Hematopoietic Stem Cell Transplantation Resolves the Immune Deficit Associated with STAT3-Dominant-Negative Hyper-IgE Syndrome

Stephanie C Harrison 1, Christo Tsilifis 1 2, Mary A Slatter 1 2, Zohreh Nademi 2, Austen Worth 3, Paul Veys 3, Mark J Ponsford 4 5, Stephen Jolles 4, Waleed Al-Herz 6, Terence Flood 2, Andrew J Cant 1 2, Rainer Doffinger 7, Gabriela Barcenas-Morales 8, Ben Carpenter 9, Rachael Hough 9, Ásgeir Haraldsson 10, Jennifer Heimall 11, Bodo Grimbacher 12, Mario Abinun 1 2, Andrew R Gennery 13 14

Affiliations

01 July 2021

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doi: 10.1007/s10875-021-00971-2

Abstract

Autosomal dominant hyper-IgE syndrome caused by dominant-negative loss-of-function mutations in signal transducer and activator of transcription factor 3 (STAT3) (STAT3-HIES) is a rare primary immunodeficiency with multisystem pathology. The quality of life in patients with STAT3-HIES is determined by not only the progressive, life-limiting pulmonary disease, but also significant skin disease including recurrent infections and abscesses requiring surgery. Our early report indicated that hematopoietic stem cell transplantation might not be effective in patients with STAT3-HIES, although a few subsequent reports have reported successful outcomes. We update on progress of our patient now with over 18 years of follow-up and report on an additional seven cases, all of whom have survived despite demonstrating significant disease-related pathology prior to transplant. We conclude that effective cure of the immunological aspects of the disease and stabilization of even severe lung involvement may be achieved by allogeneic hematopoietic stem cell transplantation. Recurrent skin infections and abscesses may be abolished. Donor TH17 cells may produce comparable levels of IL17A to healthy controls. The future challenge will be to determine which patients should best be offered this treatment and at what point in their disease history.

Keywords: Autosomal dominant hyper IgE syndrome; Job syndrome; STAT3-HIES TH17 cells; dominant-negative STAT3 mutations; hematopoietic stem cell transplantation.

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1 IL17A levels in healthy controls and patients post-transplant. IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls (historical and contemporary) and patients (P2—blue diamonds, P3—blue triangles, P4—blue squares, P5 (pre and post HSCT) —blue circles). Stimulations were done using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples (Med)

Fig. 1 IL17A levels in healthy controls and patients post-transplant. IL17A levels were measured by Luminex (Bio-Plex, Biorad, UK) 24 hours after stimulation in whole blood (96 Costar-F plates, 1:5 diluted in RPMI) of healthy controls (historical and contemporary) and patients (P2—blue diamonds, P3—blue triangles, P4—blue squares, P5 (pre and post HSCT) —blue circles). Stimulations were done using PHA (Sigma-Aldrich, 10 μg/ml) and compared with unstimulated medium samples (Med)

Fig. 2 Pre- and post-transplant peripheral blood mononuclear cells demonstrate that IL17A is absent pre-transplant and present post-transplant (patient 3), with normal control and a negative control patient who has not been transplanted (p.V637M)

Fig. 2 Pre- and post-transplant peripheral blood mononuclear cells demonstrate that IL17A is absent pre-transplant and present post-transplant (patient 3), with normal control and a negative control patient who has not been transplanted (p.V637M)

Fig. 3 Thoracic computerized tomography images from patient 4. a Images taken 1 year pre-transplant showing markedly abnormal lung parenchyma with large cysts, bullae, and cystic bronchiectasis particularly in the right lower lobe in association with cylindrical bronchiectasis, bronchial wall thickening, bronchocoeles, and reduced lung attenuation. b Images taken 1 year post-transplant showing several thin walled pulmonary “cysts,” similar to previous pre-transplant findings and are therefore most likely to result from previous infection and lung destruction. Some regions of parenchymal distortion and scarring are also similar. There is some bronchial dilatation and distortion in regions of scarring, but no convincing evidence of bronchiectasis

Fig. 3 Thoracic computerized tomography images from patient 4. a Images taken 1 year pre-transplant showing markedly abnormal lung parenchyma with large cysts, bullae, and cystic bronchiectasis particularly in the right lower lobe in association with cylindrical bronchiectasis, bronchial wall thickening, bronchocoeles, and reduced lung attenuation. b Images taken 1 year post-transplant showing several thin walled pulmonary “cysts,” similar to previous pre-transplant findings and are therefore most likely to result from previous infection and lung destruction. Some regions of parenchymal distortion and scarring are also similar. There is some bronchial dilatation and distortion in regions of scarring, but no convincing evidence of bronchiectasis

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References

  1.  
    1. Grimbacher B, Holland SM, Gallin JI, Greenberg F, Hill SC, Malech HL, Miller JA, O'Connell AC, Puck JM. Hyper-IgE syndrome with recurrent infections--an autosomal dominant multisystem disorder. N Engl J Med. 1999;340:692–702. doi: 10.1056/NEJM199903043400904. - DOI - PubMed
  2.  
    1. Holland SM, DeLeo FR, Elloumi HZ, et al. STAT3 mutations in the Hyper-IgE-syndrome. N Engl J Med. 2007;357:1608–1619. doi: 10.1056/NEJMoa073687. - DOI - PubMed
  3.  
    1. Minegishi Y, Saito M, Tsuchiya S, Tsuge I, Takada H, Hara T, Kawamura N, Ariga T, Pasic S, Stojkovic O, Metin A, Karasuyama H. Dominant negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome. Nature. 2007;448:1058–1062. doi: 10.1038/nature06096. - DOI - PubMed
  4.  
    1. Kane A, Deenick EK, Ma CS, Cook MC, Uzel G, Tangye SG. STAT 3 is a central regulator of lymphocyte differentiation and function. Curr Opin Immunol. 2014;28:49–57. doi: 10.1016/j.coi.2014.01.015. - DOI - PubMed
  5.  
    1. Steward-Tharp SM, Laurence A, Kanno Y, Kotlyar A, Villarino AV, Sciume G, Kuchen S, Resch W, Wohlfert EA, Jiang K, Hirahara K, Vahedi G, Sun HW, Feigenbaum L, Milner JD, Holland SM, Casellas R, Powrie F, O'Shea JJ. A mouse model of HIES reveals pro and anti-inflammatory functions of STAT 3. Blood. 2014;123:2978–2987. doi: 10.1182/blood-2013-09-523167. - DOI - PMC - PubMed
  6.  
    1. de Beaucoudrey L, Puel A, Filipe-Santos O, Cobat A, Ghandil P, Chrabieh M, et al. Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells. J Exp Med. 2008;205:1543–1550. doi: 10.1084/jem.20080321. - DOI - PMC - PubMed
  7.  
    1. Gennery AR, Flood TJ, Abinun M, Cant AJ. 2000. Bone marrow transplantation does not correct the hyper IgE syndrome. Bone Marrow Transplant. 2000;25:1303–1305. doi: 10.1038/sj.bmt.1702446. - DOI - PubMed
  8.  
    1. Yanagimachi M, Ohya T, Yokosuka T, Kajiwara R, Tanaka F, Goto H, Takashima T, Morio T, Yokota S. The potential and limits of hematopoietic stem cell transplantation for the treatment of autosomal dominant Hyper-IgE syndrome. J Clin Immunol. 2016;36:511–516. doi: 10.1007/s10875-016-0278-1. - DOI - PubMed
  9.  
    1. Goussetis E, Peristeri I, Kitra V, Traeger-Synodinos J, Theodosaki M, Psarra K, Kanariou M, Tzortzatou-Stathopoulou F, Petrakou E, Fylaktou I, Kanavakis E, Graphakos S. Successful long-term immunologic reconstitution by allogeneic hematopoietic stem cell transplantation cures patients with autosomal dominant hyper-IgE syndrome. J Allergy Clin Immunol. 2010;126:392–394. doi: 10.1016/j.jaci.2010.05.005. - DOI - PubMed
  10.  
    1. Nester TA, Wagnon AH, Reilly WF, Spitzer G, Kjeldsberg CR, Hill HR. Effects of allogeneic peripheral stem cell transplantation in a patient with Job syndrome of hyperimmunoglobulinaemia E and recurrent infections. Am J Med. 1998;105:162–164. doi: 10.1016/S0002-9343(98)00200-9. - DOI - PubMed
  11.  
    1. Patel NC, Gallagher JL, Torgerson TR, Gilman AL. Successful haploidentical donor hematopoietic stem cell transplant and restoration of STAT3 function in an adolescent with autosomal dominant hyper-IgE syndrome. J Clin Immunol. 2015;35:479–485. doi: 10.1007/s10875-015-0167-z. - DOI - PubMed
  12.  
    1. Ponsford MJ, Clark J, Mock J, Abinun M, Carne E, El-Shanawany T, et al. Hematopoietic stem cell transplantation and vasculopathy associated with STAT3-dominant-negative hyper-IgE syndrome. Front Pediatr. 2020;8(September):1–8. - PMC - PubMed
  13.  
    1. Oikonomopoulou C, Goussetis E. Autosomal dominant hyper-IgE syndrome: when hematopoietic stem cell transplantation should be considered? Pediatr Transplant. 2020;24:e13699. doi: 10.1111/petr.13699. - DOI - PubMed
  14.  
    1. von Stemann JH, Rigas AS, Thorner LW, et al. Prevalence and correlation of cytokine-specific autoantibodies with epidemiological factors and C-reactive protein in 8,972 healthy individuals: results from the Danish Blood Donor Study. PLoS One. 2017;12:e0179981. doi: 10.1371/journal.pone.0179981. - DOI - PMC - PubMed
  15.  
    1. Morbach H, Eichhorn EM, Liese JG, Girschick HJ. Reference values for B cell subpopulations from infancy to adulthood. Clin Exp Immunol. 2010;162:271–279. doi: 10.1111/j.1365-2249.2010.04206.x. - DOI - PMC - PubMed
  16.  
    1. Jodele S, Laskin BL, Dandoy CE, Myers KC, el-Bietar J, Davies SM, Goebel J, Dixon BP. A new paradigm: diagnosis and management of HSCT-associated thrombotic microangiopathy as multi-system endothelial injury. Blood Rev. 2015;29(3):191–204. doi: 10.1016/j.blre.2014.11.001. - DOI - PMC - PubMed
  17.  
    1. Hox V, O’Connell MP, Lyons JJ, et al. Diminution of signal transducer and activator of transcription 3 signaling inhibits vascular permeability and anaphylaxis. J Allergy Clin Immunol. 2016;138:187–199. doi: 10.1016/j.jaci.2015.11.024. - DOI - PMC - PubMed

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