Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1997 Dec 1;100(11):2658–2664. doi: 10.1172/JCI119810

Partial interferon-gamma receptor 1 deficiency in a child with tuberculoid bacillus Calmette-Guérin infection and a sibling with clinical tuberculosis.

E Jouanguy 1, S Lamhamedi-Cherradi 1, F Altare 1, M C Fondanèche 1, D Tuerlinckx 1, S Blanche 1, J F Emile 1, J L Gaillard 1, R Schreiber 1, M Levin 1, A Fischer 1, C Hivroz 1, J L Casanova 1
PMCID: PMC508468  PMID: 9389728

Abstract

Complete interferon-gamma receptor 1 (IFNgammaR1) deficiency has been identified previously as a cause of fatal bacillus Calmette-Guérin (BCG) infection with lepromatoid granulomas, and of disseminated nontuberculous mycobacterial (NTM) infection in children who had not been inoculated with BCG. We report here a kindred with partial IFNgammaR1 deficiency: one child afflicted by disseminated BCG infection with tuberculoid granulomas, and a sibling, who had not been inoculated previously with BCG, with clinical tuberculosis. Both responded to antimicrobials and are currently well without prophylactic therapy. Impaired response to IFN-gamma was documented in B cells by signal transducer and activator of transcription 1 nuclear translocation, in fibroblasts by cell surface HLA class II induction, and in monocytes by cell surface CD64 induction and TNF-alpha secretion. Whereas cells from healthy children responded to even low IFN-gamma concentrations (10 IU/ml), and cells from a child with complete IFNgammaR1 deficiency did not respond to even high IFN-gamma concentrations (10,000 IU/ml), cells from the two siblings did not respond to low or intermediate concentrations, yet responded to high IFN-gamma concentrations. A homozygous missense IFNgR1 mutation was identified, and its pathogenic role was ascertained by molecular complementation. Thus, whereas complete IFNgammaR1 deficiency in previously identified kindreds caused fatal lepromatoid BCG infection and disseminated NTM infection, partial IFNgammaR1 deficiency in this kindred caused curable tuberculoid BCG infection and clinical tuberculosis.

Full Text

The Full Text of this article is available as a PDF (399.5 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aguet M., Dembić Z., Merlin G. Molecular cloning and expression of the human interferon-gamma receptor. Cell. 1988 Oct 21;55(2):273–280. doi: 10.1016/0092-8674(88)90050-5. [DOI] [PubMed] [Google Scholar]
  2. Bach E. A., Aguet M., Schreiber R. D. The IFN gamma receptor: a paradigm for cytokine receptor signaling. Annu Rev Immunol. 1997;15:563–591. doi: 10.1146/annurev.immunol.15.1.563. [DOI] [PubMed] [Google Scholar]
  3. Casanova J. L., Blanche S., Emile J. F., Jouanguy E., Lamhamedi S., Altare F., Stéphan J. L., Bernaudin F., Bordigoni P., Turck D. Idiopathic disseminated bacillus Calmette-Guérin infection: a French national retrospective study. Pediatrics. 1996 Oct;98(4 Pt 1):774–778. [PubMed] [Google Scholar]
  4. Casanova J. L., Jouanguy E., Lamhamedi S., Blanche S., Fischer A. Immunological conditions of children with BCG disseminated infection. Lancet. 1995 Aug 26;346(8974):581–581. doi: 10.1016/s0140-6736(95)91421-8. [DOI] [PubMed] [Google Scholar]
  5. Cooper A. M., Dalton D. K., Stewart T. A., Griffin J. P., Russell D. G., Orme I. M. Disseminated tuberculosis in interferon gamma gene-disrupted mice. J Exp Med. 1993 Dec 1;178(6):2243–2247. doi: 10.1084/jem.178.6.2243. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Dalton D. K., Pitts-Meek S., Keshav S., Figari I. S., Bradley A., Stewart T. A. Multiple defects of immune cell function in mice with disrupted interferon-gamma genes. Science. 1993 Mar 19;259(5102):1739–1742. doi: 10.1126/science.8456300. [DOI] [PubMed] [Google Scholar]
  7. Doherty T. M., Sher A. Defects in cell-mediated immunity affect chronic, but not innate, resistance of mice to Mycobacterium avium infection. J Immunol. 1997 May 15;158(10):4822–4831. [PubMed] [Google Scholar]
  8. Emile J. F., Patey N., Altare F., Lamhamedi S., Jouanguy E., Boman F., Quillard J., Lecomte-Houcke M., Verola O., Mousnier J. F. Correlation of granuloma structure with clinical outcome defines two types of idiopathic disseminated BCG infection. J Pathol. 1997 Jan;181(1):25–30. doi: 10.1002/(SICI)1096-9896(199701)181:1<25::AID-PATH747>3.0.CO;2-Z. [DOI] [PubMed] [Google Scholar]
  9. Flynn J. L., Chan J., Triebold K. J., Dalton D. K., Stewart T. A., Bloom B. R. An essential role for interferon gamma in resistance to Mycobacterium tuberculosis infection. J Exp Med. 1993 Dec 1;178(6):2249–2254. doi: 10.1084/jem.178.6.2249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Garotta G., Ozmen L., Fountoulakis M., Dembic Z., van Loon A. P., Stüber D. Human interferon-gamma receptor. Mapping of epitopes recognized by neutralizing antibodies using native and recombinant receptor proteins. J Biol Chem. 1990 Apr 25;265(12):6908–6915. [PubMed] [Google Scholar]
  11. Greenlund A. C., Farrar M. A., Viviano B. L., Schreiber R. D. Ligand-induced IFN gamma receptor tyrosine phosphorylation couples the receptor to its signal transduction system (p91). EMBO J. 1994 Apr 1;13(7):1591–1600. doi: 10.1002/j.1460-2075.1994.tb06422.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Heath L., Chrisp C., Huffnagle G., LeGendre M., Osawa Y., Hurley M., Engleberg C., Fantone J., Brieland J. Effector mechanisms responsible for gamma interferon-mediated host resistance to Legionella pneumophila lung infection: the role of endogenous nitric oxide differs in susceptible and resistant murine hosts. Infect Immun. 1996 Dec;64(12):5151–5160. doi: 10.1128/iai.64.12.5151-5160.1996. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Jouanguy E., Altare F., Lamhamedi-Cherradi S., Casanova J. L. Infections in IFNGR-1-deficient children. J Interferon Cytokine Res. 1997 Oct;17(10):583–587. doi: 10.1089/jir.1997.17.583. [DOI] [PubMed] [Google Scholar]
  14. Jouanguy E., Altare F., Lamhamedi S., Revy P., Emile J. F., Newport M., Levin M., Blanche S., Seboun E., Fischer A. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection. N Engl J Med. 1996 Dec 26;335(26):1956–1961. doi: 10.1056/NEJM199612263352604. [DOI] [PubMed] [Google Scholar]
  15. Kamijo R., Le J., Shapiro D., Havell E. A., Huang S., Aguet M., Bosland M., Vilcek J. Mice that lack the interferon-gamma receptor have profoundly altered responses to infection with Bacillus Calmette-Guérin and subsequent challenge with lipopolysaccharide. J Exp Med. 1993 Oct 1;178(4):1435–1440. doi: 10.1084/jem.178.4.1435. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Levin M., Newport M. J., D'Souza S., Kalabalikis P., Brown I. N., Lenicker H. M., Agius P. V., Davies E. G., Thrasher A., Klein N. Familial disseminated atypical mycobacterial infection in childhood: a human mycobacterial susceptibility gene? Lancet. 1995 Jan 14;345(8942):79–83. doi: 10.1016/s0140-6736(95)90059-4. [DOI] [PubMed] [Google Scholar]
  17. Merlin G., van der Leede B. J., McKune K., Knezevic N., Bannwarth W., Romquin N., Viegas-Pequignot E., Kiefer H., Aguet M., Dembic Z. The gene for the ligand binding chain of the human interferon gamma receptor. Immunogenetics. 1997;45(6):413–421. doi: 10.1007/s002510050223. [DOI] [PubMed] [Google Scholar]
  18. Newport M. J., Huxley C. M., Huston S., Hawrylowicz C. M., Oostra B. A., Williamson R., Levin M. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996 Dec 26;335(26):1941–1949. doi: 10.1056/NEJM199612263352602. [DOI] [PubMed] [Google Scholar]
  19. Pierre-Audigier C., Jouanguy E., Lamhamedi S., Altare F., Rauzier J., Vincent V., Canioni D., Emile J. F., Fischer A., Blanche S. Fatal disseminated Mycobacterium smegmatis infection in a child with inherited interferon gamma receptor deficiency. Clin Infect Dis. 1997 May;24(5):982–984. doi: 10.1093/clinids/24.5.982. [DOI] [PubMed] [Google Scholar]
  20. Sheehan K. C., Calderon J., Schreiber R. D. Generation and characterization of monoclonal antibodies specific for the human IFN-gamma receptor. J Immunol. 1988 Jun 15;140(12):4231–4237. [PubMed] [Google Scholar]
  21. Stead W. W. Genetics and resistance to tuberculosis. Could resistance be enhanced by genetic engineering? Ann Intern Med. 1992 Jun 1;116(11):937–941. doi: 10.7326/0003-4819-116-11-937. [DOI] [PubMed] [Google Scholar]
  22. Walter M. R., Windsor W. T., Nagabhushan T. L., Lundell D. J., Lunn C. A., Zauodny P. J., Narula S. K. Crystal structure of a complex between interferon-gamma and its soluble high-affinity receptor. Nature. 1995 Jul 20;376(6537):230–235. doi: 10.1038/376230a0. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES