*This website was produced as an assignment for an undergraduate course at Davidson College.*

Note: This web page should NOT be used for medical advice. Please consult your physician for information on the disease

Interferon-gamma Receptor Deficiency
(IFNgR deficiency)

1. 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 IFNg-activated macrophage. IFNg activates transcription of a large number of genes that play roles in antiviral activity, apoptosis, antigen processing, MHC protein expression, and type 1 T helper cell (TH1) development. IFNg also activates macrophages to kill or restrict growth of microbial targets; thus the appropriate function of IFNg receptor appears to be important in host defense against mycobacteria (Rosen et al., 2004).

1.1. IFNg and the IFNg receptor

IFNg 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 (Janeway et al., 2005) (for more information on IFNg, you can access my IFNg protein webpage). IFNg receptors are expressed on almost all nucleated cells, and show species specificity in their ability to bind IFNg (Farrar et al., 1993). The functional IFNg receptor is composed of two 90 kDa IFNgR1 proteins and two 62 kDa IFNgR2 proteins . The human IFNgR1 gene contains seven exons, and is located on chromosome 6. The extracellular portion of IFNgR1 contains the IFNg ligand-binding domain; the intracellular portion contains domains necessary for signal transduction and receptor recycling. The IFNgR2 gene also contains seven exons, and is located on human chromosome 21. The intracellular IFNgR2 domain is necessary for signal transduction. The extracellular domain of IFNgR2 interacts with the IFNgR1/IFNg complex, but does not itself play a major role in ligand binding (Bach et al., 1997) (see Fig. 1) .

Figure 1. A schematic representation of the interferon-g receptor (IFN-gR) and its signalling pathway. The receptor for IFN-g has two subunits: IFN-gR1, the ligand-binding chain (also known as the a chain) and IFN-gR2, the signal-transducing chain (also known as the b chain or accessory factor 1). These proteins are encoded by separate genes (IFNGR1 and IFNGR2, respectively) that are located on different chromosomes. As the ligand-binding (or a) chains interact with IFN-g they dimerise and become associated with two signal-transducing (or b) chains. Receptor assembly leads to activation of the Janus kinases JAK1 and JAK2 and phosphorylation of a tyrosine residue on the intracellular domain of IFN-gR1. This leads to the recruitment and phosphorylation of STAT1 (for ‘signal transducers and activators of transcription’), which forms homodimers and translocates to the nucleus to activate a wide range of IFN-g-responsive genes. After signalling, the ligand-binding chains are internalised and dissociate. The chains are then recycled to the cell surface (Image permit pending).


2. IFNgR deficiency

2.1 WT phenotype vs. IFNgR deficient:

Individuals with defective IFNg receptor expression or function have a widespread defect in macrophage activation, which results in reduced production of TNFa and other proinflammatory cytokines in response to IFNg and endotoxin, defective MHC class II expression in response to IFNg or antigenic stimulation, and reduced ability to present antigen to T cells (Dorman et al., 1998). This importance of IFNg pathways in host defense has been demonstrated in mice with targeted disruptions of the IFNg, IFNGR1, or IFNGR2 genes. IFNgR knockout mice have increased susceptibility to experimental challenge with infectious agents. In contrast to wild-type (WT) mice, IFNg and IFNgR knockout mice develop neither mature granulomas nor protective immunity after experimental infection with mycobacteria (Jouanguy et al., 1999). Thus, IFNgR deficiency is an inherited disorder associated with complications from infections caused by mycobateria, and other microorganisms such as Listeria and Salmonella species.

2.2 Symptoms and Diagnosis

The attenuated strain of Mycobacterium bovis bacille Calmette–Guérin (BCG) is the most widely used standard vaccine in the world. In most children, inoculation of live BCG vaccine is harmless. In rare cases, however, vaccination causes disseminated BCG infection, which may be lethal. Therefore one of the first symptoms is that affected children invariably develop disseminated (BCG) infection shortly after inoculation with live BCG vaccine (Roesler et al., 1999). Later on, the IFNgR deficiency patient will develop a history of severe or repeated mycobacterial infections that may involve the lungs, lymph nodes, blood and bone marrow. People with complete IFNGR deficiency have more serious infections than those with partial IFNGR deficiency. The disease occurs early in infancy in those with complete IFNGR deficiency. Those with partial deficiency are more likely to develop illness later in childhood (Fieschi et al., 2001). Sophisticated laboratory tests measure the amount of interferon gamma in the blood and show the patient's white blood cells respond poorly, or not at all, to interferon gamma. Depending on whether the patient has complete or partial IFNGR deficiency, the blood will have either very high or very low levels of interferon gamma. Genetic testing can determine whether the patient has mutations that cause IFNgR deficiency (Roesler et al., 1999).

2.3 Mutations that give rise to IFNgR deficiency

The existence of a genetic component to human mycobacterial disease susceptibility had long been postulated. Now we know that a variety of IFNgR mutations are associated with complete or partial IFNgR deficiency. They include nonsense and splice mutations and frameshift insertions and deletions. All result in a premature stop codon upstream from the segment encoding the transmembrane and the extracellular ligand-binding domain, either precluding cell surface expression of the receptors at the cell surface or by disrupting the IFNg binding site without affecting surface expression respectively. Phenotype-to-genotype correlations are being established as more affected individuals are identified. However, for IFNgR defficiency, the phenotype appears to depend less on which gene (IFNgR1 vs IFNgR2) is mutated, but rather on the extent to which the mutation reduces IFNg responsiveness (Dorman et al., 2004).

2.3.1 Complete IFNgR deficiency

Complete absence of IFNg responsiveness is associated with a more severe clinical phenotype. Such affected individuals characteristically have severe disseminated mycobacterial infections that may involve lungs, viscera, lymph nodes, blood, and bone marrow. Onset of first environmentally acquired mycobacterial infection is usually during infancy. Infections are typically caused either by NTM species that are poorly pathogenic in immunocompetent hosts and presumably acquired from environmental exposure, or by BCG acquired by vaccination. In these children, such infections are usually fatal if untreated (Jouanguy et al., 2000).

2.3.2 Partial IFNgR deficiency

Partial deficiency has been shown conclusively to result from one group of IFNGR1 mutations. These mutations confer partial, but not complete, loss of IFNg responsiveness, where mutant proteins are expressed on the cell surface and bind IFNg ligand, but cannot transduce signal due to absence of JAK1 and STAT1 binding sites. Moreover, the absence of the IFNgR1 recycling motif results in an increased number of mutant proteins expressed on the cell surface. Residual IFNg responsiveness is mediated by the normal IFNgR1 proteins expressed from the normal allele in these individuals. The clinical phenotype associated with this group is milder than that seen in children with complete absence of IFNg responsiveness. Environmental mycobacterial infections may first occur during childhood rather than infancy and may be localized rather than disseminated (Jouanguy et al., 1997).

2.4 Treatment

Aggressive and prolonged antibiotic therapy can lead to the control of infection in some patients with complete IFNgR deficiency. However, the overall prognosis for these patients is poor since antibiotic therapy apparently does not give sustained remission, and there is continued susceptibility to new mycobacterial infection. IFNg administration would not be expected to be of therapeutic benefit in patients with complete absence of IFNg responsiveness due o the absence of cell surface expression of receptors. Bone marrow transplantation is the only curative treatment available. Scientists are developing methods to add a corrective gene to bone marrow cells that will become granulocytes. They are also working to improve the multi-drug treatment that is the mainstay for IFNgR-deficient patients. Patients with complete IFNgR deficiency may especially benefit from treatment that includes cytokines such as IL-2, IL-12, and GM-CSF. Patients with partial INFgR deficiency have a milder disease, and are usually responsive to appropriate antimicrobial therapy and IFNg administration (Reuter et al., 2002)

3. Conclusion

IFNgR deficiency is listed as a "rare disease" by the Office of Rare Diseases (ORD) of the National Institutes of Health (NIH). This means that Interferon gamma receptor deficiency, affects roughly 200,000 people in the US population. However, the diversity of the genes and pathogenic mutations involved renders molecular diagnosis challenging. An accurate and rapid molecular diagnosis is essential for the rational and efficient treatment of the patient. Indeed, children with complete IFNgR deficiency do not achieve sustained remission with antibiotics alone and do not respond to exogenous IFNg, resulting from a lack of functional receptors. The lack of a simple method for rapidly discriminating between patients with complete or partial IFNgR deficiency and patients with other genetic etiologies greatly compromises the management of these patients. Recognition of the role of IFNgR in human host defense against intracellular pathogens emphasizes the importance of research to understand the mechanisms by which IFNg activates macrophage killing of intracellular organisms. Better understanding these mechanisms will lead to the development of rational preventive and therapeutic strategies



Davidson College Biology Department Home Page

Immunology Home Page

Davidson College Home Page

Return to My Main Page

© Copyright 2005, Department of Biology, Davidson College, Davidson, NC 28036
Send comments, questions, and suggestions to: Daniela V. Alvarez (davillarrealalvarez@davidson.edu).