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Interferon Regulatory Factor 8 Deficiency

MedGen UID:
1785891
•Concept ID:
C5447454
•
Disease or Syndrome
Synonym: IRF8 Deficiency

Definition

A genetic condition caused by mutation(s) in the IRF8 gene encoding interferon regulatory factor 8. Autosomal dominant (Immunodeficiency 32A) and autosomal recessive (Immunodeficiency 32B) genetic alterations result in different phenotypes, both of which have impairment of function in dendritic cells. [from NCI]

Term Hierarchy

CClinical test,  RResearch test,  OOMIM,  GGeneReviews,  VClinVar  
  • CROGVInterferon Regulatory Factor 8 Deficiency

Professional guidelines

PubMed

Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs).
Lee WI, Huang JL, Yeh KW, Jaing TH, Lin TY, Huang YC, Chiu CH
J Formos Med Assoc 2011 Dec;110(12):750-8. Epub 2011 Dec 23 doi: 10.1016/j.jfma.2011.11.004. PMID: 22248828

Recent clinical studies

Etiology

Role of IRF8 in immune cells functions, protection against infections, and susceptibility to inflammatory diseases.
Salem S, Salem D, Gros P
Hum Genet 2020 Jun;139(6-7):707-721. Epub 2020 Mar 30 doi: 10.1007/s00439-020-02154-2. PMID: 32232558
Increased Fanconi C expression contributes to the emergency granulopoiesis response.
Hu L, Huang W, Hjort E, Eklund EA
J Clin Invest 2013 Sep;123(9):3952-66. Epub 2013 Aug 8 doi: 10.1172/JCI69032. PMID: 23925293Free PMC Article
Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis.
Rocca S, Schiavoni G, Sali M, Anfossi AG, Abalsamo L, Palucci I, Mattei F, Sanchez M, Giagu A, Antuofermo E, Fadda G, Belardelli F, Delogu G, Gabriele L
PLoS One 2013;8(5):e62751. Epub 2013 May 24 doi: 10.1371/journal.pone.0062751. PMID: 23717393Free PMC Article
Immune defects in active mycobacterial diseases in patients with primary immunodeficiency diseases (PIDs).
Lee WI, Huang JL, Yeh KW, Jaing TH, Lin TY, Huang YC, Chiu CH
J Formos Med Assoc 2011 Dec;110(12):750-8. Epub 2011 Dec 23 doi: 10.1016/j.jfma.2011.11.004. PMID: 22248828
The interferon consensus sequence binding protein (ICSBP/IRF8) activates transcription of the FANCF gene during myeloid differentiation.
Saberwal G, Horvath E, Hu L, Zhu C, Hjort E, Eklund EA
J Biol Chem 2009 Nov 27;284(48):33242-54. Epub 2009 Oct 2 doi: 10.1074/jbc.M109.010231. PMID: 19801548Free PMC Article

Diagnosis

IRF8 Regulates Intrinsic Ferroptosis through Repressing p53 Expression to Maintain Tumor Cell Sensitivity to Cytotoxic T Lymphocytes.
Poschel DB, Kehinde-Ige M, Klement JD, Yang D, Merting AD, Savage NM, Shi H, Liu K
Cells 2023 Jan 13;12(2) doi: 10.3390/cells12020310. PMID: 36672246Free PMC Article
Deregulation of apoptotic factors Bcl-xL and Bax confers apoptotic resistance to myeloid-derived suppressor cells and contributes to their persistence in cancer.
Hu X, Bardhan K, Paschall AV, Yang D, Waller JL, Park MA, Nayak-Kapoor A, Samuel TA, Abrams SI, Liu K
J Biol Chem 2013 Jun 28;288(26):19103-15. Epub 2013 May 15 doi: 10.1074/jbc.M112.434530. PMID: 23677993Free PMC Article
IRF8 regulates acid ceramidase expression to mediate apoptosis and suppresses myelogeneous leukemia.
Hu X, Yang D, Zimmerman M, Liu F, Yang J, Kannan S, Burchert A, Szulc Z, Bielawska A, Ozato K, Bhalla K, Liu K
Cancer Res 2011 Apr 15;71(8):2882-91. Epub 2011 Apr 12 doi: 10.1158/0008-5472.CAN-10-2493. PMID: 21487040Free PMC Article
Repression of IFN regulatory factor 8 by DNA methylation is a molecular determinant of apoptotic resistance and metastatic phenotype in metastatic tumor cells.
Yang D, Thangaraju M, Greeneltch K, Browning DD, Schoenlein PV, Tamura T, Ozato K, Ganapathy V, Abrams SI, Liu K
Cancer Res 2007 Apr 1;67(7):3301-9. doi: 10.1158/0008-5472.CAN-06-4068. PMID: 17409439
Regulation of apoptosis in myeloid cells by interferon consensus sequence-binding protein.
Gabriele L, Phung J, Fukumoto J, Segal D, Wang IM, Giannakakou P, Giese NA, Ozato K, Morse HC 3rd
J Exp Med 1999 Aug 2;190(3):411-21. doi: 10.1084/jem.190.3.411. PMID: 10430629Free PMC Article

Therapy

Mitigating the prevalence and function of myeloid-derived suppressor cells by redirecting myeloid differentiation using a novel immune modulator.
Oliver L, Alvarez R, Diaz R, Valdés A, Colligan SH, Nemeth MJ, Twum DYF, Fernández A, Fernández-Medina O, Carlson LM, Yu H, Eng KH, Hensen ML, Rábade-Chediak ML, Fernández LE, Lee KP, Perez L, Muhitch JB, Mesa C, Abrams SI
J Immunother Cancer 2022 Sep;10(9) doi: 10.1136/jitc-2022-004710. PMID: 36150744Free PMC Article
Mannan-binding lectin exacerbates the severity of psoriasis by promoting plasmacytoid dendritic cell differentiation via the signal transducer and activator of transcription 3-interferon regulatory factor 8 axis.
Zeng J, Wang D, Luo J, Li L, Lin L, Li J, Zheng W, Zuo D, Yang B
J Dermatol 2022 May;49(5):496-507. Epub 2022 Mar 29 doi: 10.1111/1346-8138.16323. PMID: 35347767
High-dimensional analysis reveals a pathogenic role of inflammatory monocytes in experimental diffuse alveolar hemorrhage.
Lee PY, Nelson-Maney N, Huang Y, Levescot A, Wang Q, Wei K, Cunin P, Li Y, Lederer JA, Zhuang H, Han S, Kim EY, Reeves WH, Nigrovic PA
JCI Insight 2019 Aug 8;4(15) doi: 10.1172/jci.insight.129703. PMID: 31391335Free PMC Article
An aberrant NOTCH2-BCR signaling axis in B cells from patients with chronic GVHD.
Poe JC, Jia W, Su H, Anand S, Rose JJ, Tata PV, Suthers AN, Jones CD, Kuan PF, Vincent BG, Serody JS, Horwitz ME, Ho VT, Pavletic SZ, Hakim FT, Owzar K, Zhang D, Blazar BR, Siebel CW, Chao NJ, Maillard I, Sarantopoulos S
Blood 2017 Nov 9;130(19):2131-2145. Epub 2017 Aug 29 doi: 10.1182/blood-2017-05-782466. PMID: 28851699Free PMC Article
Genetic determinants of susceptibility to Mycobacterial infections: IRF8, a new kid on the block.
Salem S, Gros P
Adv Exp Med Biol 2013;783:45-80. doi: 10.1007/978-1-4614-6111-1_3. PMID: 23468103

Prognosis

High IRF8 expression correlates with CD8 T cell infiltration and is a predictive biomarker of therapy response in ER-negative breast cancer.
Gatti G, Betts C, Rocha D, Nicola M, Grupe V, Ditada C, Nuñez NG, Roselli E, Araya P, Dutto J, Boffelli L, Fernández E, Coussens LM, Maccioni M
Breast Cancer Res 2021 Mar 25;23(1):40. doi: 10.1186/s13058-021-01418-7. PMID: 33766090Free PMC Article
Inactivating Mutation in IRF8 Promotes Osteoclast Transcriptional Programs and Increases Susceptibility to Tooth Root Resorption.
Thumbigere-Math V, Foster BL, Bachu M, Yoshii H, Brooks SR, Coulter A, Chavez MB, Togi S, Neely AL, Deng Z, Mansky KC, Ozato K, Somerman MJ
J Bone Miner Res 2019 Jun;34(6):1155-1168. Epub 2019 Mar 6 doi: 10.1002/jbmr.3690. PMID: 30840779Free PMC Article
Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation.
Bigley V, Maisuria S, Cytlak U, Jardine L, Care MA, Green K, Gunawan M, Milne P, Dickinson R, Wiscombe S, Parry D, Doffinger R, Laurence A, Fonseca C, Stoevesandt O, Gennery A, Cant A, Tooze R, Simpson AJ, Hambleton S, Savic S, Doody G, Collin M
J Allergy Clin Immunol 2018 Jun;141(6):2234-2248. Epub 2017 Nov 8 doi: 10.1016/j.jaci.2017.08.044. PMID: 29128673Free PMC Article
Interleukin-12 from CD103(+) Batf3-Dependent Dendritic Cells Required for NK-Cell Suppression of Metastasis.
Mittal D, Vijayan D, Putz EM, Aguilera AR, Markey KA, Straube J, Kazakoff S, Nutt SL, Takeda K, Hill GR, Waddell N, Smyth MJ
Cancer Immunol Res 2017 Dec;5(12):1098-1108. Epub 2017 Oct 25 doi: 10.1158/2326-6066.CIR-17-0341. PMID: 29070650
Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis.
Rocca S, Schiavoni G, Sali M, Anfossi AG, Abalsamo L, Palucci I, Mattei F, Sanchez M, Giagu A, Antuofermo E, Fadda G, Belardelli F, Delogu G, Gabriele L
PLoS One 2013;8(5):e62751. Epub 2013 May 24 doi: 10.1371/journal.pone.0062751. PMID: 23717393Free PMC Article

Clinical prediction guides

Biallelic interferon regulatory factor 8 mutation: A complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia, and immune dysregulation.
Bigley V, Maisuria S, Cytlak U, Jardine L, Care MA, Green K, Gunawan M, Milne P, Dickinson R, Wiscombe S, Parry D, Doffinger R, Laurence A, Fonseca C, Stoevesandt O, Gennery A, Cant A, Tooze R, Simpson AJ, Hambleton S, Savic S, Doody G, Collin M
J Allergy Clin Immunol 2018 Jun;141(6):2234-2248. Epub 2017 Nov 8 doi: 10.1016/j.jaci.2017.08.044. PMID: 29128673Free PMC Article
Interferon regulatory factor 8-deficiency determines massive neutrophil recruitment but T cell defect in fast growing granulomas during tuberculosis.
Rocca S, Schiavoni G, Sali M, Anfossi AG, Abalsamo L, Palucci I, Mattei F, Sanchez M, Giagu A, Antuofermo E, Fadda G, Belardelli F, Delogu G, Gabriele L
PLoS One 2013;8(5):e62751. Epub 2013 May 24 doi: 10.1371/journal.pone.0062751. PMID: 23717393Free PMC Article
Activation of IL-27 p28 gene transcription by interferon regulatory factor 8 in cooperation with interferon regulatory factor 1.
Zhang J, Qian X, Ning H, Yang J, Xiong H, Liu J
J Biol Chem 2010 Jul 9;285(28):21269-81. Epub 2010 Apr 30 doi: 10.1074/jbc.M110.100818. PMID: 20435892Free PMC Article
PU.1, interferon regulatory factor (IRF) 2, and the interferon consensus sequence-binding protein (ICSBP/IRF8) cooperate to activate NF1 transcription in differentiating myeloid cells.
Huang W, Horvath E, Eklund EA
J Biol Chem 2007 Mar 2;282(9):6629-43. Epub 2007 Jan 2 doi: 10.1074/jbc.M607760200. PMID: 17200120
Synergistic activation of interleukin-12 p35 gene transcription by interferon regulatory factor-1 and interferon consensus sequence-binding protein.
Liu J, Guan X, Tamura T, Ozato K, Ma X
J Biol Chem 2004 Dec 31;279(53):55609-17. Epub 2004 Oct 15 doi: 10.1074/jbc.M406565200. PMID: 15489234

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