Human Deficiencies in Type-1 Cytokine Receptors Reveal the Essential Role of Type-1 Cytokines in Immunity to Intracellular Bacteria

Abstract

Protective immunity to intracellular bacteria such as mycobacteria and salmonellae depends on an effective cell-mediated immune response (CMI). A major effector mechanism of CMI is the activation of infected macrophages by type-1 cytokines, particularly interferon-gamma (IFN-y). IFN-y is produced by natural killer (NK) and T helper-1 (Thl) cells and its production is regulated by interleukin-12 (IL-12) and interleukin-18 (IL-18), both of which are released by activated macrophages and dendritic cells (Fig. 1) [Ottenhoff and Mutis, 1995; Kumararatne et al., 1990]. IFN-y together with monokines such as TNF-a, activates microbicidal mechanisms of macrophages that are thought to be responsible for the control and elimination of the intracellular infectious pathogen. Moreover, IFN-y induces and enhances MHC class I and II expression, and modulates expression of other molecules involved in antigen presentation, such as proteasomes and TAP, thus resulting in increased immune T cell activation. Patients are likely to benefit from supplementary IFN-y therapy and in the case of IL-12 deficiency, IL-12 supplementation may be an option as well. As a prophylactic measure, live bacterial vaccines such as M. bovis BCG and typhoid vaccines, as well as live viral vaccines, such as yellow fever, should preferably be avoided. Exposure to infectious diseases, such as tuberculosis, listeriosis, salmonellosis and leishmaniasis should obviously be minimized, given the increased risk to develop severe infections. Genetic correction strategies may be developed in the nearby future, including transplantation with gene transduced autologous stem cells.