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Interferon-γ and interleukin-12 pathway defects and human disease

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Abstract

A genetic component to human mycobacterial disease susceptibility has long been postulated. Over the past five years, mutations in the interferon-γ (IFNγ) receptor, IL-12 receptor β1 (IL-12Rβ1), and IL-12 p40 genes have been recognized. These mutations are associated with heightened susceptibility to disease caused by intracellular pathogens including nontuberculous mycobacteria, vaccine-associated bacille Calmette Guerin (BCG), Salmonella species, and some viruses. We describe the genotype-phenotype correlations in IFNγ receptor, IL-12Rβ1, and IL-12 p40 deficiency, and discuss how study of these diseases has enhanced knowledge of human host defense against mycobacteria and other intracellular pathogens.

Introduction

Infections with intracellular bacteria such as mycobacteria remain an important cause of human morbidity and mortality worldwide. Immunologic protection against such organisms depends on cell mediated immunity, the major effector of which is the IFNγ-activated macrophage. The importance of IFNγ pathways in host defense against intracellular bacteria was initially made clear through the experimental study of knockout mice. More recently, the identification and characterization of humans with mutations in IFNγ receptor proteins, IL-12 receptor β1, or IL-12 p40 has confirmed the importance of these pathways in human host defense.

Section snippets

IFNγ and the IFNγ receptor

IFNγ was first identified on the basis of its in vitro antiviral activity [1]. It is produced predominantly by T cells and NK cells in response to a variety of inflammatory or immune stimuli, and in general, it stimulates the development and function of immune effector cells. IL-12 and IL-18 secreted by macrophages and dendritic cells are thought to be the primary inducers of IFNγ production in an inflammatory reaction [2], [3], [4], [5] (Fig. 1).

IFNγ receptors are expressed on almost all

IL-12 and the IL-12 receptor

IL-12 is a heterodimeric cytokine produced primarily by antigen presenting cells. It enhances proliferation and cytolytic activity of natural killer (NK) and T cells, and stimulates their IFNγ production [32]. IL-12 plays a key role in promoting TH1 responses and subsequent cell mediated immunity [33], [34], [35]. Production of IL-12 stimulated by microbial lipoproteins, including a 19-kD M. tuberculosis lipoprotein, is mediated by Toll-like receptors [36]. IL-12 is composed of two

Knock-out murine models

The importance of IFNγ pathways in host defense has been demonstrated in mice with targeted disruptions of the IFNγ, IFNGR1, or IFNGR2 genes [45]. After experimental inoculation, IFNγ and IFNGR1 knockout mice have increased susceptibility to experimental challenge with a wide spectrum of infectious agents, including mycobacteria [46], [47], [48], [49], bacteria [50], [51], parasites [52], [53], [54], and viruses [55], [56], [57], [58]. In contrast to wild-type (WT) mice, IFNγ and IFNGR1

Human IFNγ receptor deficiencies

The existence of a genetic component to human mycobacterial disease susceptibility has long been postulated. Differences in susceptibility to M. tuberculosis infection among different racial groups [69] and in twins [70], and manifestations of leprosy [71] support this hypothesis. Also in support of this idea is a tragic incident in which a single virulent viable M. tuberculosis strain was inadvertently used to immunize infants [72], [73]. Responses to the vaccine ranged from death to recovery,

IL12 and IL12 receptor deficiency

Patients with severe mycobacterial disease and autosomal recessive mutations in the genes encoding IL-12 p40 [90] or IL-12Rβ1 [91], [92] have recently been identified (Table 1). In each case, the mutation precluded protein expression. Each patient suffered from severe infection with either NTM or vaccine-associated BCG, and most had severe Salmonella infections. However, in most instances, infection was effectively treated with antibiotics. In several patients, administration of adjunctive IFNγ

Human IFNγ deficiency?

To date human IFNγ deficiency has not been described, despite identification of at least ten different human IFNγ receptor mutations. The current model of IFNγ ligand-receptor interactions does not provide a ready explanation for this discrepancy. The IFNγ knockout mouse model indicates that in mice, IFNγ is not required for normal growth and development. Moreover, disease due to experimental infection with HSV1 or vaccinia virus is less severe in IFNγ knockout mice than in IFNγR1 knockout mice

Tuberculosis in IFNγ receptor, IL-12Rβ1, and IL-12 p40 deficient patients

Among the described patients with known IFNγ or IL-12 pathway defects, only one case of probable tuberculosis has been diagnosed [87]. In a 3-year-old girl with AR partial IFNγR1 deficiency who developed cough, pneumonia, and erythema nodosum, a clinical diagnosis of tuberculosis was made on the basis of development of delayed-type hypersensitivity to tuberculin purified protein derivative and clinical response to administration of anti-tuberculosis antibiotics. Unfortunately, no microbiologic

Nonmycobacterial infections in IFNγ receptor, IL-12Rβ1, and IL-12 p40 deficient patients

While mycobacterial infections have been the major recognized cause of morbidity and mortality in IFNγ receptor, IL-12Rβ1, and IL-12 p40 deficient patients, infections with other intracellular microorganisms have been described. Severe infections with Salmonella species have been diagnosed in a small number of reported IFNγ receptor deficient patients [78], [87], 70% of reported IL-12Rβ1 deficient patients [91], [92], and the single reported IL-12 p40 deficient patient [90]. One patient with L.

Conclusions

Identification of humans with mutations in genes for IFNγ receptor proteins, IL-12 p40, and IL-12Rβ1 has highlighted the importance of IFNγ pathways in human host defense against intracellular pathogens including mycobacteria, Salmonella, and some viruses. Phenotype to genotype correlations are emerging as more patients are identified. In patients with IFNγ receptor deficiency, phenotype, as assessed by infection severity and histopathology, is related to degree of IFNγ responsiveness. Children

Future directions

Recognition of IFNγ’s role in human host defense against intracellular pathogens emphasizes the importance of research to understand the mechanisms by which IFNγ activates macrophage killing of intracellular organisms, and the mechanisms by which pathogens such as M. tuberculosis apparently circumvent macrophage killing. Better understanding these mechanisms will lead to the development of rational preventive and therapeutic strategies directed against M. tuberculosis and other intracellular

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