A Point Mutation in a Domain of Gamma Interferon Receptor 1 Provokes Severe Immunodeficiency

Abstract

Gamma interferon (IFN-␥) and the cellular responses induced by it are essential for controlling mycobacterial infections. Most patients bearing an IFN-␥ receptor ligand-binding chain (IFN-␥R1) deficiency present gross mutations that truncate the protein and prevent its expression, giving rise to severe mycobacterial infections and, frequently, a fatal outcome. In this report a new mutation that affects the IFN-␥R1 ligandbinding domain in a Spanish patient with mycobacterial disseminated infection and multifocal osteomyelitis is characterized. The mutation generates an amino acid change that does not abrogate protein expression on the cellular surface but that severely impairs responses after the binding of IFN-␥ (CD64 and HLA class II induction and tumor necrosis factor alpha and interleukin-12 production). A patient's younger brother, who was also probably homozygous for the mutation, died from meningitis due to Mycobacterium bovis. These findings suggest that a point mutation may be fatal when it affects functionally important domains of the receptor and that the severity is not directly related to a lack of IFN-␥ receptor expression. Future research on these nontruncating mutations will make it possible to develop new therapeutical alternatives in this group of patients.Gamma interferon (IFN-␥) is a widely studied cytokine and one of the most promising biological agents, with great therapeutic potential for several pathologies. This is mainly due to its immunomodulatory and antiproliferative effects and, probably, to its antiviral capacity (13). IFN-␥, after binding to its highaffinity receptor, regulates over 200 genes (7). IFN-␥ upregulates major histocompatibility complex (MHC) class I protein expression and induces MHC class II proteins on a variety of leucocytes and epithelial cells. IFN-␥ is also the major cytokine responsible for activating or regulating the phagocytic function of mononuclear cells. It also regulates the production of several immunomodulatory or proinflammatory cytokines such as interleukin-12 (IL-12) and tumor necrosis factor alpha (TNF-␣) (7).The IFN-␥ high-affinity receptor is composed of at least two subunits. IFN-␥R1 (alpha chain or CD119) is the IFN-␥ binding chain. It is encoded by a 30-kb gene located on the long arm of chromosome 6 (23), and it is expressed at moderate levels on the surfaces of nearly all cells. IFN-␥R2 (beta chain or accessory factor 1) is the signaling chain (27), and it is encoded by a gene located on chromosome 21q22.1 (8).The relationship between IFN-␥, IL-12, and TNF-␣ makes up a particularly important system, since it controls mycobacterial infections in humans (14). Recently, several mutations in some components of this system (ligands or receptors) have been described (4,11,12,(17)(18)(19)21). Patients with these mutations have similar susceptibilities to infections by atypical and nontuberculous mycobacteria (5). MATERIALS AND METHODS Subjects.A 5-year-old Spanish girl from consanguineous parents was referred to our hospital with disseminated infecti...

Susceptibility to mycobacterial infections: the importance of host genetics

“…80 The IFNgR1 gene mutations are inherited as autosomal recessive traits and either abolish receptor expression 78,[80][81][82][83][84][85] or binding of the receptor to IFNg. [86][87] Partial IFNgR1 deficiency has also been described in two siblings, one of whom developed disseminated BCG infection and the other clinical tuberculosis. 88 In addition, there are two reports of disseminated mycobacterial infections caused by dominant IFNgR1 gene mutations.…”

Impaired Interferon Gamma-Mediated Immunity and Susceptibility to Mycobacterial Infection in Childhood

“…4) may be due to recessive mutations that either preclude surface expression of the receptor ligand-binding chain (6,7,(27)(28)(29)(30) or result in normal surface expression of IFN␥R1 chains that do not bind IFN␥ (31,32). One child has been reported to have complete IFN␥R2 deficiency (Fig.…”

Infections in Patients with Inherited Defects in Phagocytic Function

“…She also had a mutation in the gamma interferon receptor 1 chain. Since the initial descriptions, over 50 patients with mutations in the gamma interferon receptor 1 chain have been described (6,9,65,83,123,143,223,240,243). Gamma interferon and TNF-␣ are the final common mediators of granuloma formation and intracellular killing.…”