The last ten years have seen an explosive growth in our understanding of IFN gamma. The cloning of the cDNAs for IFN gamma and its receptor have made available large amounts of highly purified recombinant IFN gamma and soluble IFN gamma receptor. In addition, highly specific neutralizing monoclonal antibodies have been generated to both of these proteins. Using these reagents, IFN gamma and the IFN gamma receptor have been characterized on a molecular basis. Structure-function studies carried out on these proteins have identified key molecular regions that are required for biologic activity. Moreover, a great deal is now known concerning the physiologic role that IFN gamma plays in vivo. In this review we focus on the new developments in the areas of IFN gamma biochemistry and biology and pay particular attention to the IFN gamma receptor and three aspects of IFN gamma biology that are of special interest to immunologists: host defense, inflammation, and autoimmunity.

/pdf/the-molecular-cell-biology-of-interferon-gamma-and-its-3by8w0vlph.pdf

The Molecular Cell Biology of Interferon-gamma and its Receptor

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 Sjogren's 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.

https://www.nejm.org/doi/pdf/10.1056/NEJM197907053010102?listPDF=true

Immune interferon in the circulation of patients with autoimmune disease.

Immune interferon: a pleiotropic lymphokine with multiple effects.

Publisher Summary The chapter focuses on the salient issues and most recent advances concerning IFN-γ's biological function to provide a framework for understanding its role in disease. Medical interest in IFN-γ stems from awareness that a prominent target cell of IFN-γ, the macrophage, occupies a central position in the immune system. Adequate function of the IFN-γ/macrophage system is essential for natural as well as acquired resistance to infection and cancer. Malfunctioning of the system is recognized to be instrumental in inflammatory and autoimmune disease. Of all known cytokines, IFN-γ belongs to the small group that has already been tested for therapeutical effects in patients. IFN-γ is a glycoprotein the size, amino acid sequence, and glycosylation of that are well conserved among animal species. Investigation of IFN-γ signal transduction has brought to light a new pathway—that is, the STAT molecules that are used by many different cytokines. The NK cell population has been identified as a source of IFN-γ that appears to be as important as the T cells. Identification of IFN-γ as a mediator of tissue reactions in inflammatory and autoimmune disease has generated a cogent quest for usable antagonists—for example, humanized monoclonal antibodies, soluble receptors, or antagonistic cytokines.

Interferon-gamma: biology and role in pathogenesis.

Interferon-γ: A historical perspective

Further evidence is presented of the coordinate production and similar properties of two mediators, migration inhibitory factor (MIF) and interferon, in the circulation of BCG-infected mice inoculated with specific antigen (Old Tuberculin, OT). In addition, the interferon elicited by OT in BCG-infected mice is shown to be a distinct molecular species of viral inhibitor and is designated “Type II interferon.” The designation “Type I interferon” is used to describe the viral inhibitor produced in BCG-infected or control mice given nonspecific stimuli such as bacterial lipopolysaccharide (LPS) or Newcastle disease virus (NDV). Although Type II interferon possesses the biologic attributes required to classify a viral inhibitor as “interferon,” it, as well as MIF, differs markedly from Type I interferon in stability at pH 2 and at 56°C, range of species specificity, and antigenicity. Antibodies against highly purified L cell interferon induced by NDV (anti-Type I interferon antibodies) neutralize the activity of interferons elicited in mice by nonspecific stimuli such as LPS or NDV. In contrast, the antiviral activity of Type II interferon and the macrophage-inhibitory activity of MIF, elicited by specific antigen in mice with delayed hypersensitivity, are not affected by high concentrations of antibody against Type I interferon. Evidence is presented which emphasizes the striking similarities in properties of MIF and Type II interferon, although it is not possible to determine whether the two mediators are the same or different protein molecules.

S. B. Salvin

Papers

Production and properties of migration inhibitory factor and interferon in the circulation of mice with delayed hypersensitivity.