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Hindawi Case Reports in Immunology Volume 2020, Article ID 6694957, 9 pages https://doi.org/10.1155/2020/6694957 Case Report On Two Cases with Autosomal Dominant Hyper IgE Syndrome: Importance of Immunological Parameters for Clinical Course and Follow-Up 1 1 Snezhina Mihailova Kandilarova , Spaska Stoyneva Lesichkova, 1 1 1 Nevena Todorova Gesheva, Petya Stefanova Yankova, Nedelcho Hristov Ivanov, 2 2 1 Guergana Petrova Stoyanova, Penka Ilieva Perenovska, Marta Petrova Baleva, and Elissaveta Jordanova Naumova Department of Clinical Immunology with Stem Cell Bank, University Hospital “Alexandrovska”, PID National Expert Center, Medical University, Soﬁa, Bulgaria Department of Pediatric Diseases, University Hospital “Alexandrovska”, Medical University, Soﬁa, Bulgaria Correspondence should be addressed to Snezhina Mihailova Kandilarova; firstname.lastname@example.org Received 5 October 2020; Revised 8 November 2020; Accepted 24 November 2020; Published 3 December 2020 Academic Editor: Claudio Pignata Copyright © 2020 Snezhina Mihailova Kandilarova et al. +is 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. Autosomal dominant hyper-IgE syndrome (AD-HIES) is a rare disease described in 1966. It is characterized by severe dermatitis, a peculiar face, frequent infections, extremely high levels of serum IgE and eosinophilia, all resulting from a defect in the STAT3 gene. A variety of mutations in the SH2 and DNA-binding domain have been described, and several studies have searched for associations between the severity of the clinical symptoms, laboratory ﬁndings, and the type of genetic alteration. We present two children with AD-HIES–a girl with the most common STAT3 mutation (R382W) and a boy with a rare variant (G617E) in the same gene, previously reported in only one other patient. Herein, we discuss the clinical and immunological ﬁndings in our patients, focusing on their importance on disease course and management. “Hyperimmunoglobulin E recurrent infection syndrome- 1. Introduction HIES.” +e disease is autosomal dominant and belongs to In 1966, Davis et al.  published two interesting clinical the family of primary immune deﬁciencies (PIDs). In 2004, cases in Lancet: two red-haired white-skinned girls who Renner et al. described six families with diﬀerent charac- presented with severe dermatitis several weeks after birth, teristics of hyper IgE syndrome, which was inherited in an recurrent cutaneous staphylococcal abscesses, sinusitis, and autosomal recessive manner . In 2007, genetic defects in the STAT3 were demonstrated in the autosomal dominant treatment-resistant pulmonary infections. +ey named this new nosological entity “Job Syndrome.” None of the parents form [6, 7], in 2009 in the DOCK8 gene  and in 2006–2007 and siblings shared similar complaints. Six years later, in the TYK2 gene in an autosomal recessive form [9, 10]. Buckley et al.  described two boys with severe dermatitis, a Subsequently, several articles reported data on a diﬀerent characteristic face, frequent infections, extremely high levels number of patients, detecting both established and new of serum IgE and eosinophilia, and termed the disease mutations [6, 11–15]. “Buckley’s syndrome.” In 1974, Hill et al. [3, 4] found that In this article, we present 2 children with an autosomal patients with similar diseases had high levels of serum IgE dominant form of HIES (AD-HIES)—a girl with one of the and defects in the chemotactic function of granulocytes. +e most commonly detected STAT3 mutations and a boy with a syndrome was designated as Job’s-Buckley syndrome or very rare mutation in the same gene. We discuss the clinical 2 Case Reports in Immunology intervention. At age 2.8, she was hospitalized with hydro- and immunological ﬁndings in patients and the importance of determining the cytokine proﬁle for disease evaluation. thorax and at age 3, was admitted with peritonsillar abscess. At age 4, she had pneumonia and pleuritis and at age 6, retroperitoneal abscess, subphrenic abscess, and diﬀuse 2. Case Presentation ﬁbrinopurulent peritonitis. +e microbiological investiga- tion at that time revealed Candida albicans in feces and 2.1. Case 1. Patient 1 is a 10-year-old male who was born throat swab, Proteus mirabilis in abdominal exudate, full-term . He has no siblings. Family history for PIDs Klebsiella pneumonia, Acinetobacter baumannii, and Ste- was negative. Vaccines were given on schedule. Since in- phanoascus ciferrii in a hemoculture specimen. Densito- fancy, he suﬀered from recurrent staphylococcal skin in- metric studies revealed that bone density was within the fections, bacterial otitis at 2 months, subcutaneous abscess of expected for her age. +e diagnosis was conﬁrmed at age 7 by the hairy part of the head at 10 month, and styes of both the presence of the heterozygous R382W germline mutation eyelids at age 3. At age 4, he had pneumonia. At age 8, he in the STAT3 gene. +e patient was put on prophylaxis with developed pleuropneumonia complicated by empyema and Itraconazole (10 mg/kg/day) and Sulfamethoxazolum/Tri- pulmonary abscesses with multiple pneumatoceles. Imaging methoprim at a dose of 480 mg twice per day every other day studies of the lungs conducted in the past and during the with relatively good clinical response. Her dermatitis persists current examination revealed numerous changes such as despite treatment and prevention (Figure 2(c) and 2(d)). emphysema, pneumoﬁbrosis with adhesion, atelectasis, Furthermore, at age 10, hyperplasia of the thymus was pleural eﬀusions, and partial pneumothorax. Physical ex- observed. However, despite the therapy, in the seventh year amination at admission revealed a polymorphic erythema- of follow-up, there was a worsening of the existing pneu- tous rash of the face and eyelids, dry skin with matocele complicated with abscess. Aspergillus fumigatus hyperpigmentation on the limbs, onychomycosis of the nails was isolated from sputum. (Figure 1(a)), a dolichocephalic conﬁguration of the head, Hyper IgE Syndrome Scores, according to Grimbacher dysmorphic face (Figure 1(c)), and multiple dental abnor- et al.  and STAT3 variants of both cases, are presented in malities: retention, hyperdontia, and alignment of the teeth Table 1. Data from immunological tests are shown in in two rows (Figure 1(b)). Allergy to nuts, house dust, and Tables 2–4. cow’s milk protein has been proven. Microbiological in- Written informed consent was obtained from the par- vestigation of sputum/throat smear showed various path- ents of Patient 1 and from the mother of Patient 2. ogenic microorganisms such as group A beta-hemolytic streptococci, Moraxella nonliquefaciens, and Streptococcus pneumoniae. Bone density was estimated from spinal den- 3. Discussion sitometry and was age-relevant. +e deﬁnitive diagnosis was 3.1. Increased Serum IgE. In 97% of the patients, IgE levels made at age 8. Genetic testing showed a heterozygous variant are above 2000 IU/ml . +e diagnostic sensitivity of the p.1850 G> A (p.Gly617Glu) in exon 20 of the STAT3 gene, elevated IgE levels is 95.8%, but the speciﬁcity is very low which encodes a transcription factor with key gene regu- −3.3% . In the course of the disease, a decrease and even lation activity. According to the criteria of the American a normalization of high serum IgE levels have been observed College of Medical Genetics, the described variant was in some patients . So far, there is no satisfactory ex- categorized as probably pathogenic and, in principal, could planation for the cause of the extremely high serum IgE explain the observed clinical symptoms. +e child was levels in patients with AD-HIES. +e following hypothesis monitored for 4 years after admission. Long-term pro- has been discussed: association with IL-21 signaling [19, 20], phylaxis with Itraconazole 100 mg/day and Sulfamethox- low catabolic rate of IgE , unconventional way of binding azolum/Trimethoprimum 960 mg daily dose, three times per of S. aureus superantigens with MHC class II molecules, the week, was initiated. A suﬃcient clinical response was inclusion of a much larger number of T-cell receptors, achieved with no severe infections. production of IgE antibodies to staphylococcal super- antigens, and massive cytokine production [22–25]. +e data 2.2. Case 2. Patient 2 is an 11-year-old female, born full- concerning food allergy in AD-HIES are controversial: term. She has no siblings and no family history for PIDs. +e Gernez et al.  have found allergy to food in 37% of AD- child was vaccinated with no side eﬀects or complications. HIES patients, Siegel et al. –in 8, 5%, Chandesris et al. No dysmorphic features or skeletal abnormalities were −8% of AD-HIES patients had asthma and 22%-allergic noted; however on the physical examination, hypoplasia of symptoms mainly food and pollen allergy. +erefore, these the upper teeth and oral ulcers were observed (Figure 2(a) reactions are rare in AD-HIES, may possibly be a result of and 2(b)). Since the age of 1 year, she has been having impairment of mastocyte and basophil degranulation, but recurrent fungal infections of the oral cavity, skin, and nails symptoms of allergy have been described in AD-HIES. +is (Candida albicans, Zygomycetes species). +e patient has had fact points to the importance of diet in these patients, es- several manifestations of bronchial obstruction from in- pecially in the presence of food allergies. Both patients fancy. At 18 months, she had pneumonia with pleural described by us have elevated levels of IgE (Tables 1 and 2). empyema and subsequent lobectomy. At age 2, she devel- Patient 1 had a history of rash after oral administration of oped diﬀuse ﬁbrinopurulent peritonitis with necrosis and Amoxicillin/Clavulanic acid, while at the same time allergy colon transversum perforation resolved by surgical to nuts and cow’s milk protein has been proven (results not Case Reports in Immunology 3 (a) (b) (c) Figure 1: Data of some physical manifestations of Patient 1. (a) Onychomycosis of the thumbnail. (b) Retained deciduous teeth at 7 years. (c) Facial features at 11 years. (a) (b) (c) (d) Figure 2: Data of some physical manifestations of Patient 2. (a) Hypoplasia of upper teeth at 7 years. (b) Recurrent oral ulcers at 7 years. (c) Resistant to treatment dermatitis to the scalp. (d) Resistant to treatment dermatitis of the gluteal area. shown). Patient 2 had recurrent pulmonary aspergillosis and 3.2. Hypereosinophilia. Hypereosinophilia is due to the showed a trend of increasing IgE levels over the years: from increased production of granulocyte-monocyte colony- 431 IU/ml at the time of diagnosis to 22 400 IU/ml. In this stimulating factor (GM-CSF) [28, 29]. Eosinophils in the case, the course of the dermatitis is relatively severe and blood are elevated in 70–93% of patients , but no cor- resistant to treatment. +e progressive increase of the disease relation was found with IgE levels and clinical symptoms in Patient 2 might be associated with inadequate infection . +e diagnostic value of hypereosinophilia in AD-HIES control and could be a marker of persistent aspergillosis. We has 93.5% sensitivity, but the speciﬁcity is low −23.3% . suggest that the regular monitoring of IgE titer is important Mild hypereosinophilia was observed in both patients; for patients with AD-HIES. however, the higher values in Patient 1 were not related to a 4 Case Reports in Immunology Table 1: Hyper IgE Syndrome Scores and STAT3 mutation data. Symptoms Patient 1 Points Patient 2 Points Highest IgE 2180 IU/ml 10 9740 IU/ml 10 Skin abscesses 3-4 4 3-4 4 Pneumonia 2 4 2 4 Parenchymal lung abnormalities Pneumatocele 8 Pneumatocele 8 Abscesses retroperitonealis and Other serious infection Empyema and abscesses pulmonum 4 4 subfrenicus dextra Peritonitis, perforation colon Fatal infection Absent 0 4 transversum Highest eosinophils (10 L) 0.94 6 0, 7 6 Newborn rash Absent 0 Absent 0 Eczema (worst stage) Moderate 2 Moderate 2 Sinusitis/otitis 1–3 1 Absent 0 Candidiasis Finger/nail 2 Systemic 4 Retained primary teeth >3 8 >3 8 Scoliosis, max curve Absent 0 Absent 0 Fractures with little trauma Absent 0 Absent 0 Hyperextensibility Absent 0 Absent 0 Characteristic face Mild 2 Absent 0 Increased nose width (interallar 1-2 SD 1 Absent 0 distance) High palate Present 2 Present 2 Midline anomaly Absent 0 Absent 0 Lymphoma Absent 0 Absent 0 Young age add-on <1 year 7 <1 year 7 SCORE 61 63 NM_139276.2(STAT3):s.1850 NM_139276.2 STAT3 mutations G> A(p.Gly617Glu) (STAT3):c.1145 G> T (p.Arg382Leu) Table 2: Evaluation of STAT3 signaling pathway activation in patients. Individuals tested STAT3 activation in CD4+ STAT3 activation in CD8+ CD4+ (U) Geo MFI 5 CD8+ (U) Geo MFI 5 Patient 1 CD4+ (S) Geo MFI 16 CD8+ (S) Geo MFI 17 Geo MFI index 3.2 Geo MFI index 3.4 CD4+ (U) Geo MFI 7 CD8+ (U) Geo MFI 5 Healthy control 1 CD4+ (S) Geo MFI 42 CD8+ (S) Geo MFI 40 Geo MFI index 6 Geo MFI index 8 CD4+ (U) Geo MFI 13 CD8+ (U) Geo MFI 9 Patient 2 CD4+ (S) Geo MFI 32 CD8+ (S) Geo MFI 37 Geo MFI index 2.5 Geo MFI index 4.1 CD4+ (U) Geo MFI 139 CD8+ (U) Geo MFI 170 Healthy control 2 CD4+ (S) Geo MFI 901 CD8+ (S) Geo MFI 971 Geo MFI index 6.5 Geo MFI index 5.7 U: unstimulated; S: stimulated; Geo MFI: geometric mean ﬂuorescence intensity; Geo MFI index: ratio of Geo MFI of stimulated to Geo MFI of unstimulated cells. worse disease course. +e number of eosinophils did not HIES, dermatitis is very prolonged, severe, and methicillin- correlate with the measured GM-CSF levels in both cases resistant. Involvement of the skin, nails, and mucous mem- (Table 3). branes in fungal infections is another common manifestation of the disease and is found in 43–85% of patients (11, 12, 14, 15). During infancy, Patient 1 had staphylococcal pyoderma 3.3. Skin Manifestations. +e main skin manifestations in and onychomycosis, but at the same time, he also presented AD-HIES are eczema (90%), neonatal rash (45–74%), and with signs of atopic rash on the ﬂexor surfaces of the limbs skin abscesses (85%) (11, 12, 14, 15). In some cases, the rash is and eyelids, drug-induced rash, and allergy to nuts and cow’s diﬃcult to be distinguished from atopic dermatitis. +e milk protein. Dermatitis in Patient 2 was persistent, mainly typical localization and the presence of licheniﬁed plaques of aﬀecting the head and buttocks without a satisfactory ther- the anterior neck, antecubital and popliteal fossa in atopic apeutic response. Nails, oral cavity, skin, and intestines were dermatitis come into consideration here. In addition, in AD- aﬀected by Candida albicans and Zygomycetes spp. Case Reports in Immunology 5 Table 3: Immunological phenotype of Patients 1 and 2. Immune phenotype/marker (units) Patient 1 Patient 2 Reference range WBC (cells × 10 /L) 7.3 7.0 4.5÷13 ANC (cells × 109/L) 1.97 2.0 1.8÷ 8.0 ALC (cells × 109/µL) 3.79 3.8 1.5÷ 6.5 Eos (%) 12 10.2 0.0÷ 6.0 CD3+ (%Ly) 63 77 66÷ 76 CD3+DR+ (%Ly) 9 5 9.5÷17 ∗∗ CD3+CD4+ (%Ly) 36 45 33÷ 41 CD45RA+62L+ from CD4+ (%Ly) 24.8 73.6 46÷ 99 CD45RA-62L+ from CD4+ (%Ly) 6.4 19.8 0.35÷100 ∗∗ CD45RA-62L− from CD4+ (%Ly) 24.8 4.8 0.27÷18 ∗∗ CD45RA+62L− from CD4+ (%Ly) 44.0 1.8 <1.8 ∗ ∗ CD3+CD8+ (%Ly) 19 21 27÷ 35 CD45RA+62L+ from CD8+ (%Ly) 45.5 68.1 16÷100 CD45RA-62L+ from CD8+ (%Ly) 5.6 5.9 1÷ 6 CD45RA-62L- from CD8+ (%Ly) 23.6 12.4 5÷100 CD45RA+62L- from CD8+ (%Ly) 25.3 13.6 15÷ 41 CD19+ (%Ly) 18 20 12÷ 22 CD3-CD16 + 56 (%Ly) 14 6 9± 16 CD3+CD16 + 56+ (%Ly) 10 3 4÷ 26 CD25+CD127low (%Ly) 8.4 6.2 5÷10 ∗ ∗ CD4+CD161+CD196+ (%Ly) 2.34; 2.0 1.2 12.5÷14.9 IgG (g/l) 16.079 10.64 5.40–16.10 IgG1(g/l) 10.902 8.482 4.23–10.6 IgG2 (g/l) 2.5 2.738 0.72–4.3 IgG3 (g/l) 0.681 0.934 0.127–1.731 IgG4 (g/l) 0.428 0.24 0.016–1.151 IgA (g/l) 1,742 0.75 0.50–2.80 ∗∗ IgM (g/l) 1.400 2.41 0.5–1.90 ∗∗∗ ∗∗ ∗∗ IgE (U/ml) 2180; 1995; 1104; 1414; 2000 431; >2500; 9740; 22400 <87 Aspergillus fumigates-speciﬁc IgE Negative Positive Negative C3 (g/l) 1,557 1.303 0.75–1.65 C4 (g/l) 0.510 0.118 0.20–0.65 ANA (U/ml) 1 :160 1 :160 1 :160 ∗∗ ASO (U/ml) 1066; 522 U/ml 12 <200 PCP IgG (mg/L) 85.6 15.4 >30 PCP IgG2 (mg/L) 32.0 2.88 >11 PCP IgA (mg/L) 1.03 74.6 NA PCP IgM (mg/L) 3.53 209.4 NA Hib IgG (mg/L) 16.5 6.43 >0.15 ∗ ∗ DT IgG (mg/L) 0.04 0.025 >0.1 TT IgG (mg/L) 0.11 0.35 >0.1 ∗ ∗∗ ∗∗∗ Low values; high values; measurement of IgE is in ﬂux with approximately one-year follow-up intervals. WBC: white blood cell count; ANC: absolute neutrophil count; ALC: absolute lymphocyte count; Eos: eosinophils; PCP: pneumococcal capsular polysaccharide; Hib: Haemophilus inﬂuenzae type B; DT: diphtheria toxoid; Td: tetanus toxoid; NA: not applicable. +e estimation of PCP IgA and IgM values was based on the comparison with the titer of the same antibodies in children tested in our laboratory (data not published). 3.4. Pulmonary Manifestations and Severe Infections. publications reported lower frequency −27% (11). We ob- Pneumonia and pneumatocele are established in 90–100% and served dental problems in both children, but there were in 45–74.5% of patients, respectively (11, 12, 14, 15). Our subjects neither abnormalities in bone density nor pathological were suﬀering from frequent pneumonia and pneumatoceles fractures, scoliosis, or hyperextensible joints. formation. A more severe course related to pulmonary com- plications was observed in the case of the common AD-HIES 3.6. Facial Dysmorphism. Facial anomalies were visible mutation. Life-threatening infections have been observed in only in Patient 1. +e symptom is important for the 43–89% of patients (12, 14, 15). Patient 1 had empyema and diagnosis of the disease and occurs in over 90% of pa- pulmonary abscess. However, Patient 2 presented with more tients (11, 12, 14, 15). Usually, at an earlier age, the frequent and severe infections and complications. dysmorphic manifestations could be quite discrete and become more obvious until puberty. +erefore, in Patient 3.5. Pathologic Dentition and Bone Anomalies. +ey were 2, the presence of facial dysmorphism will be evaluated found in 65–80% of patients (12, 14, 15), but some over time. 6 Case Reports in Immunology the majority of AD-HIES patients did not show signiﬁcant 3.7. STAT3 Mutations. Prior to the detection of STAT3 mutations, the diagnosis of HIES was made based on the changes in these cell populations [15, 34]. Patients with AD- HIES were reported to have a decrease of CD4+ T-eﬀector scoring system . +e establishment of a STAT3 patho- genic variant conﬁrms the diagnosis. +e STAT3 gene plays memory cells (TEMs) and an increase of CD4+ T-eﬀector an important role in the signal transduction of multiple pro- memory RA cells (TEMRAs) . +e percentage of and anti-inﬂammatory cytokines [30, 31] and in the dif- T-lymphocytes in both of our patients was within reference ferentiation of +17 cells, respectively, in IL-17 secretion values (Table 3). In Patient 1, the percentage of na¨ıve CD4+ . +e variant R382W in Patient 2 (DNA-binding do- T cells (CD45RA+62L+) was signiﬁcantly reduced, and the main) is one of the most common in AD-HIES , whereas eﬀector memory and eﬀector subsets predominated (24.8 and c.1850 G> A (p.Gly617Glu) mutation (BC6 position of SH2 44.0% of CD4+ T cells, respectively). Siegel et al.  showed domain) in Patient 1 has been described only in a 19-year- that STAT3 deﬁciency leads to a reduction of memory CD8+ Tcells, which according to Ives et al. , is due to mutations in old man by Schimke et al.  in 2010 and “classiﬁed as probably damaging.” According to the authors, the G617E STAT3 and IL-21R genes. Both of our patients had a decreased percentage of CD8+ Tcells with a nearly normal distribution of variant arose de novo, and the patient presented with a high serum IgE level (>5,000 IU/mL), eczema, scoliosis, skin na¨ıve and memory cells (Table 3). In most studies, memory abscesses, and characteristic facies, without any pulmonary B cells in AD-HIES patients are reduced [15, 38, 39], and there infections, pathologic fractures, or retained primary teeth. are no correlations between low memory B cells, the ability for Although there is currently no reliable evidence that dif- production of antibodies, and accompanied infections . In ferent mutations correlate with a speciﬁc clinical manifes- our study, B cells were within the normal range. A slightly tation of the disease , patients with SH2 mutations have reduced percentage of NK cells was observed in Patient 2 (Table 3). +e eﬀects of STAT3 deﬁciency on NK cells need been reported to have a slightly higher arched palate, widened interalar distance, upper respiratory tract infec- furder evaluation. +e main change in T-lymphocytes asso- ciated with dominant negative STAT3 mutations is a low tions, and scoliosis, and those with DNA-binding domain mutations have a higher mortality rate . Both our pa- percentage of +17-cells [14, 15, 30, 40–42]. +is population was extremely reduced in our patients as well (Table 3). Several tients suﬀer from multiple infections, but in Patient 2, they were more severe. Patient 1 had a typical face dysmorphism. authors [31, 41, 42] showed a great impairment in the ability of +17 generation in vivo and in vitro to secrete IL-17 and 22 and generation of antigen-speciﬁc +17 to diﬀerent pathogens. 3.8.FunctionalStudiesonSTAT3Phosphorylation. +e study T-cell function assessed by expression of the CD69 marker of the intracellular STAT3 signaling activation pathway of upon stimulation with phytohaemagglutinin in Patient 1 was T cells was performed with the BD Phosﬂow T-cell activation retained but remarkably decreased via CD3 receptor pathway kit. +e expression of phosphorylated STAT3 proteins was in comparison to age-matched healthy controls (2.1% of determined by ﬂow cytometry. CD4+ and CD8+ cells from nonactivated PBMC expressed CD69+ and only 23.6% after both patients were stimulated with IL-6 (100 ng/ml) and la- T-cell receptor stimulation). At the time of the investigation, beled with appropriate monoclonal antibodies for surface Patient 1 was not under corticosteroid or other immuno- markers and intracellular phosphorylated proteins. Initially, suppressive therapy. labeled and unlabeled control beads were used to adjust the ﬂuorescent compensations. Lyophilized control cells were tested as negative and positive controls. Subsequently, pa- 3.10. Humoral Immunity and Vaccination-Induced Response. tient’s samples and samples from corresponding age-matched ANA, IgG, IgA, IgM, and IgG subclasses were normal in healthy controls were tested simultaneously. +e analysis was both cases. IgE was very high, especially in Patient 2 (Ta- performed on FACS Canto II, FACS Diva software. +e ble 3), and a decrease in C4 was also observed. +e ASO titer expression of intracellular phosphorylated proteins resulting was high in Patient 1 but displayed optimal therapeutic from signaling pathway activation was determined by his- response (results are not shown). Chandesriset et al.  togram based on the signal from Alexa Fluor 647 anti- described the following changes in serum immunoglobulin phosphoprotein antibody. We have determined the geometric levels in AD-HIES patients: high serum IgG in 27%, high mean ﬂuorescence intensity (Geo MFI) value of each signal serum IgA–in 18%, high serum IgM–in 31%, and high serum pathway of unstimulated and stimulated CD4+ and CD8+ IgE–in 96%. Moreover, low serum IgG was detected in 2% of Tcells. +e calculated ratio of Geo MFI stimulated to Geo MFI the AD-HIES patients, low IgG1, IgG2, and IgG3–in overall of unstimulated cells in patient-control pairs was used to 14%, and low serum IgA–in 13%. According to our data, estimate the deviation in the STAT3 signaling ability. +e Patient 1 had a protective level of Pneumococcal Capsular results showed that phosphorylation capacity via STAT3 in Polysaccharide (PCP) IgG and PCP IgG2, but the level of both patents was lower in comparison to healthy individuals PCP IgA was decreased. +e second patient had decreased for both CD4+and CD8+ cells (Table 2). protective levels of PCP IgG and PCP IgG2, but PCP IgA was normal. +e titers of Haemophilus inﬂuenzae type B IgG and Tetanus toxoid IgG in both patients were comparable to 3.9. Immune Cells Subsets. STAT3 plays an important role in the regulation of B cells, CD4+, and CD8+ T cells. +e dif- those of the majority of children at that age, but the pro- ferentiation of CD3+CD4+ cells is determined by the acti- tective titer of antibodies against diphtheria toxoid in both vation of the STAT3 pathway and related cytokines. However, cases was very low (Table 3). According to the literature, 21% Case Reports in Immunology 7 Table 4: Serum levels of cytokines investigated in Patients 1 and 2. Concentration (pg/ml) Cytokine Reference Patient 1 Patient 2 range At the time of At the time of After 2 y of After 4 y of After 5 y of After 6 y of diagnosis, without diagnosis, without prophylactic prophylactic prophylactic prophylactic prophylactic prophylactic treatment treatment treatment treatment treatment treatment IFN- 143.85 14.5 244.37 6.47 17.75 3.92 8.08± 25.32 gamma IL-12p70 54.46 0.0 50.96 2.83 2.63 0.0 0.90± 1.26 IL-13 1.17 0.0 3.81 0.0 0.70 0.56 0.09± 0.26 IL1beta 1.76 0.0 47.04 1.32 1.76 0.0 0.09± 0.23 IL-2 0.0 0.0 404.17 0.87 7.93 0.0 0.57± 1.41 IL-4 8.42 0.0 217.52 0.0 6.59 0.0 0.0 IL-5 1.22 0.0 10.39 0.0 0.61 0.0 0.94± 1.26 IL-6 25.71 0.0 18.46 1.70 1.70 3.12 0.07± 0.24 TNF- 2.09 0.0 9.64 0.0 6.26 4.17 0.08± 0.28 alpha GM-CSF 5.11 0.0 31.46 0.0 23.39 0.0 0.64± 1.34 IL-18 113.32 16.0 43.61 22.4 43.52 4.53 1.67± 1.75 +e values are laboratory speciﬁc based on healthy controls tested. of AD-HIES patients in a French study  have low an- depending on the stimulus. In our study, we tested the serum tibodies against protein antigens (tetanus, diphtheria, or levels of 11 proinﬂammatory and anti-inﬂammatory cyto- polio), 7%-low antibodies against S. pneumoniae, but 100%- kines in both patients (Table 4). +e serum levels of normal antibodies against Haemophilus inﬂuence type B. proinﬂammatory cytokines (IFN-c, IL-12p70, IL-1β, TNF-α, IL-18, and IL-6) and IL-2, IL-4, IL-5, GM-CSF in Patient 2 were increased, resembling a “cytokine storm.” After 4 years of symptomatic treatment, the follow-up values of the same 3.11. Cytokines. STAT3 is the basis of signal transduction of cytokines were normal except IL-12p70, IL-1β, IL-6, and IL- multiple cytokines and growth factors. . On the other 18. However, the values were reduced several-fold compared hand, STAT3 is involved in the diﬀerentiation of +17 and to the previous testing. In the ﬁfth year after the treatment the production of IL-17. A number of authors reported that initiation, the levels of IL-2, IL-4, TNF-α, GM-CSF, and IL- in HIES patients, +17 cells are signiﬁcantly reduced and IL- 18 were elevated again, reﬂecting some subclinical mani- 17 production is severely impaired [40–42]. IL-17 is known festations and exacerbation of persistent dermatitis. +e to stimulate neutrophil proliferation and the production of elevated proinﬂammatory cytokines TNF-α and IL-6 after 6 colony-stimulating factor (G-CSF) and epithelial cell IL-8 years of treatment probably preceded the reported episode of [31, 44]. An impaired neutrophilic function is one of the pulmonary complication several months later. In Patient 1, main causes of poor response to pathogens, such as strep- the +1 proﬁle and a relatively elevated level of IL-4 and tococci and Candida in patients with HIES. In AD-HIES, an GM-CSF predominated at the time of diagnosis. After the imbalance between +1 and +2 responses, decreased initiation of anti-infectious prophylaxis (no severe infections production/expression of IFN-c and relatively increased so far), the values of the cytokines became normal except IL- level/expression of IL-4, defects in IFN-c and IL-12 signaling 18, which had a sevenfold decrease. In our opinion, the pathways, insuﬃcient expression of some chemokines and observed changes in cytokines in both patients were mostly adhesion molecules have been described and decreased associated with concomitant infections. In a patient with the expression of TGF-β and IFN-c mRNA in circulating ac- common STAT3 variant who presented with a more severe tivated T-cells [45, 46]. +e cytokine production capacity of course, the cytokine disturbance was most signiﬁcant and HIES patients was tested in whole-blood cultures stimulated persistent over time. +e changes in cytokine levels could with heat-killed Staphylococcus aureus, Candida albicans, or serve as an important laboratory indicator of therapeutic a combination of IL-12/IL-18 . +e results revealed that response to infections and an early marker of recurrence of IFN-c production, in addition to IFN-c/IL-10 ratio, was 10- complications. More studies with a larger number of patients 30-fold lower in the HIES patients compared to the healthy are needed to conﬁrm or reject these considerations. subjects. In contrast, TNF, IL-1β, and IL-8 secretions were normal. +e authors concluded that there was an imbalance towards a +2 phenotype in HIES patients, which possibly 4. Concluding Remarks contributes to the speciﬁc pattern of infections related to this particular PID. Holland et al.  demonstrated that the Several hundred cases of AD-HIES have been described in levels of TNF-α, IL-12p70, and IFN-c produced by PBMC of the medical literature so far, and few studies have focused on patients with HIES were elevated in comparison to controls, the genotype-phenotype correlations and the changes in 8 Case Reports in Immunology staphylococcal abscesses,” Ee Lancet, vol. 304, no. 7881, humoral and cellular immune response and cytokine pro- pp. 617–619, 1974. ﬁles. +e study participants fulﬁll the criteria for AD-HIES  E. D. Renner, J. M. Puck, S. M. Holland et al., “Autosomal with an approximately equal score index. 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Case Reports in Immunology – Hindawi Publishing Corporation
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