Ariane Chapgier - Academia.edu (original) (raw)
Papers by Ariane Chapgier
Journal of Immunology, Apr 15, 2006
Seminars in Immunology, 2006
Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease cau... more Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease caused by weakly virulent mycobacterial species in otherwise healthy individuals. Since 1996, disease-causing mutations have been found in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1) and one X-linked gene (NEMO). These genes display a high degree of allelic heterogeneity, defining at least 13 disorders. Although genetically different, these conditions are immunologically related, as all result in impaired IL-12/23-IFN-␥-mediated immunity. These disorders were initially thought to be rare, but have now been diagnosed in over 220 patients from over 43 countries worldwide. We review here the molecular, cellular, and clinical features of patients with inborn errors of the IL-12/23-IFN-␥ circuit.
![Research paper thumbnail of Corrigendum to “Inborn errors of IL-12/23- and IFN-γ-mediated immunity: Molecular, cellular, and clinical features” [Semin. Immunol. 18 (2006) 347–361]](https://attachments.academia-assets.com/106519134/thumbnails/1.jpg)
](Seminars in Immunology, 2007
Nature Immunology, 2011
C. designed the study and contributed intellectually to the experimental process; J.B. did most o... more C. designed the study and contributed intellectually to the experimental process; J.B. did most of the experiments under the supervision of J.-L.C.; A.A.A., C.C.M., E.V. and M.C.D. did the experiments with retroviral transduction of gp91 phox into EBV-B, CHO and PLB-985 cells; G.V. made the nonretroviral CYBB vectors, infected macrophages with BCG and made intellectual contributions to various experiments; C. Picard contributed to the recruitment of patients and initiated the clinical investigation; L.B.
Nature Genetics, 2005
Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of ... more Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNcR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNc. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations (B1.4%) in 77 genes (B13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate. Mendelian susceptibility to mycobacterial disease (MSMD; OMIM 209950) is a rare syndrome that confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guérin (BCG) vaccines and nontuberculous environmental mycobacteria, and by the more virulent Mycobacterium tuberculosis 1. Other types of microorganism rarely cause severe clinical disease in individuals with MSMD, with the exception of Salmonella, which infects o50% of these individuals. The demonstration that this condition was associated in some affected individuals with deficiency of interferon g receptor ligand-binding chain (IFNgR1) provided the first evidence for a genetic etiology 2,3. Subsequent studies identified mutations in the genes encoding IFNgR2 (ref. 4), the interleukin-12 p40 (IL-12p40) subunit shared by IL-12 and IL-23 (ref. 5), the IL-12Rb1 subunit shared by the IL-12 and IL-23 receptors 6,7 , and the signal transducer and activator of transcription-1 (Stat-1) 8. Allelic heterogeneity at these five disease-associated autosomal gene loci is responsible for ten known disorders, all of which involve impaired function of the IL-12/23-IFNg circuit 9-15. Complete Stat-1 deficiency is associated with a related but more severe syndrome of vulnerability to mycobacterial and viral infections due to an impaired cellular response to both IFNg and IFNa/b 16. IFNgR2 deficiency is the most infrequent of the inherited forms of MSMD: only three children with MSMD have been reported, two with complete IFNgR2 deficiency 4,17 and one with partial IFNgR2 deficiency 14. By contrast, 22 individuals are known to have complete IFNgR1 deficiency, and 38 are known to have partial IFNgR1 deficiency 15. Here we report four children with complete IFNgR2 deficiency, from three unrelated families. One of these children has an in-frame microdeletion in the gene IFNGR2 such that the encoded protein does not reach the cell surface normally. The other three
The Journal of Immunology, 2006
Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display inc... more Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display increased susceptibility to mycobacterial infections. We analyzed in this group of patients the cross-talk between human CD4+ T lymphocytes and dendritic cells (DCs) that leads to maturation of DC into producers of bioactive IL-12 and to activation of T cells into IFN-γ producers. We found that this cross-talk is defective in all patients from this group. Unraveling the mechanisms underlying this deficiency, we showed that IL-12 signaling in T cells is required to induce expression of costimulatory molecules and secretion of IL-12 by DCs and that IFNGR expression is required on both DCs and CD4+ T cells to induce IL-12 secretion by DCs. These data suggest that CD4+ T cell-mediated activation of DCs plays a critical role in the defense against mycobacterial infections in humans.
The Journal of Experimental Medicine, 2006
Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon ... more Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon (IFN)-γ–mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)–MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-κB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell–dependent IL-12 production, resulting in defective IFN-γ secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-κB/c-Rel–mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immuno...
Journal of Biotechnology, 2008
Human Molecular Genetics, 2011
The most recent common ancestors of the patients with the I87T and V63G mutations probably lived ... more 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.
Medicine, 2010
Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibil... more Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infec...
European Journal of Pediatrics, 2005
Disseminated BCG infection is a rare complication of vaccination that occurs in patients with imp... more Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN-gamma circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN-gamma receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12Rbeta1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN-gamma circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN-gamma circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.
Archives de Pédiatrie, 2006
Les déficits immunitaires héréditaires classiques sont responsables d'une prédisposition infectie... more Les déficits immunitaires héréditaires classiques sont responsables d'une prédisposition infectieuse large et multiple. Cependant, depuis une dizaine d'année, des infections sévères pédiatriques qui étaient considérées comme idiopathiques ont trouvé une explication génétique. Plusieurs défauts génétiques responsables d'une prédisposition infectieuse spécifique à un type de pathogène chez des individus ne présentant pas d'autre susceptibilité ont été identifiés. Ces enfants présentent un nouveau type de déficit immunitaire héréditaire caractérisé par des infections sévères (et/ou récurrentes) à une famille de microorganismes, par opposition aux enfants avec déficits immunitaires classiques.
M/S: médecine …, 2006
... Ariane Chapgier. ... En effet, certains malades présentent une vulnérabilité héréditaire spéc... more ... Ariane Chapgier. ... En effet, certains malades présentent une vulnérabilité héréditaire spécifique vis-à-vis des infections mycobactériennes [1-3]. Des études moléculaires ont montré qu'ils sont porteurs de mutations germinales dans cinq gènes participant aux voies d'activation ...
Human Molecular Genetics, 2012
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic e... more Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-g). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-g, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-gR2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFNg-related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-gR2 deficiency respond poorly to IFN-g, in some cases as poorly as the cells of P1. Naive CD4 1 T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-g, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-gR2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-gR2 deficiency, resulting
Journal of Immunology, Apr 15, 2006
Seminars in Immunology, 2006
Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease cau... more Mendelian susceptibility to mycobacterial diseases confers predisposition to clinical disease caused by weakly virulent mycobacterial species in otherwise healthy individuals. Since 1996, disease-causing mutations have been found in five autosomal genes (IFNGR1, IFNGR2, STAT1, IL12B, IL12BR1) and one X-linked gene (NEMO). These genes display a high degree of allelic heterogeneity, defining at least 13 disorders. Although genetically different, these conditions are immunologically related, as all result in impaired IL-12/23-IFN-␥-mediated immunity. These disorders were initially thought to be rare, but have now been diagnosed in over 220 patients from over 43 countries worldwide. We review here the molecular, cellular, and clinical features of patients with inborn errors of the IL-12/23-IFN-␥ circuit.
Seminars in Immunology, 2007
Nature Immunology, 2011
C. designed the study and contributed intellectually to the experimental process; J.B. did most o... more C. designed the study and contributed intellectually to the experimental process; J.B. did most of the experiments under the supervision of J.-L.C.; A.A.A., C.C.M., E.V. and M.C.D. did the experiments with retroviral transduction of gp91 phox into EBV-B, CHO and PLB-985 cells; G.V. made the nonretroviral CYBB vectors, infected macrophages with BCG and made intellectual contributions to various experiments; C. Picard contributed to the recruitment of patients and initiated the clinical investigation; L.B.
Nature Genetics, 2005
Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of ... more Mutations involving gains of glycosylation have been considered rare, and the pathogenic role of the new carbohydrate chains has never been formally established. We identified three children with mendelian susceptibility to mycobacterial disease who were homozygous with respect to a missense mutation in IFNGR2 creating a new N-glycosylation site in the IFNcR2 chain. The resulting additional carbohydrate moiety was both necessary and sufficient to abolish the cellular response to IFNc. We then searched the Human Gene Mutation Database for potential gain-of-N-glycosylation missense mutations; of 10,047 mutations in 577 genes encoding proteins trafficked through the secretory pathway, we identified 142 candidate mutations (B1.4%) in 77 genes (B13.3%). Six mutant proteins bore new N-linked carbohydrate moieties. Thus, an unexpectedly high proportion of mutations that cause human genetic disease might lead to the creation of new N-glycosylation sites. Their pathogenic effects may be a direct consequence of the addition of N-linked carbohydrate. Mendelian susceptibility to mycobacterial disease (MSMD; OMIM 209950) is a rare syndrome that confers predisposition to illness caused by moderately virulent mycobacterial species, such as Bacillus Calmette-Guérin (BCG) vaccines and nontuberculous environmental mycobacteria, and by the more virulent Mycobacterium tuberculosis 1. Other types of microorganism rarely cause severe clinical disease in individuals with MSMD, with the exception of Salmonella, which infects o50% of these individuals. The demonstration that this condition was associated in some affected individuals with deficiency of interferon g receptor ligand-binding chain (IFNgR1) provided the first evidence for a genetic etiology 2,3. Subsequent studies identified mutations in the genes encoding IFNgR2 (ref. 4), the interleukin-12 p40 (IL-12p40) subunit shared by IL-12 and IL-23 (ref. 5), the IL-12Rb1 subunit shared by the IL-12 and IL-23 receptors 6,7 , and the signal transducer and activator of transcription-1 (Stat-1) 8. Allelic heterogeneity at these five disease-associated autosomal gene loci is responsible for ten known disorders, all of which involve impaired function of the IL-12/23-IFNg circuit 9-15. Complete Stat-1 deficiency is associated with a related but more severe syndrome of vulnerability to mycobacterial and viral infections due to an impaired cellular response to both IFNg and IFNa/b 16. IFNgR2 deficiency is the most infrequent of the inherited forms of MSMD: only three children with MSMD have been reported, two with complete IFNgR2 deficiency 4,17 and one with partial IFNgR2 deficiency 14. By contrast, 22 individuals are known to have complete IFNgR1 deficiency, and 38 are known to have partial IFNgR1 deficiency 15. Here we report four children with complete IFNgR2 deficiency, from three unrelated families. One of these children has an in-frame microdeletion in the gene IFNGR2 such that the encoded protein does not reach the cell surface normally. The other three
The Journal of Immunology, 2006
Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display inc... more Patients presenting with genetic deficiencies in IFNGR1, IFNGR2, IL-12B, and IL-12RB1 display increased susceptibility to mycobacterial infections. We analyzed in this group of patients the cross-talk between human CD4+ T lymphocytes and dendritic cells (DCs) that leads to maturation of DC into producers of bioactive IL-12 and to activation of T cells into IFN-γ producers. We found that this cross-talk is defective in all patients from this group. Unraveling the mechanisms underlying this deficiency, we showed that IL-12 signaling in T cells is required to induce expression of costimulatory molecules and secretion of IL-12 by DCs and that IFNGR expression is required on both DCs and CD4+ T cells to induce IL-12 secretion by DCs. These data suggest that CD4+ T cell-mediated activation of DCs plays a critical role in the defense against mycobacterial infections in humans.
The Journal of Experimental Medicine, 2006
Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon ... more Germline mutations in five autosomal genes involved in interleukin (IL)-12–dependent, interferon (IFN)-γ–mediated immunity cause Mendelian susceptibility to mycobacterial diseases (MSMD). The molecular basis of X-linked recessive (XR)–MSMD remains unknown. We report here mutations in the leucine zipper (LZ) domain of the NF-κB essential modulator (NEMO) gene in three unrelated kindreds with XR-MSMD. The mutant proteins were produced in normal amounts in blood and fibroblastic cells. However, the patients' monocytes presented an intrinsic defect in T cell–dependent IL-12 production, resulting in defective IFN-γ secretion by T cells. IL-12 production was also impaired as the result of a specific defect in NEMO- and NF-κB/c-Rel–mediated CD40 signaling after the stimulation of monocytes and dendritic cells by CD40L-expressing T cells and fibroblasts, respectively. However, the CD40-dependent up-regulation of costimulatory molecules of dendritic cells and the proliferation and immuno...
Journal of Biotechnology, 2008
Human Molecular Genetics, 2011
The most recent common ancestors of the patients with the I87T and V63G mutations probably lived ... more 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.
Medicine, 2010
Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibil... more Interleukin-12 receptor β1 (IL-12Rβ1) deficiency is the most common form of Mendelian susceptibility to mycobacterial disease (MSMD). We undertook an international survey of 141 patients from 102 kindreds in 30 countries. Among 102 probands, the first infection occurred at a mean age of 2.4 years. In 78 patients, this infection was caused by Bacille Calmette-Guérin (BCG; n = 65), environmental mycobacteria (EM; also known as atypical or nontuberculous mycobacteria) (n = 9) or Mycobacterium tuberculosis (n = 4). Twenty-two of the remaining 24 probands initially presented with nontyphoidal, extraintestinal salmonellosis. Twenty of the 29 genetically affected sibs displayed clinical signs (69%); however 8 remained asymptomatic (27%). Nine nongenotyped sibs with symptoms died. Recurrent BCG infection was diagnosed in 15 cases, recurrent EM in 3 cases, recurrent salmonellosis in 22 patients. Ninety of the 132 symptomatic patients had infections with a single microorganism. Multiple infec...
European Journal of Pediatrics, 2005
Disseminated BCG infection is a rare complication of vaccination that occurs in patients with imp... more Disseminated BCG infection is a rare complication of vaccination that occurs in patients with impaired immunity. In recent years, a series of inherited disorders of the IL-12-IFN-gamma axis have been described that predispose affected individuals to disseminated disease caused by BCG, environmental Mycobacteria, and non-typhoidal Salmonella. The routine immunological work-up of these patients is normal and the diagnosis requires specific investigation of the IL-12-IFN-gamma circuit. We report here the first two such patients originating from and living in Iran. The first child is two years old and suffers from complete IFN-gamma receptor 2 deficiency and disseminated BCG infection. He is currently in clinical remission thanks to prolonged multiple antibiotic therapy. The other, a 28-year-old adult, suffers from IL-12p40 deficiency and presented with disseminated BCG infection followed by recurrent episodes of systemic salmonellosis. He is now doing well. A third patient of Iranian descent, living in North America, was reported elsewhere to suffer from IL-12Rbeta1 deficiency. These three patients thus indicate that various inherited defects of the IL-12-IFN-gamma circuit can be found in Iranian people. In conclusion we recommend to consider the disorders of the IL-12-IFN-gamma circuit in all patients with severe BCG infection, disseminated environmental mycobacterial disease, or systemic non-typhoidal salmonellosis, regardless of their ethnic origin and country of residence.
Archives de Pédiatrie, 2006
Les déficits immunitaires héréditaires classiques sont responsables d'une prédisposition infectie... more Les déficits immunitaires héréditaires classiques sont responsables d'une prédisposition infectieuse large et multiple. Cependant, depuis une dizaine d'année, des infections sévères pédiatriques qui étaient considérées comme idiopathiques ont trouvé une explication génétique. Plusieurs défauts génétiques responsables d'une prédisposition infectieuse spécifique à un type de pathogène chez des individus ne présentant pas d'autre susceptibilité ont été identifiés. Ces enfants présentent un nouveau type de déficit immunitaire héréditaire caractérisé par des infections sévères (et/ou récurrentes) à une famille de microorganismes, par opposition aux enfants avec déficits immunitaires classiques.
M/S: médecine …, 2006
... Ariane Chapgier. ... En effet, certains malades présentent une vulnérabilité héréditaire spéc... more ... Ariane Chapgier. ... En effet, certains malades présentent une vulnérabilité héréditaire spécifique vis-à-vis des infections mycobactériennes [1-3]. Des études moléculaires ont montré qu'ils sont porteurs de mutations germinales dans cinq gènes participant aux voies d'activation ...
Human Molecular Genetics, 2012
Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic e... more Mendelian susceptibility to mycobacterial diseases (MSMD) is a rare syndrome, the known genetic etiologies of which impair the production of, or the response to interferon-gamma (IFN-g). We report here a patient (P1) with MSMD whose cells display mildly impaired responses to IFN-g, at levels, however, similar to those from MSMD patients with autosomal recessive (AR) partial IFN-gR2 or STAT1 deficiency. Whole-exome sequencing (WES) and Sanger sequencing revealed only one candidate variation for both MSMD-causing and IFNg-related genes. P1 carried a heterozygous frame-shift IFNGR2 mutation inherited from her father. We show that the mutant allele is intrinsically loss-of-function and not dominant-negative, suggesting haploinsufficiency at the IFNGR2 locus. We also show that Epstein-Barr virus transformed B lymphocyte cells from 10 heterozygous relatives of patients with AR complete IFN-gR2 deficiency respond poorly to IFN-g, in some cases as poorly as the cells of P1. Naive CD4 1 T cells and memory IL-4-producing T cells from these individuals also responded poorly to IFN-g, whereas monocytes and monocyte-derived macrophages (MDMs) did not. This is consistent with the lower levels of expression of IFN-gR2 in lymphoid than in myeloid cells. Overall, MSMD in this patient is probably due to autosomal dominant (AD) IFN-gR2 deficiency, resulting