Granulomatous skin lesions, severe scrotal and lower limb edema due to mycobacterial infections in a child with complete IFN-γ receptor-1 deficiency (original) (raw)
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Journal of Clinical Immunology, 2014
Interferon-γ receptor 2 (IFN-γR2) deficiency is a rare primary immunodeficiency characterized by predisposition to infections with weakly virulent mycobacteria, such as environmental mycobacteria and BCG vaccines. We describe here two children with IFN-γR2 deficiency, from unrelated, consanguineous kindreds of Arab and Israeli descent. The first patient was a boy who died at the age of 4.5 years, from recurrent, disseminated disease caused by Mycobacterium simiae. His IFN-γR2 defect was autosomal recessive and complete. The second patient was a girl with multiple Rubén Martínez-Barricarte, Orli Megged, Polina Stepensky contributed equally to this work. Jean-Laurent Casanova and Jacinta Bustamante contributed equally to this work.
Clinical Infectious Diseases, 2008
Background. Atypical mycobacteria can cause systemic infections in patients with certain types of immunodeficiency. Methods. Clinical samples were decontaminated and cultured to assess the presence of mycobacterial species. Gene sequencing was performed to reveal interferon-g receptor 1 (IFN-gR1) deficiency. Results. The index patient received a diagnosis of dominant IFN-gR1 deficiency during treatment for a serious infection due to atypical mycobacteria. She belongs to a Norwegian multiplex family comprising 3 generations and 5 patients with dominant IFN-gR1 deficiency. Four of these patients have been treated with tuberculostatics because of extensive infection due to atypical mycobacteria, such as Mycobacterium avium-intracellulare, Mycobacterium scrofulaceum, Mycobacterium bovis (bacille Calmette-Guérin), Mycobacterium bohemicum, and Mycobacterium gordonae. Two of the patients have also received subcutaneous injections of IFN-g. One family member with the deficiency has not received treatment and is still healthy at 13 years of age. Conclusions. Serious infection due to atypical mycobacteria should initiate a search for primary immunodeficiencies, particularly IFN-gR1 deficiency. Treatment with IFN-g should be started when serious infection due to atypical mycobacteria is verified and dominant partial IFN-gR1 deficiency is suspected.
Normal expression of IFN-gammaR in four patients with uncommon mycobacterial infection phenotypes
Brazilian Journal of Medical and Biological Research, 2004
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.
Acquired predisposition to mycobacterial disease due to autoantibodies to IFN-γ
Journal of Clinical Investigation, 2005
Genetic defects in the IFN-γ response pathway cause unique susceptibility to intracellular pathogens, particularly mycobacteria, but are rare and do not explain mycobacterial disease in the majority of affected patients. We postulated that acquired defects in macrophage activation by IFN-γ may cause a similar immunological phenotype and thus explain the occurrence of disseminated intracellular infections in some patients without identifiable immune deficiency. Macrophage activation in response to IFN-γ and IFN-γ production were studied in whole blood and PBMCs of 3 patients with severe, unexplained nontuberculous mycobacterial infection. In all 3 patients, IFN-γ was undetectable following mitogen stimulation of whole blood, but significant quantities were detectable in the supernatants of PBMCs when stimulated in the absence of the patients' own plasma. The patients' plasma inhibited the ability of IFN-γ to increase production of TNF-α by both autologous and normal donor PBMCs, and recovery of exogenous IFN-γ from the patients' plasma was greatly reduced. Using affinity chromatography, surface-enhanced laser desorption/ionization mass spectrometry, and sequencing, we isolated an IFN-γ-neutralizing factor from the patients' plasma and showed it to be an autoantibody against IFN-γ. The purified anti-IFN-γ antibody was shown to be functional first in blocking the upregulation of TNF-α production in response to endotoxin; second in blocking induction of IFN-γ-inducible genes (according to results of high-density cDNA microarrays); and third in inhibiting upregulation of HLA class II expression on PBMCs. Acquired defects in the IFN-γ pathway may explain unusual susceptibility to intracellular pathogens in other patients without underlying, genetically determined immunological defects.
2021
IFN-gamma receptor (IFNGR) signaling via STAT1 is crucial in the defense against intracellular pathogens. Defects in this pathway enhance the susceptibility to infection by otherwise weak pathogenic mycobacteria, resulting in a primary immunodeficiency called mendelian susceptibility to mycobacterial disease (MSMD). Here we describe three patients with MSMD caused by variants in the IFNGR1 or STAT1 genes. All three patients presented with disseminated non-tuberculous mycobacterial infections caused by M. avium, M. persicum or M. bovis BCG respectively. Whole-exome sequencing (WES) was used as the first line diagnostic approach, however in all patients additional analysis was crucial to make the definite diagnosis. In Patient 1, only one heterozygous autosomal recessive variant p.(Val63Gly) in the IFNGR1 gene was identified. Patient 2 was compound heterozygous for the pathogenic null p.(Val68Lysfs*6) variant and the hypomorphic p.(Ile37Thr) variant in IFNGR1. In Patient 3 a novel variant in the STAT1 gene c.1379A>T, p.(Asn460Ile) was identified. Additional genetic analysis identified a second novel complex Alu-insertion in the IFNGR1 gene in Patient 1. Functional analysis showed that Patients 1 and 2 had reduced expression of IFNGR1. All patients had reduced phosphorylation of STAT1 and absent induction of SOCS1 mRNA after IFN-γ stimulation. While STAT1 phosphorylation was normal after IFN-α stimulation in Patient 1 and 2, it was mildly reduced in Patient 3. We conclude that functional assays are crucial to assess the extent of IFNGR signaling defects when new combinations of bi-allelic or non-conclusive genetic variants are found, which is important in the determination of clinical treatment.
Inherited human IFNγ deficiency underlies mycobacterial disease
Journal of Clinical Investigation
Mendelian susceptibility to mycobacterial disease (MSMD) is characterized by a selective predisposition to clinical disease caused by BCG vaccines and environmental mycobacteria. The known genetic etiologies of MSMD are inborn errors of IFN- immunity, due to mutations of 15 genes controlling the production of, or response to IFN-. Since the first MSMD-causing mutations were reported in 1996, biallelic mutations in the genes encoding IFN-R1 and IFN-R2 have been reported in many patients of diverse ancestries. Surprisingly, mutations of the gene encoding the IFN- cytokine itself have not been reported, raising the remote possibility that there might be other agonists of the IFN- receptor. We report two Lebanese cousins with MSMD, living in Kuwait, who are both homozygous for a small deletion within the IFNG gene (c.354_357del) causing a frameshift that generates a premature stop codon (p.T119Ifs4*). The mutant allele is loss-of-expression and loss-of-function. We also show that the patients' herpesvirus Saimiri-immortalized T lymphocytes do not produce IFN-, a phenotype that can be rescued by retrotransduction with wild-type IFNG cDNA. The blood T and NK lymphocytes of these patients also fail to produce and secrete detectable amounts of IFN-. Finally, we show that human IFNG has evolved under stronger negative selection than IFNGR1 and IFNGR2, suggesting that it is less tolerant to heterozygous deleterious mutations than IFNGR1 and IFNGR2. This may account for the rarity of patients with autosomal recessive, complete IFN- deficiency relative to patients with complete IFN-R and IFN-R2 deficiencies.
Human Molecular Genetics, 2011
The most recent common ancestors of the patients with the I87T and V63G mutations probably lived 1600 (875-2950) and 500 (200-1275) years ago, respectively. The two alleles confer phenotypes that are similar but differ in terms of IFN-gR1 levels and residual response to IFN-g. The patients suffered from bacillus Calmette-Guérin-osis (n 5 6), environmental mycobacteriosis (n 5 6) or tuberculosis (n 5 1). One patient did not suffer from mycobacterial infections but had disseminated salmonellosis, which was also present in two other patients. Age at onset of the first environmental mycobacterial disease differed widely between patients, with a mean value of 11.25 + + + + + 9.13 years. Thirteen patients survived until the age of 14.82 + + + + + 11.2 years, and one patient died at the age of 7 years, 9 days after the diagnosis of long-term Mycobacterium avium infection and the initiation of antimycobacterial treatment. Up to 10 patients are currently free of infection with no prophylaxis. The clinical heterogeneity of the 14 patients was not clearly related to either IFNGR1 genotype or the resulting cellular phenotype. RP-IFN-gR1 deficiency is, thus, more common than initially thought and should be considered in both children and adults with mild or severe mycobacterial diseases.
American journal of clinical and experimental immunology, 2015
Cutaneous non-disseminated, non-tuberculous mycobacterial infections have been reported in both immunocompetent and immunocompromised subjects. Systemic Mycobacterium avium intracellulaire (MAI) have been reported in non-HIV patients with Idiopathic CD4 lymphocytopenia. We report a comprehensive immunological analysis in syndrome of selective IgM deficiency and T lymphocytopenia (both CD4+ and CD8+) with disseminated cutaneous MAI infection. Naïve (TN) and Central memory (TCM) subsets of both CD4+ and CD8+ T cells were decreased, whereas terminally differentiated effector memory (TEMRA) subset of CD4+ and CD8+ T cells were markedly increased. IFN-γ producing T cells were markedly decreased. Although CD14(high)CD16- proinflammatory monocytes were modestly increased, IFN-γR+ monocytes were markedly decreased. The expression of TLR3, TLR5, TLR7, and TLR9 on monocytes was decreased. Germinal center B cells (CD19+IgD-CD38+CD27(lo)) and B1 cells (CD20+CD27+CD43+CD70-) were markedly decrea...