defense mechanism, thus permitting the onset of exacerbations, the avoidance of such exacerbations by blood-brain barrier protection with a phenothiazine during the prodromal pressor phase, and the probable site of action of the drug. The processes described may be general rather than specific to M.S. and may also occur in other encephalitides of viral or other slow agent origin.

[Paget's bone disease and virus (author's transl)]. / Maldie osseuse de Paget et virus.

In spite of the large number of theories advanced to clarify the etiology of Paget's disease, its cause is still being discussed, and no satisfactory conclusion has been reached. The possibility of a viral origin was raised by the discovery of inclusion bodies, detectable by electron microscopy, in the nuclei and cytoplasm of the osteoclasts in the affected bone tissue, in 1974. In fact, the microcylindrical structures described by various authors, and visible only in osteoclasts and only in Paget's disease, if one excepts certain giant-cell bone tumors, have a close analogy, morphologically, with the nucleocapsids of paramyxovirus of the measles group, described in experimental infections or human diseases (subacute sclerosing panencephalitis). Various morphological arguments, drawn from studies of inclusions in richly nucleated giant osteoclasts found in Paget's disease, are in favor of the viral nature of these formations. Immunocytological methods have constituted another approach to the problem raised by the discovery of inclusions. They have demonstrated the existence of an antigenic material in the osteoclasts found in Paget's disease which reacts positively with antiserums containing anti-measles antibodies or with produce a crossed reaction with them. Controlled tests have confirmed these findings. Biological arguments are presently sufficient, therefore, for the possibility of a viral etiology of Paget's disease to be validly accepted from among the pathogenic hypotheses proposed for a disease that was first described a century ago.

The immunology of virus infections.

In order to describe the complex virus-host relationship the authors review the viral mechanisms of infection and viral replication as well as the basic pattern of the immune responses. The delicate balance of the infection-immunity equation is complicated by the instability of both entities. The better understanding of these factors provides a rationale for the therapeutic counteraction of virus infections, reducing the likelihood of viral exposure becoming clinical viral infection.

[Characteristics of immune reactions to the influenza virus in mice with a slow influenzal infection]. / Osobennosti immunnykh reaktsii na virus grippa u myshei pri medlennoi grippoznoi infektsii.

It had previously been shown that intrauterine infection of mice with influenza virus resulted in growth retardation and significant immunosuppression to various nonspecific agents and influenza virus. The present study demonstrated that such mice also had lower production of specific antibody and reduced capacity to form the delayed hypersensitivity to influenza virus. Despite the lack of specific immune response, such mice had high levels of response to influenza virus in adoptive transfer. The reasons for which lymphocytes of mice with slow influenza infection fail to manifest their immunological potentials in situ require further study.

[The humoral immunity system of mice with experimental slow influenzal infection]. / Sostoianie sistemy gumoral'nogo immuniteta u myshei pri éksperimental'noi medlennoi grippoznoi infektsii.

The status of the interferon system and level of immunoglobulins were studied in C57BL6 mice with slow influenza infection. These mice showed signs of immunosuppression: low endogenous interferon production, synthesis of alpha- and gamma-interferon by splenocytes of these mice in vitro 4-8 times lower than by those of the controls, lower levels of IgG in the blood serum. These data indicate general suppression of humoral immunity.

[Immunologic analysis of the pathology developing in mice as a results of intrauterine infection with the influenza virus]. / Immunologicheskii analiz patologii, razvivaiushcheisia u myshei v rezul'tate vnutriutrobongo zarazheniia virusom grippa.

The progency of C57BL/6 mice consisting of three groups: with signs of slow influenza infection ("dwarf"), "nude-like" resembling nude mice, and "nude-like" with spontaneous fur growth, was examined. The slow influenza infection in "dwarf" mice was found to be characterized by marked immunosuppression manifested by a sharp reduction of the number of antibody- and rosette-forming cells and blasttransformation of spleen lymphocytes into T- and B-mitogens. The most marked immuno-suppression was found in the "dwarfs" born to the females infected with the virus enriched with standard virions. "Nude-like" animals also had marked immunosuppression (particularly with regard to the rosette-formation), however, the "dwarfs" appeared to have more marked affection of B-cells as compared with "nude-like" mice. Gradual restoration of fur in a portion of "nude-like" animals (spontaneous growth) was due to sharp stimulation of immune responsiveness in them as manifested by a two-fold (as compared with the controls) increase in the number of antibody- and rosette-forming cells and normalization of spleen cell response to T- and B-mitogens. Differences between nude and "nude-like" mice consisting in the latter in the affection of not only T- but also B-link of immunity are discussed.

[Pathogenesis of amyotrophic leukospongiosis reproduced in guinea pigs by retrobulbar infection]. / Patogenez amiotroficheskogo leikospongioza, vosproizvedennogo u morskikh svinok pri retrobul'barnom zarazhenii.

Pathogenesis of amyotrophic leukospongiosis (ALSP) with a short incubation period induced in guinea pigs was studied. After retrobulbar inoculation, the unconventional ALSP virus disseminated both neurogenically (along the optic nerve) and hematogenically. At early stages of the disease the spleen appeared to play the leading role in multiplication and/or accumulation of the agent. The earliest morphological sign of the CNS involvement was vacuolation of motoneuron cytoplasm. The ALSP agent first affected the spinal motoneurons, then an ascending pathological process developed. In the terminal stage of the disease, the unconventional ALSP virus was also detected in visceral tissue, besides the CNS, spleen, and peripheral blood lymphocytes.

[The role of suppressor cells in congenital influenza infection in mice]. / Rol' supressornykh kletok pri vrozhdennoi gippoznoi infektsii u myshei.

Young mice with congenital influenza infection have lower immune responsiveness of lymphocytes to nonspecific mitogens and influenza virus antigens. Lymphocytes of such animals inhibit proliferation of normal lymphoid cells activated with concanavalin A and immune lymphocytes activated with influenza virus antigens. It is assumed that in congenital influenza infection one of the possible mechanisms of immunosuppression in mice is the activation of suppressor T-cells.

[The role of maternal virus-specific cytotoxic T-lymphocytes in the immunopathology of congenital influenza infection in mice]. / Rol' materinskikh virusspetsificheskikh tsitotoksicheskikh T-limfotsitov v immunopatologii pri vrozhdennoi grippoznoi infektsii u myshei.

Using 51Cr isotope label it was demonstrated that a very low per cent of syngeneic lymphocytes derived from healthy donors and inoculated in the blood stream of uninfected or influenza virus-infected pregnant mice is found in fetuses before delivery. Similar results were obtained after inoculation of virus-specific cytotoxic lymphocytes (CTL) into uninfected pregnant mice. After inoculation into the blood stream of infected pregnant mice of virus-specific CTL their migration into fetuses before delivery increases, being most marked in 25-30% of mice. Intravenous inoculation of excess CTL (10(6) cells) to infected pregnant mice resulted in rapid development of signs of slow influenza infection in the progeny with typical clinical picture and histopathological lesions in organs and tissues. Large doses (10(7)-10(8) cells) of CTL inoculated into the blood stream cause higher reduction and death of fetuses and increase the rate of stillbirths. The role of maternal virus-specific CTL in the pathogenesis of experimental congenital and especially slow influenza infection is discussed.

[Anti-neurofilament antibodies in slow infections of the nervous system]. / Antitela k neirofilamentam pri medlennykh infektsiiakh nervnoi sistemy.

Twenty-six patients including 12 with lateral amyotrophic sclerosis, 7 with multiple sclerosis, 5 with the Creutzfeld-Jakob disease and 2 with Alzheimer's disease were examined. Antibodies to neurofilaments in the blood serum were detected in all cases of the Creutzfeld-Jakob disease and Alzheimer's disease and in 8 patients with lateral amyotrophic sclerosis with clinical evidence of supranuclear structure involvement. A conclusion is drawn about a certain similarity of pathogenic mechanisms of these diseases, as well as about heterogeneity of the cytoskeleton of neurons in the brain and the spinal cord.