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Open Access 01-03-2024 | Interferon | Original Article

Recombinant IFN-γ1b Treatment in a Patient with Inherited IFN-γ Deficiency

Authors: Jérémie Rosain, Ayca Kiykim, Alexandre Michev, Yasemin Kendir-Demirkol, Darawan Rinchai, Jessica N. Peel, Hailun Li, Suheyla Ocak, Pinar Gokmirza Ozdemir, Tom Le Voyer, Quentin Philippot, Taushif Khan, Anna-Lena Neehus, Mélanie Migaud, Camille Soudée, Stéphanie Boisson-Dupuis, Nico Marr, Alessandro Borghesi, Jean-Laurent Casanova, Jacinta Bustamante

Published in: Journal of Clinical Immunology | Issue 3/2024

Abstract

Purpose

Inborn errors of IFN-γ immunity underlie Mendelian susceptibility to mycobacterial disease (MSMD). Twenty-two genes with products involved in the production of, or response to, IFN-γ and variants of which underlie MSMD have been identified. However, pathogenic variants of IFNG encoding a defective IFN-γ have been described in only two siblings, who both underwent hematopoietic stem cell transplantation (HCST).

Methods

We characterized a new patient with MSMD by genetic, immunological, and clinical means. Therapeutic decisions were taken on the basis of these findings.

Results

The patient was born to consanguineous Turkish parents and developed bacillus Calmette-Guérin (BCG) disease following vaccination at birth. Whole-exome sequencing revealed a homozygous private IFNG variant (c.224 T > C, p.F75S). Upon overexpression in recipient cells or constitutive expression in the patient’s cells, the mutant IFN-γ was produced within the cells but was not correctly folded or secreted. The patient was treated for 6 months with two or three antimycobacterial drugs only and then for 30 months with subcutaneous recombinant IFN-γ1b plus two antimycobacterial drugs. Treatment with IFN-γ1b finally normalized all biological parameters. The patient presented no recurrence of mycobacterial disease or other related infectious diseases. The treatment was well tolerated, without the production of detectable autoantibodies against IFN-γ.

Conclusion

We describe a patient with a new form of autosomal recessive IFN-γ deficiency, with intracellular, but not extracellular IFN-γ. IFN-γ1b treatment appears to have been beneficial in this patient, with no recurrence of mycobacterial infection over a period of more than 30 months. This targeted treatment provides an alternative to HCST in patients with complete IFN-γ deficiency or at least an option to better control mycobacterial infection prior to HCST.

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Bustamante J. Mendelian susceptibility to mycobacterial disease: recent discoveries. Hum Genet. 2020;139(6–7):993–1000.PubMedPubMedCentral

Kerner G, Rosain J, Guerin A, Al-Khabaz A, Oleaga-Quintas C, Rapaport F, et al. Inherited human IFN-gamma deficiency underlies mycobacterial disease. J Clin Invest. 2020;130(6):3158–71.PubMedPubMedCentral

Le Voyer T, Neehus AL, Yang R, Ogishi M, Rosain J, Alroqi F, et al. Inherited deficiency of stress granule ZNFX1 in patients with monocytosis and mycobacterial disease. Proc Natl Acad Sci U S A. 2021;118(15):e2102804118.PubMedPubMedCentral

Yang R, Mele F, Worley L, Langlais D, Rosain J, Benhsaien I, et al. Human T-bet governs innate and innate-like adaptive IFN-γ immunity against mycobacteria. Cell. 2020;183(7):1826-1847.e31.PubMedPubMedCentral

Martin-Fernandez M, Buta S, Le Voyer T, Li Z, Dynesen LT, Vuillier F, et al. A partial form of inherited human USP18 deficiency underlies infection and inflammation. J Exp Med. 2022;219(4):e20211273.PubMedPubMedCentral

Rosain J. Human IRF1 governs macrophagic IFN-γ immunity to mycobacteria. Cell. 2023;186(3):621–45.PubMedPubMedCentral

Bohlen J, Zhou Q, Philippot Q, Ogishi M, Rinchai D, Nieminen T, et al. Human MCTS1-dependent translation of JAK2 is essential for IFN-γ immunity to mycobacteria. Cell. 2023;S0092–8674(23):01078–84.

Philippot Q, Ogishi M, Bohlen J, Puchan J, Arias AA, Nguyen T, et al. Human IL-23 is essential for IFN-γ-dependent immunity to mycobacteria. Sci Immunol. 2023;8(80):eabq5204.PubMedPubMedCentral

Neehus A-L, Carey B, Landekic M, Panikulam P, Deutsch G, Ogishi M, et al. Human inherited CCR2 deficiency underlies progressive polycystic lung disease. Cell. 2024;187(2):390-408.e23. https://doi.org/10.1016/j.cell.2023.11.036.CrossRefPubMed

10.

Newport MJ, Huxley CM, Huston S, Hawrylowicz CM, Oostra BA, Williamson R, et al. A mutation in the interferon-gamma-receptor gene and susceptibility to mycobacterial infection. N Engl J Med. 1996;335(26):1941–9.PubMed

11.

Jouanguy E, Altare F, Lamhamedi S, Revy P, Emile JF, Newport M, et al. Interferon-gamma-receptor deficiency in an infant with fatal bacille Calmette-Guérin infection. N Engl J Med. 1996;335(26):1956–61.PubMed

12.

Rosain J, Kong XF, Martinez-Barricarte R, Oleaga-Quintas C, Ramirez-Alejo N, Markle J, et al. Mendelian susceptibility to mycobacterial disease: 2014–2018 update. Immunol Cell Biol. 2019;97(4):360–7.PubMed

13.

Jouanguy E, Dupuis S, Pallier A, Döffinger R, Fondanèche MC, Fieschi C, et al. In a novel form of IFN-gamma receptor 1 deficiency, cell surface receptors fail to bind IFN-gamma. J Clin Invest. 2000;105(10):1429–36.PubMedPubMedCentral

14.

Dorman SE, Holland SM. Mutation in the signal-transducing chain of the interferon-gamma receptor and susceptibility to mycobacterial infection. J Clin Invest. 1998;101(11):2364–9.PubMedPubMedCentral

15.

Humblet-Baron S, Franckaert D, Dooley J, Ailal F, Bousfiha A, Deswarte C, et al. IFN-γ and CD25 drive distinct pathologic features during hemophagocytic lymphohistiocytosis. J Allergy Clin Immunol. 2019;143(6):2215-2226.e7.PubMed

16.

Michniacki TF, Walkovich KJ, Frame DG, Vander Lugt MT. Interferon-γ receptor 1 deficiency corrected by umbilical cord blood transplantation. J Clin Immunol. 2019;39(3):257–60.PubMed

17.

Shabani M, Aleyasin S, Kashef S, Zoghi S, Deswarte C, Casanova JL, et al. A novel recessive mutation of interferon-γ receptor 1 in a patient with mycobacterium tuberculosis in bone marrow aspirate. J Clin Immunol. 2019;39(2):127–30.PubMed

18.

Bossi G, Errichiello E, Zuffardi O, Marone P, Monzillo V, Barbarini D, et al. Disseminated mycobacterium avium infection in a child with complete interferon-γ receptor 1 deficiency due to compound heterozygosis of IFNGR1 for a subpolymorphic copy number variation and a novel splice-site variant. J Pediatr Genet. 2020;9(3):186–92.PubMed

19.

Zhang P, Ying W, Wu B, Liu R, Wang H, Wang X, et al. Complete IFN-γR1 deficiency in a boy due to UPD(6)mat with IFNGR1 novel splicing variant. J Clin Immunol. 2021;41(4):834–6.PubMed

20.

Vogt G, Chapgier A, Yang K, Chuzhanova N, Feinberg J, Fieschi C, et al. Gains of glycosylation comprise an unexpectedly large group of pathogenic mutations. Nat Genet. 2005;37(7):692–700.PubMed

21.

Zhou Z, Hollink IHIM, Bouman A, Lourens MS, Brooimans RA, van Ham TJ, et al. Three patients with defects in interferon gamma receptor signaling: a challenging diagnosis. Pediatr Allergy Immunol Off Publ Eur Soc Pediatr Allergy Immunol. 2022;33(4):e13768.

22.

Taur PD, Gowri V, Pandrowala AA, Iyengar VV, Chougule A, Golwala Z, et al. Clinical and molecular findings in mendelian susceptibility to mycobacterial diseases: experience from India. Front Immunol. 2021;12:631298.PubMedPubMedCentral

23.

Yadav RM, Gupta M, Dalvi A, Bargir UA, Hule G, Shabrish S, et al. Prenatal diagnosis for primary immunodeficiency disorders-an overview of the Indian scenario. Front Immunol. 2020;11:612316.PubMedPubMedCentral

24.

Tovo PA, Garazzino S, Saglio F, Scolfaro C, Bustamante J, Badolato R, et al. Successful hematopoietic stem cell transplantation in a patient with complete IFN-γ receptor 2 deficiency: a case report and literature review. J Clin Immunol. 2020;40(8):1191–5.PubMedPubMedCentral

25.

Platt CD, Zaman F, Bainter W, Stafstrom K, Almutairi A, Reigle M, et al. Efficacy and economics of targeted panel versus whole-exome sequencing in 878 patients with suspected primary immunodeficiency. J Allergy Clin Immunol. 2021;147(2):723–6.PubMed

26.

Xiao H, Guo X, Hu B, Liu J, Zhao S, Xu Z, et al. Generalized pustular psoriasis in patients with interferon gamma (IFN-γ) receptor deficiency and mycobacterial infection. J Clin Immunol. 2021;41(4):829–33.PubMed

27.

Peñafiel Vicuña AK, Yamazaki Nakashimada M, León Lara X, Mendieta Flores E, NuñezNúñez ME, Lona-Reyes JC, et al. Mendelian susceptibility to mycobacterial disease: retrospective clinical and genetic study in Mexico. J Clin Immunol. 2023;43(1):123–35.PubMed

28.

Errami A, Baghdadi JE, Ailal F, Benhsaien I, Bakkouri JE, Jeddane L, et al. Mendelian susceptibility to mycobacterial disease (MSMD): clinical, immunological, and genetic features of 22 patients from 15 Moroccan kindreds. J Clin Immunol. 2023;43(4):728–40.PubMed

29.

Le Voyer T, Sakata S, Tsumura M, Khan T, Esteve-Sole A, Al-Saud BK, et al. Genetic, immunological, and clinical features of 32 patients with autosomal recessive STAT1 deficiency. J Immunol. 2021;ji2001451.

30.

Rosain J, Bernasconi A, Prieto E, Caputi L, Le Voyer T, Buda G, et al. Pulmonary alveolar proteinosis and multiple infectious diseases in a child with autosomal recessive complete IRF8 deficiency. J Clin Immunol. 2022;42(5):975–85.PubMedPubMedCentral

31.

Casanova JL, Abel L. Lethal infectious diseases as inborn errors of immunity: toward a synthesis of the germ and genetic theories. Annu Rev Pathol. 2021;24(16):23–50.

32.

Hambleton S, Salem S, Bustamante J, Bigley V, Boisson-Dupuis S, Azevedo J, et al. IRF8 mutations and human dendritic-cell immunodeficiency. N Engl J Med. 2011;365(2):127–38.PubMedPubMedCentral

33.

Bigley V, Maisuria S, Cytlak U, Jardine L, Care MA, Green K, et al. Biallelic interferon regulatory factor 8 mutation: a complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation. J Allergy Clin Immunol. 2018;141(6):2234–48.PubMedPubMedCentral

34.

Holland SM, Eisenstein EM, Kuhns DB, Turner ML, Fleisher TA, Strober W, et al. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma A preliminary report. N Engl J Med. 1994;330(19):1348–55.PubMed

35.

Ulrichs T, Fieschi C, Nevicka E, Hahn H, Brezina M, Kaufmann SHE, et al. Variable outcome of experimental interferon-gamma therapy of disseminated Bacillus Calmette-Guerin infection in two unrelated interleukin-12Rbeta1-deficient Slovakian children. Eur J Pediatr. 2005;164(3):166–72.PubMed

36.

Rosenzweig SD, Yancoski J, Bernasconi A, Krasovec S, Marciano BE, Casimir L, et al. Thirteen years of culture-positive M bovis-BCG infection in an IL-12Rbeta1 deficient patient: treatment and outcome. J Infect. 2006;52(3):e69-72.PubMed

37.

Alangari AA, Al-Zamil F, Al-Mazrou A, Al-Muhsen S, Boisson-Dupuis S, Awadallah S, et al. Treatment of disseminated mycobacterial infection with high-dose IFN-γ in a patient with IL-12Rβ1 deficiency. Clin Dev Immunol. 2011;2011:691956.PubMed

38.

Filipe-Santos O, Bustamante J, Haverkamp MH, Vinolo E, Ku CL, Puel A, et al. X-linked susceptibility to mycobacteria is caused by mutations in NEMO impairing CD40-dependent IL-12 production. J Exp Med. 2006;203(7):1745–59.PubMedPubMedCentral

39.

Bustamante J, Boisson-Dupuis S, Abel L, Casanova JL. Mendelian susceptibility to mycobacterial disease: genetic, immunological, and clinical features of inborn errors of IFN-gamma immunity. Semin Immunol. 2014;26(6):454–70.PubMedPubMedCentral

40.

Ying W, Liu D, Dong X, Wang W, Hui X, Hou J, et al. Current status of the management of mendelian susceptibility to mycobacterial disease in Mainland China. J Clin Immunol. 2019;39(6):600–10.PubMed

41.

Mendoza JL, Escalante NK, Jude KM, SotolongoBellon J, Su L, Horton TM, et al. Structure of the IFNγ receptor complex guides design of biased agonists. Nature. 2019;567(7746):56–60.PubMedPubMedCentral

42.

Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581(7809):434–43.PubMedPubMedCentral

43.

Taliun D, Harris DN, Kessler MD, Carlson J, Szpiech ZA, Torres R, et al. Sequencing of 53,831 diverse genomes from the NHLBI TOPMed Program. Nature. 2021;590(7845):290–9.PubMedPubMedCentral

44.

Halldorsson BV, Eggertsson HP, Moore KHS, Hauswedell H, Eiriksson O, Ulfarsson MO, et al. The sequences of 150,119 genomes in the UK Biobank. Nature. 2022;607(7920):732–40.PubMedPubMedCentral

45.

Ren Z, Povysil G, Hostyk JA, Cui H, Bhardwaj N, Goldstein DB. ATAV: a comprehensive platform for population-scale genomic analyses. BMC Bioinformatics. 2021;22(1):149.PubMedPubMedCentral

46.

Scott EM, Halees A, Itan Y, Spencer EG, He Y, Azab MA, et al. Characterization of Greater Middle Eastern genetic variation for enhanced disease gene discovery. Nat Genet. 2016;48(9):1071–6.PubMedPubMedCentral

47.

Kars ME, Başak AN, Onat OE, Bilguvar K, Choi J, Itan Y, et al. The genetic structure of the Turkish population reveals high levels of variation and admixture. Proc Natl Acad Sci U S A. 2021;118(36):e2026076118.PubMedPubMedCentral

48.

Itan Y, Shang L, Boisson B, Ciancanelli MJ, Markle JG, Martinez-Barricarte R, et al. The mutation significance cutoff: gene-level thresholds for variant predictions. Nat Methods. 2016;13(2):109–10.PubMedPubMedCentral

49.

Zhang P, Bigio B, Rapaport F, Zhang SY, Casanova JL, Abel L, et al. PopViz: a webserver for visualizing minor allele frequencies and damage prediction scores of human genetic variations. Bioinformatics. 2018;34(24):4307–9.PubMedPubMedCentral

50.

Savan R, Ravichandran S, Collins JR, Sakai M, Young HA. Structural conservation of interferon gamma among vertebrates. Cytokine Growth Factor Rev. 2009;20(2):115–24.PubMedPubMedCentral

51.

Vandenbroeck K, Alloza I, Brehmer D, Billiau A, Proost P, McFerran N, et al. The conserved helix C region in the superfamily of interferon-gamma /interleukin-10-related cytokines corresponds to a high-affinity binding site for the HSP70 chaperone DnaK. J Biol Chem. 2002;277(28):25668–76.PubMed

52.

Sareneva T, Pirhonen J, Cantell K, Kalkkinen N, Julkunen I. Role of N-glycosylation in the synthesis, dimerization and secretion of human interferon-gamma. Biochem J. 1994;303(Pt 3):831–40.PubMedPubMedCentral

53.

Favre C, Wijdenes J, Cabrillat H, Djossou O, Banchereau J, de Vries JE. Epitope mapping of recombinant human gamma interferon using monoclonal antibodies. Mol Immunol. 1989;26(1):17–25.PubMed

54.

Ikeda Y, Miyake K, Toda G, Yamada H, Yamanaka M, Oka H. Detection of anti-interferon-alpha 2a antibodies in chronic liver disease. J Gastroenterol Hepatol. 1989;4(5):411–8.PubMed

55.

Protzman WP, Jacobs SL, Minnicozzi M, Oden EM, Kelsey DK. A radioimmunologic technique to screen for antibodies to alpha-2 interferon. J Immunol Methods. 1984;75(2):317–23.PubMed

56.

Bonetti P, Diodati G, Drago C, Casarin C, Scaccabarozzi S, Realdi G, et al. Interferon antibodies in patients with chronic hepatitic C virus infection treated with recombinant interferon alpha-2 alpha. J Hepatol. 1994;20(3):416–20.PubMed

57.

Vallbracht A, Treuner J, Flehmig B, Joester KE, Niethammer D. Interferon-neutralizing antibodies in a patient treated with human fibroblast interferon. Nature. 1981;289(5797):496–7.PubMed

58.

Baker MP, Reynolds HM, Lumicisi B, Bryson CJ. Immunogenicity of protein therapeutics: the key causes, consequences and challenges. Self/Nonself. 2010;1(4):314–22.PubMedPubMedCentral

59.

Sagara R, Ishigaki M, Otsuka M, Murayama K, Ida H, Fernandez J. Long-term safety and effectiveness of velaglucerase alfa in Gaucher disease: 6-year interim analysis of a post-marketing surveillance in Japan. Orphanet J Rare Dis. 2021;16(1):502.PubMedPubMedCentral

60.

Chun JD, Lee N, Kobayashi RH, Chaffee S, Hershfield MS, Stiehm ER. Suppression of an antibody to adenosine-deaminase (ADA) in an ADA-deficient patient receiving polyethylene glycol modified adenosine deaminase. Ann Allergy. 1993;70(6):462–6.PubMed

61.

Feinberg J, Fieschi C, Doffinger R, Feinberg M, Leclerc T, Boisson-Dupuis S, et al. Bacillus Calmette Guerin triggers the IL-12/IFN-gamma axis by an IRAK-4- and NEMO-dependent, non-cognate interaction between monocytes, NK, and T lymphocytes. Eur J Immunol. 2004;34(11):3276–84.PubMed

62.

Esteve-Solé A, Sologuren I, Martínez-Saavedra MT, Deyà-Martínez À, Oleaga-Quintas C, Martinez-Barricarte R, et al. Laboratory evaluation of the IFN-γ circuit for the molecular diagnosis of Mendelian susceptibility to mycobacterial disease. Crit Rev Clin Lab Sci. 2018;55(3):184–204.PubMedPubMedCentral

63.

Xu GJ, Kula T, Xu Q, Li MZ, Vernon SD, Ndung’u T, et al. Viral immunology. Comprehensive serological profiling of human populations using a synthetic human virome. Science. 2015;348(6239):aaa0698.PubMedPubMedCentral

64.

Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, Hum D, Bryk R, et al. Fatal cytomegalovirus infection in an adult with inherited NOS2 deficiency. N Engl J Med. 2020;382(5):437–45.PubMedPubMedCentral

65.

Hasan MR, Rahman M, Khan T, Saeed A, Sundararaju S, Flores A, et al. Virome-wide serological profiling reveals association of herpesviruses with obesity. Sci Rep. 2021;11(1):2562.PubMedPubMedCentral

66.

Khan T, Rahman M, Ali FA, Huang SSY, Ata M, Zhang Q, et al. Distinct antibody repertoires against endemic human coronaviruses in children and adults. JCI Insight. 2021;6(4):e144499.PubMedPubMedCentral

67.

Love MI, Huber W, Anders S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 2014;15(12):550.PubMedPubMedCentral

68.

Gu Z, Eils R, Schlesner M. Complex heatmaps reveal patterns and correlations in multidimensional genomic data. Bioinforma Oxf Engl. 2016;32(18):2847–9.

Title: Recombinant IFN-γ1b Treatment in a Patient with Inherited IFN-γ Deficiency
Authors: Jérémie Rosain
Ayca Kiykim
Alexandre Michev
Yasemin Kendir-Demirkol
Darawan Rinchai
Jessica N. Peel
Hailun Li
Suheyla Ocak
Pinar Gokmirza Ozdemir
Tom Le Voyer
Quentin Philippot
Taushif Khan
Anna-Lena Neehus
Mélanie Migaud
Camille Soudée
Stéphanie Boisson-Dupuis
Nico Marr
Alessandro Borghesi
Jean-Laurent Casanova
Jacinta Bustamante
Publication date: 01-03-2024
Publisher: Springer US
Keyword: Interferon
Published in: Journal of Clinical Immunology / Issue 3/2024
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-024-01661-5

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