Normal expression of IFN-gammaR in four patients with uncommon mycobacterial infection phenotypes

Abstract

Several primary immunodeficiency diseases affecting the interleukin 12/interferon gamma (IFN-γ) pathway have been identified, most of them characterized by recurrent and protracted infections produced by intracellular microorganisms, particularly by several species of mycobacteria. In the present study we analyzed the expression of IFN-γ receptor (IFN-γR) and signal transducer and activator of transcription 1 (STAT-1) in 4 children with Mycobacterium tuberculosis infection of uncommon clinical presentation. These molecules were evaluated by flow cytometry and Western blotting in B cells transformed with Epstein-Barr virus and mutations were scanned by single-strand conformational polymorphisms and DNA sequencing. The expression of IFN-γR1 was normal in all 4 patients. The genetic analysis of IFN-γR1 and IFN-γR2 coding sequences did not reveal any mutation. The expression of the STAT-1 molecule was similar in patients and healthy controls; however, when the phosphorylation of this transcription factor in response to IFN-γ activation was evaluated by Western blot, a significant lower signal was evident in one patient. These data indicate that there are no alterations in the expression or function of the IFN-γR chains in these patients. However, the low level of STAT-1 phosphorylation found in one of these patients might be explained by a defect in one of the molecules involved in the signal transduction pathway after IFN-γ interacts with its receptor. In the other three patients the inability to eliminate the mycobacteria may be due to a defect in another effector mechanism of the mononuclear phagocytes.

Genetic polymorphisms in vitamin D receptor, vitamin D-binding protein, Toll-like receptor 2, nitric oxide synthase 2, and interferon-γ genes and its association with susceptibility to tuberculosis

“…This cytokine is produced as a consequence of antigenic activation by natural killer (NK) and T cells, especially T helper 1 (Th1), and its production is increased by antigen-presenting cellderived cytokines such as IL-12 and -18. IFN-γ has regulatory effects in both innate and adaptive immune responses, which include activation of mononuclear phagocytes and NK cells, increased expression of major histocompatibility complex I and II, induction of CD8+ lymphocyte maturation into cytotoxic cells, and promotion of the immunoglobulin isotype switch in B cells towards immunoglobulin G1 and G3 in humans (45).…”