Abner Louis Notkins

Virus-induced diabetes mellitus. Isolation of a virus from the pancreas of a child with diabetic ketoacidosis.

A healthy 10-year-old boy was admitted to the hospital in diabetic ketoacidosis within three days of onset of symptoms of a flu-like illness. He died seven days later and post-mortem examination showed lymphocytic infiltration of the islets of Langerhans and necrosis of beta cells. Inoculation of mouse, monkey and human cell cultures with homogenates from the patients pancreas led to isolation of a virus. Serologic studies revealed a rise in the titer of neutralizing antibody to this virus from less than 4 on the second hospital day to 32 on the day of death. Neutralization data showed that the virus was related to a diabetogenic variant derived from Coxsackievirus B4. Inoculation of mice with the human isolate produced hyperglycemia, inflammatory cells in the islets of Langerhans and beta-cell necrosis. Staining of mouse pancreatic sections with fluorescein-labeled antiviral antibody revealed viral antigens in beta cells. Both the clinical picture and animal studies suggested that the patients diabetes was virus induced.

Immune Interferon in the Circulation of Patients with Autoimmune Disease

The observation that type II, or immune, interferon could be produced by peripheral-blood leukocytes in vitro on an immune-specific basis suggested that it also might be produced in vivo in various autoimmune disorders. We found immune interferon in the serums of patients with systemic lupus erythematosus, rheumatoid arthritis, scleroderma and Sjögrens syndrome. Among 28 patients with systemic lupus erythematosus, 71 per cent of those with active and 21 per cent of those with inactive disease showed interferon in their serums. Serial serum samples showed a good correlation between interferon titers and disease activity. Moreover, interferon titers correlated positively with antibodies to DNA and negatively with serum levels of the third component of complement. It is possible that the production of interferon may contribute to immunologic aberrations in auto-immune diseases and also protect the already compromised host from viral infections.

Autoimmune type 1 diabetes: resolved and unresolved issues

Based on the presence of autoantibodies and a strong HLA linkage, type 1 diabetes is now classified as a chronic autoimmune disease. Many issues, however, remain unresolved. Although autoantibodies to GAD65, IA-2, and insulin are clearly markers for this disease, it is not known whether they contribute to pathogenesis or are simply the response to an existing underlying destructive process. Based on extensive studies in animal models, it is thought that it is the cell-mediated immune response that is actually responsible for the destruction of β cells. However, this has not been unequivocally established in humans because of the lack of a reliable assay for measuring cell-mediated immunity to β cell antigens. What triggers the autoimmune response also is not known. The search for type 1 diabetes -specific genes so far has not been revealing, and environmental triggers, although widely viewed as important, have remained elusive. Despite enormous interest in the basis of the disease, type 1 diabetes pathogenesis remains understudied because of the difficulty and hazards in biopsying the pancreas. Nevertheless, the studies on autoimmunity have provided clinically useful information. In particular, the demonstration of the presence of autoantibodies years before the onset of clinical symptoms has made it possible to identify individuals at high risk of developing type 1 diabetes and to initiate therapeutic intervention trials on relatively small numbers of subjects. Thus, to a very large degree, type 1 diabetes is a predictable disease. In addition, the demonstration of autoantibodies in 5-10% of individuals who were classified with type 2 diabetes suggests either that some of these individuals have a combination of type 1 and type 2 diabetes or that the number of patients with type 1 diabetes may be nearly twice as great as previously thought. (Less)

Concepts in Viral Pathogenesis II

This paper contains papers divided among 10 sections. The section titles are: Viral Structure and Function; Viral Constructs; Oncogenes, Transfection, and Differentiation; Viral Tropism and Entry into Cells; Immune Recognition of Viruses; Evolving Concepts in Viral Pathogenesis Illustrated by Selected Plant and Animal Models; Evolving Concepts in Viral Pathogenesis Illustrated by Selected Diseases in Humans; New Trends in Diagnosis and Epidemiology; and Vaccines and Antiviral Therapy.

Cytotoxic Autoantibodies to Beta Cells in the Serum of Patients with Insulin-Dependent Diabetes Mellitus

We studied serum from 36 patients with insulin-dependent diabetes mellitus (IDDM) for the capacity to lyse beta cells. Immunofluorescence revealed an islet-cell cytoplasmic antibody (ICA) in 20 patients with IDDM and an islet-cell-surface antibody (ICSA) in 23. Neither ICA nor ICSA was found in any of 21 normal controls or 15 patients with non-insulin-dependent diabetes. In the presence of complement. ICSA-positive serum caused significant lysis as measured by release of 51Cr (50.1 +/- 8.8 per cent) from cultured rat islet cells, but ICSA-negative serum did not (17.7 +/- 7.3 per cent) (P < 0.001). Proof that ICSA-positive serum was lytic for beta cells was obtained by a double-fluorescence technique that identified lysed cells by their capacity to take up ethidium bromide and beta cells by their staining with fluorescein-conjugated antibody to insulin. These findings suggest that cytotoxic ICSA contributes to the pathogenesis of IDDM, but the mere presence of ICSA does not appear to be sufficient to produce diabetes; family studies showed that one fourth of the serum samples from nondiabetic first-degree relatives of diabetic probands were ICSA-positive and cytotoxic for beta cells.

HIV-associated nephropathy in transgenic mice expressing HIV-1 genes

Transgenic mice were produced that bore copies of a defective HIV provirus. The transgenic offspring from three independently derived mouse lines manifested renal disease associated with proteinuria, a high mortality rate, and HIV-specific gene expression in the kidney. An early histopathological lesion in the kidney was focal glomerulosclerosis. Moribund animals had diffuse glomerulosclerosis with prominent microcystic tubular dilatation, tubular epithelial degeneration, and interstitial nephritis. Electron microscopy revealed ultrastructural features consistent with the glomerulosclerosis: effacement of the foot processes of visceral epithelium and an increase in mesangial cell matrix. Transgenic mice variably expressed 6-, 4.3-, and 2-kb HIV-specific RNAs and HIV-related polypeptides in several tissues including kidney. Immunocytostaining revealed the presence of HIV-related protein in the glomeruli of affected animals. Glomerulopathy in these transgenic mice and HIV-associated nephropathy in man have similar features.

Autoantibodies as predictors of disease

Activation of the immune response is a major feature of many disease processes. Immune responses can be protective, as in infectious diseases, or destructive, as in autoimmune inflammatory diseases, or both. The immune response usually involves activation of both T and B cells, the latter producing antibodies that can be detected in the sera and can be used to guide the clinical management of certain diseases. Here, we focus on autoantibodies as predictive markers of disease. While the practical value of autoantibodies has been realized in some clinical conditions, it remains underutilized in the majority of diseases. Recognizing the clinical potential of autoantibodies and identifying appropriate populations to screen for such autoantibodies, we argue, could have rich practical rewards.

Latent Ganglionic Infection with Herpes Simplex Virus Types 1 and 2: Viral Reactivation in vivo after Neurectomy

Inoculation of the cornea, lip, or footpad of mice with herpes simplex virus type 1 resulted in a latent infection of the local sensory ganglia. Inoculation of the vagina and cervix with herpes simplex virus type 2, as well as type 1, also induced a latent ganglionic infection. With the use of sciatic nerve section as a stimulus, a reproducible model of viral reactivation in vivo was established.

Human monoclonal autoantibodies that react with multiple endocrine organs.

MANY human diseases have an autoimmune component. In some, such as myasthenia gravis1 and Hashimotos thyroiditis,2 the autoimmune response is predominantly organ-specific. In other diseases, such ...

Multiple organ-reactive monoclonal autoantibodies

Autoantibodies directed against a wide range of normal tissue antigens have been found in the sera of patients with autoimmune diseases1–8. It is generally thought that different and specific autoantibodies react with different tissues but the possibility exists that some autoantibodies may react with common antigens found in different tissues and organs. Recently, we showed that mice infected with reovirus developed a polyendocrine disease with autoantibodies to the pancreas, anterior pituitary, thymus and gastric mucosa9,10. Using hybridoma technology, we obtained a number of monoclonal autoantibodies11 which reacted with antigens in single organs. We now report the production and pattern of reactivity of seven multiple organ-reactive monoclonal autoantibodies. By using antibody-affinity columns, autoantigens also have been isloated and their molecular weights determined. The results suggest that monoclonal multiple organ-reactive autoantibodies react either with the same molecule present in several organs or with common antigenic determinants on different molecules in multiple organs. In either case, the existence of multiple organ-reactive antibodies may be a partial explanation for multiple organ autoimmunity.