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Hindawi Case Reports in Immunology Volume 2019, Article ID 6357256, 5 pages https://doi.org/10.1155/2019/6357256 Case Report Partial and Transient Clinical Response to Omalizumab in IL-21-Induced Low STAT3-Phosphorylation on Hyper-IgE Syndrome 1 2 Cesar Daniel Alonso-Bello , Mar-a del Carmen Jiménez-Mart-nez , 1 3 Mar-a Eugenia Vargas-Camaño, Sagrario Hierro-Orozco, 4,5 6 4 Mario Alberto Ynga-Durand , Laura Berrón-Ruiz, Julio César Alcántara-Montiel, 7 1 Leopoldo Santos-Argumedo, Diana Andrea Herrera-Sánchez, 1 1 Fernando Lozano-Patiño, and Mar-a Isabel Castrejón-Vázquez Immunology and Allergy Department, Centro M´edico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico Faculty of Medicine, Universidad Nacional Auton ´ oma de M´exico, Mexico Dermatology Department, Centro M´edico Nacional 20 de Noviembre, Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado, Mexico ´ ´ Universidad Nacional Autonoma de Mexico, Facultad de Estudios Superiores Zaragoza, Facultad de Medicina, Mexico Laboratorio de Inmunidad de Mucosas, Seccion ´ de Investigacion ´ y Posgrado, Escuela Superior de Medicina, Instituto Polit´ecnico Nacional, Mexico City, Mexico Immunodeficiencies Research Unit, Instituto Nacional de Pediatria, Secretar ´ıa de Salud, Mexico Department of Molecular Biomedicine, CINVESTAV-IPN, Mexico Correspondence should be addressed to Cesar Daniel Alonso-Bello; cesar firstname.lastname@example.org Received 21 April 2019; Accepted 13 June 2019; Published 4 July 2019 Academic Editor: Necil Kut ¨ uk ¨ c¸¨uler Copyright © 2019 Cesar Daniel Alonso-Bello et al. is Th is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Hyper-IgE syndrome (HIES) is a rare primary immunodeficiency characterized by elevated levels of immunoglobulin E (IgE), eczematous dermatitis, cold abscesses, and recurrent infections of the lung and skin caused by Staphylococcus aureus.Thedominant form is characterized by nonimmunologic features including skeletal, connective tissue, and pulmonary abnormalities in addition to recurrent infections and eczema. Omalizumab is a humanized recombinant monoclonal antibody against IgE. Several studies reported clinical improvement with omalizumab in patients with severe atopic eczema with high serum IgE level. We present the case of a 37-year-old male with HIES and cutaneous manifestations, treated with humanized recombinant monoclonal antibodies efalizumab and omalizumab. After therapy for 4 years, we observed diminished eczema and serum IgE levels. 1. Introduction (greater than 1500/ml) and elevated levels of IgE, which typ- ically are above 2000 IU/ml. Leukocytes in blood and serum Hyper-IgE syndrome (HIES) is a rare primary immunode-fi immunoglobulin levels IgM, IgG, and IgA are frequently nor- ciency characterized by elevated levels of immunoglobulin E mal, but they have been found in some cases of deficiencies (IgE), eczematous dermatitis, cold abscesses, and recurrent immunoglobulins. There are two main forms of HIES: a form infections of the lung and skin caused by Staphylococcus characterized by mutations in signal transducer and activator aureus. The diagnosis of hyper-IgE syndrome is syndromic of transcription 3 gene (STAT3)with autosomal dominant and the most frequent laboratory meetings are eosinophilia inheritance (AD) (the Online Mendelian Inheritance in 2 Case Reports in Immunology (a) (b) Figure 1: Cutaneous lesions located in left costal dermatome, characterized by multiple necrotic lesions. Man (OMIM)number registered in database is#147060) tolerogenic DC and induced regulatory T cells (iTreg) which maintain an appropriate balance Th1/Th2. In patients with and a mutation in Dedicator of cytokinesis 8 (DOCK8)with autosomal recessive inheritance (AR), OMIM #243700, both HIES, signal transduction mediated by IL10-DCs is impaired, in humans and mice. The dominant form is characterized which predisposes to allergic manifestations. This generation by nonimmunologic features including skeletal abnormalities of induced FOXP3 regulatory T cells is impaired in patients (scoliosis, retained primary teeth, and fractures with minor with HIES . We describe a case of partial clinical response trauma), connective tissue, and pulmonary abnormalities in to omalizumab in IL-21-induced low STAT3-phosphorylation addition to recurrent infections and eczema. In contrast, the on a patient with HIES and very high levels of total serum recessive form lacks skeletal abnormalities and has marked IgE. viral infections caused by molluscum contagiosum and her- pes simplex virus (HSV) and neurologic complications . 2. Case Presentation The DOCK8 immunodeficiency syndrome (DIDS) is the predominant form of HIES autosomal recessive (AR-HIES). On April 2008, a 37-year-old male from Mexico City, with DOCK8 which is highly expressed in the immune system is a diagnosis of atopic dermatitis since he was 5 years old, member of a poorly characterized family of atypical guanine presented to dermatology service and was treated with dinucleotide exchange factors for Rho family GTPases. The efalizumab 1 mg/kg/SC/weekly for two months. The patient 50-80% of these patients develop severe allergies such as received twelve doses of efalizumab, but the drug was sus- asthma, anaphylaxis, and food allergy. In particular, CD8+ T pended due to herpes zoster dermatitis (Figure 1), and treat- cells from DIDS patients not only are decreased in number ment with acyclovir was indicated with adequate clinical but also fail to expand normally in vitro after stimulation and response. Two months later, the patient developed gen- produce less antiviral cytokines, which increases susceptibil- eralized erythroderma, finding high levels of total serum ity to viral infections like herpes simplex virus (HSV), human IgE (48,700 UI/ml) and interleukins levels: TNF 39.7 pg/ml, papillomavirus (HPV), molluscum contagious (MCV), and IL-1𝛽 5 pg/ml, IL-2R 1086 IU/ml, IL-6 11.9 pg/ml, and IL- varicella-zoster virus (VZV). Some patients have impaired 8 8.66 pg/ml, showing increased levels of proinflammatory humoral immunity, decreasing the number of immunoglobu- cytokines. He was sent to the service of clinical immunology lins. DIDS patients are also highly prone to malignancy, with and allergy, where he was diagnosed with HIES. To evaluate 10% to 36% of patients developing cancers in late childhood the pathway of IL-21, PBMCs of the patient were stimulated to early adulthood like squamous cell carcinomas, and lym- with rhIL-21 (militenyi) for 15 minutes and phosphorylation phomas, including Burkitt lymphoma or Epstein Barr Virus of STAT3 was evaluated by o fl w cytometry. The mAbs used (EBV) diffuse large B cell lymphoma, predominate [2, 3]. were anti CD19-APC, anti-pSTAT3 (Y705)-PE, and isotype Since the discovery in 2009 that loss-of-function mutations controls (mouse IgG1) from BD Pharmingen and Santa Cruz in DOCK8 underlie AR-HIES, an estimated >100 patients Biotechnology. Flow cytometry was performed on CYAN- worldwide have been identified. FOXP3 regulatory T cells ADP cytometer (Beckman Coulter). Cells were analyzed that produce IL-10 play an essential role in regulating allergic using Flow Jo 8.8 sow ft are (Tree Star). On September 2008, inflammation. There are two types of FOXP3 regulatory T the clinical manifestations were dry skin and lichenified cells: the natural and induced. FOXP3 gene mutations pro- upper limbs and chest, generalized itching, peeling, and duce immune deregulation with enteropathy, autoimmune scratching scars, treated with hydroxyzine 10 mg every 8 diabetes, thyroiditis, food allergies, atopic dermatitis, and hours, efalizumab, emollients, and general measures. On elevated levels of IgE. Cytokines produced by dendritic cells January 2009, the treatment was modified with monoclonal (DC) play a role in the induction and maintenance of T cell antibody omalizumab 300 mg every two weeks, with initial tolerance. IL-10 signaling-DC is needed for the generation of levels of total IgE 127,000 IU/ml. We made a new clinical Case Reports in Immunology 3 9.4 7.5 5.8 2.9 2.6 2 2.1 June-09 Apr-11 Aug-11 Aug-12 Nove-14 Apr-15 Figure 2: Comparison between CRP levels during application of omalizumab. The variation of protein levels does not correlate with the clinical manifestations of the patient and IgE levels. 73500 73600 48700 48300 851 1090 0 435 439 Figure 3: Comparison between IgE levels during application of omalizumab. The y-axis: serum IgE expressed in IU/ml; the x-axis: the dates on which these levels were taken. The decrease in IgE levels was clearly o bserved during the application of omalizumab; these increased aer ft treatment was discontinued. assessment at 6 weeks; the patient presented clinical improve- Interleukin 21 (IL-21) is needed for the differentiation of ment with eczematous lesions on the chest and upper limbs subsetsofTcellsCD4 the Th17 cells. The patient showed and secondary hypochromic lesions and traces of scratching. low phosphorylation of STAT3 aeft r 15 minutes of stimulation Reassessing their total serum IgE levels in 439 UI/ml, we with rhIL-21. Experimental controls are appended (Figures decided to increase omalizumab dose to 350 mg every two 4 and 5). The low phosphorylation of STAT3 observed in weeks. On May 2013, the patient presented skin lesions exac- HIES patients suggested that the activation and regulation of erbation with erythema, itching, eczema, and erythroderma. STAT3 might have an important role in T cell activation . To 2013 the patient received 74 doses of omalizumab with STAT3 regulates the subset Th cells which are important stability of clinical manifestations. Eczema and total IgE levels in inflammatory response to bacterial and fungal pathogens were decreased even though with variations. The variations . Defective Th17 responses are a common attribute of HIES of CRP (C-reactive protein) do not correlate with the clinical cases with different genetic forms and sporadic cases . Our manifestations of the patient and IgE levels (Figures 2 and patient had severe eczema and elevated levels of IgE that have 3). The patient decided to stop the treatment by personal never been reported in the world literature. decision. In the present case, dermatological findings led us to suspect HIES because of IgE levels and childhood onset- atopic dermatitis. Therefore, further investigations for HIES 3. Discussion were done and the diagnosis was made by Grimbacher We present the case of a patient with HIES and skin mani- Criteria . Omalizumab, the humanized recombinant mon- festations treated with humanized recombinant monoclonal oclonal antibody against IgE, is known to result in marked antibody, omalizumab. HIES is a rare primary immunodefi- reduction in serum free IgE and downregulation of IgE receptors on circulating basophiles. Omalizumab is used for ciency, characterized by high levels of serum IgE, recurrent skin abscesses, eczema, and pneumonia. Inherited patterns the treatment of moderate to severe persistent asthma in with AD, AR have been reported, but most HIES cases are adults and adolescents older than 12 years of age who have sporadic. Mutations in the signal transducer and activator of elevated levels of IgE and positive skin test to a perennial transcription 3 gene (STAT3)are amajor cause ofAD. allergen. Several studies reported clinical improvement in 4 Case Reports in Immunology PBCMs Were cultured in AIM by 2 B cells stimulated with B cells hours IL-21 for 15 minutes unstimulated Isotype CD19, Phospho- CD19,- control Phospho- STAT3 STAT3 STAT3 (Tyr705) (Tyr705) (Tyr705) 0 1 2 3 4 10 10 10 10 10 Phosphorylation of STAT3 Figure 4: Evaluation of STAT3 phosphorylation by flow cytometry. Experimental controls Experimental controls Phosphorylation of STAT3 induced with IL-21 Phosphorylation of STAT3 induced with IL-21 in permeabilized B cells in non permeabilized B cells 100 100 80 80 60 60 20 20 0 0 0 1 2 3 4 0 1 2 3 4 10 10 10 10 10 10 10 10 10 10 Phospho-STAT3 －＆） Phospho-STAT3 －＆） IL-21 16.1 IL-21 4 Non stimulated 3.2 Non stimulated 3.7 (a) (b) Figure 5: The patient showed low phosphorylation of STAT3 aer ft 15 minutes of stimulation with rhIL-21; this image shows the comparison with experimental controls. MFI % of Max % of Max MFI % of Max Case Reports in Immunology 5 patients with severe atopic eczema with high serum IgE level Asian Pacific Journal of Allergy and Immunology ,vol.27, no.4, pp. 233–236, 2009. [10–13]. However, prospective studies and long-term follow- up are required to conrfi m the ecffi acy of omalizumab in  J. C. Chia and P. R. Mydlarski, “Dermatologic uses of omal- izumab,” JournalofDermatologicalTreatment, vol.28, no.4,pp. HIES. In the present case, the clinical response was partial 332–337, 2016. because the patient did not fulfill his treatment schedule. The reactivation of skin manifestations was related to the serum  S. Bard, A. Paravisini, J. A. Aviles ´ -Izquierdo, E. Fernandez-Cruz, and S. Sanchez ´ -Ramon, ´ “Eczematous dermatitis in the setting IgE increase. of hyper-IgE syndrome successfully treated with omalizumab,” JAMA Dermatology, vol. 144,no. 12,pp. 1662-1663, 2008. Abreviations HIES: Hyper-IgE syndrome IgE: Immunoglobulin E AD: Autosomal dominant inheritance AR: Autosomal recessive inheritance HSV: Herpes simplex virus DIDS: DOCK8 immunodeficiency syndrome HPV: Human papillomavirus MCV: Molluscum contagious virus VZV: Varicella-zoster virus. Conflicts of Interest The authors have no conflicts of interest to disclose. References  A. F. Freeman and S. M. Holland, “The hyper-IgE syndromes,” Immunology and Allergy Clinics of North America, vol.28,no.2, pp. 277–291, 2008.  O. C. Vega, V. L. Hernand ´ ez, M. N. H. Segura, and S. B. A. Tor- res, “Hyper IgE syndrome. diagnosis and timely management,” Revista Alergia Mexico, vol. 55, no. 1, pp. 38–45, 2008.  J. C. Alcantara-Montiel and B. I. Vega-Torres, “Hyper-IgE syn- drome. lessons from function and defects of STAT-3 or DOCK- 8,” Revista Alergia M´exico, vol.63,no.4,pp.385–396, 2016.  E.M.Shevach, “Mechanisms of foxp3 T regulatory cell- mediated suppression,” Immunity, vol.30, no.5,pp. 636–645,  Y. 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Published: Jul 4, 2019
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