Systemic autoinflammatory diseases in pediatric population.

Background: Systemic autoinflammatory diseases (SAID) are monogenic and polygenic inherited conditions characterized by dysregulation of the innate immune system. Objective: We aimed to characterize the clinical features of patients with SAID. Methods: This study was a retrospective chart review on the clinical and genetic features of the pediatric population with SAID observed from 1998 to 2020 in our center. Results: A total of 54 patients were evaluated: 18 with periodic fever, aphthous stomatitis, pharyngitis and adenitis syndrome; 16 with Behçet disease; 13 with systemic juvenile idiopathic arthritis; 4 with syndrome of undifferentiated recurrent fever; 1 with cryopyrin associated periodic syndrome; 1 with chronic nonbacterial osteomyelitis; and 1 with Muckle-Wells syndrome. Conclusion: The analysis of clinical features of our patients are similar to other studies. Our goal was to aware the medical community to early recognize and treat SAID to improve quality of life of pediatric patients.

Spotlight on latent tuberculosis infection screening for juvenile idiopathic arthritis in two countries, comparing high and low risk patients.

BACKGROUND: Rheumatic diseases are associated with an increase in overall risks of tuberculosis (TB). The aim of this study was to evaluate the frequency of TB and the frequency of latent TB infection (LTBI), in clinical practice, for juvenile idiopathic arthritis (JIA) patients from high and low risk of TB incidence endemic countries. METHODS: This is an international, multicenter, cross-sectional, observational study of data collection from Brazil and Registry of Portugal at REUMA.PT. The inclusion criteria were patients with Juvenile Idiopathic Arthritis (JIA) with age ≤ 18 years who underwent screening for Mycobacterium tuberculosis infection [tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)]. Chest X-rays and history of exposure to TB were also assessed. RESULTS: 292 JIA patients were included; mean age 14.3 years, mean disease duration 7.5 years, 194 patients (66.4%) performed only TST, 14 (4.8%) only IGRA and 84 (28.8%) both. The frequency of LTBI (10.6%) and TB was similar between the two countries. The reasons for TB screening were different; in Brazil it was performed more often at JIA onset while in Portugal it was performed when starting Disease Modified Anti-Rheumatic Drugs (DMARD) treatment (p < 0.001). Isoniazid therapy was prescribed in 40 (13.7%) patients (31 with LTBI and 9 with epidemiologic risks and/or due to contact with sick people). Only three patients (1%) developed active TB. CONCLUSION: We found nearly 10% of patients with LTBI, a small percentage of patients with treatment due to epidemiologic risks and only 1% with active TB. Distinct reasons and screening methods for LTBI were observed between the two countries.

Spotlight on latent tuberculosis infection screening for juvenile idiopathic arthritis in two countries, comparing high and low risk patients

Abstract Background: Rheumatic diseases are associated with an increase in overall risks of tuberculosis (TB). The aim of this study was to evaluate the frequency of TB and the frequency of latent TB infection (LTBI), in clinical practice, for juvenile idiopathic arthritis (JIA) patients from high and low risk of TB incidence endemic countries. Methods: This is an international, multicenter, cross-sectional, observational study of data collection from Brazil and Registry of Portugal at REUMA.PT. The inclusion criteria were patients with Juvenile Idiopathic Arthritis (JIA) with age ≤ 18 years who underwent screening for Mycobacterium tuberculosis infection [tuberculin skin test (TST) and/or interferon gamma release assay (IGRA)]. Chest X-rays and history of exposure to TB were also assessed. Results: 292 JIA patients were included; mean age 14.3 years, mean disease duration 7.5 years, 194 patients (66.4%) performed only TST, 14 (4.8%) only IGRA and 84 (28.8%) both. The frequency of LTBI (10.6%) and TB was similar between the two countries. The reasons for TB screening were different; in Brazil it was performed more often at JIA onset while in Portugal it was performed when starting Disease Modified Anti-Rheumatic Drugs (DMARD) treatment (p < 0.001). Isoniazid therapy was prescribed in 40 (13.7%) patients (31 with LTBI and 9 with epidemiologic risks and/or due to contact with sick people). Only three patients (1%) developed active TB. Conclusion: We found nearly 10% of patients with LTBI, a small percentage of patients with treatment due to epide-miologic risks and only 1% with active TB. Distinct reasons and screening methods for LTBI were observed between the two countries.

The expansion of human T-bethighCD21low B cells is T cell dependent.

Accumulation of human CD21low B cells in peripheral blood is a hallmark of chronic activation of the adaptive immune system in certain infections and autoimmune disorders. The molecular pathways underpinning the development, function, and fate of these CD21low B cells remain incompletely characterized. Here, combined transcriptomic and chromatin accessibility analyses supported a prominent role for the transcription factor T-bet in the transcriptional regulation of these T-bethighCD21low B cells. Investigating essential signals for generating these cells in vitro established that B cell receptor (BCR)/interferon-γ receptor (IFNγR) costimulation induced the highest levels of T-bet expression and enabled their differentiation during cell cultures with Toll-like receptor (TLR) ligand or CD40L/interleukin-21 (IL-21) stimulation. Low proportions of CD21low B cells in peripheral blood from patients with defined inborn errors of immunity (IEI), because of mutations affecting canonical NF-κB, CD40, and IL-21 receptor or IL-12/IFNγ/IFNγ receptor/signal transducer and activator of transcription 1 (STAT1) signaling, substantiated the essential roles of BCR- and certain T cell­derived signals in the in vivo expansion of T-bethighCD21low B cells. Disturbed TLR signaling due to MyD88 or IRAK4 deficiency was not associated with reduced CD21low B cell proportions. The expansion of human T-bethighCD21low B cells correlated with an expansion of circulating T follicular helper 1 (cTfh1) and T peripheral helper (Tph) cells, identifying potential sources of CD40L, IL-21, and IFNγ signals. Thus, we identified important pathways to target autoreactive T-bethighCD21low B cells in human autoimmune conditions, where these cells are linked to pathogenesis and disease progression.

Granulomatosis with Polyangiitis in Adolescence: Two Distinct Presentations.

Introduction. Granulomatosis with polyangiitis (GPA) is a rare disease in pediatric age. We report two cases with distinct presentations. Case Reports. A seventeen-year-old male with prolonged febrile syndrome, cough, and constitutional symptoms. CT-scan showed cavitated lesions of the lung and bronchial biopsy a necrotizing inflammatory process. The remaining investigation revealed hematoproteinuria and positive C-ANCA and anti-PR3. Complications: Bilateral acute pulmonary thromboembolism, splenic infarction, and extensive popliteal and superficial femoral deep vein thrombosis. He was treated with corticosteroids, immunoglobulin, rituximab, and anticoagulation. Rituximab was maintained every six months during the first two years. Control angio-CT was performed with almost complete resolution of previous findings. In a twelve-year-old female with inflammatory signs of the limbs, investigation showed myositis of the thigh and tenosynovitis of the wrist, normocytic normochromic anemia (Hg 9.4 g/dL), mild elevation of inflammatory markers, and high creatine kinase. During hospitalization, she presented an extensive alveolar hemorrhage associated with severe anemia and positive C-ANCA and anti-PR3. Clinical deterioration prompted intravenous methylprednisolone pulses and plasmapheresis. Induction therapy with rituximab and prednisolone showed good results. Rituximab was maintained every six months, for 18 months, with gradual tapering of corticoids. Discussion. GPA is a systemic disease with variable clinical presentation and severity. Pediatric patients have similar clinical manifestations to adults but different frequencies of organ involvement; constitutional symptoms are also more common. We highlight the different presentation of these two cases, as well as the need for an individualized approach. Rituximab has been used for both induction-remission and maintenance therapy, with good results, particularly in young patients.

Association of body mass index with Juvenile Idiopathic Arthritis disease activity: a Portuguese and Brazilian collaborative analysis.

OBJECTIVE: To investigate the relationship between body mass index (BMI) and disease activity in patients with Juvenile Idiopathic Arthritis (JIA). METHODS: Patients with JIA, aged ≤18 years, registered at the Rheumatic Diseases Portuguese Register (Reuma.pt) in Portugal and Brazil were included. Age- and sex-specific BMI percentiles were calculated based on WHO growth standard charts and categorized into underweight (P <3), normal weight (3≤P≤85), overweight (85

97). Disease activity was assessed by Juvenile Arthritis Disease Activity Score (JADAS-27). Uni- and multivariate analyses were performed. RESULTS: A total of 275 patients were included. The prevalence of underweight, normal weight, overweight and obesity was 6.9%, 67.3%, 15.3% and 10.5%, respectively. Underweight patients had significantly higher number of active joints (p <0.001), patient's/parent's global assessment of disease activity (PGA) (p=0.020), physician's global assessment of disease activity (PhGA) (p <0.001), erythrocyte sedimentation rate (ESR) (p=0.032) and overall higher JADAS-27 (p <0.001), compared to patients with normal weight, overweight and obesity. In the multivariate regression, underweight persisted significantly associated with higher disease activity, compared to normal weight (B=-9.430, p <0.001), overweight (B=-9.295, p=0.001) and obesity (B=-9.120, p=0.001), when adjusted for age, gender, country, ethnicity, JIA category and therapies used. The diagnosis of RF- (B=3.653, p=0.006) or RF+ polyarticular JIA (B=5.287, p=0.024), the absence of DMARD therapy (B=5.542, p <0.001) and the use of oral GC (B=4.984, p=0.002) were also associated with higher JADAS-27. CONCLUSION: We found an independent association between underweight and higher disease activity in patients with JIA. Further studies are needed to understand the underlying mechanisms of this association.

Effect of Zinc Source and Exogenous Enzymes Supplementation on Zinc Status in Dogs Fed High Phytate Diets.

Zinc is an essential element, a cofactor of many enzymes, and performs catalytic, structural and regulatory functions. Once in the gastrointestinal tract, zinc can interact with food constituents. Phytic acid, the major phosphorus storage in plants, limits zinc availability from animal feeds due to the formation of insoluble complexes with phytates. This study tested the effect of supplemental zinc source (zinc sulfate and a chelate zinc proteinate) and the addition of exogenous enzymes from a solid-state fermentation product of Aspergillus niger to a high phytate diet. The study was designed according to three Latin Squares 4 × 4 with a 2 × 2 factorial arrangement of treatments, with four periods, four diets, and 12 young adult Beagles. Periods lasted 5 weeks each. Diets were supplemented with 75 mg/kg of zinc sulfate (IZ) or zinc proteinate (OZ), and without or with 200 mg/kg of exogenous enzymes (IZ+, OZ+). Results showed that zinc proteinate increased the bioavailability of phosphorus, yet the zinc biomarkers remained unaffected by the zinc source, with the exception of lymphocyte subsets that benefit from zinc proteinate. The use of exogenous enzymes did not affect zinc availability nor nutrient and energy digestibility.

Correction to: Proposal for a definition for response to treatment, inactive disease and damage for JIA associated uveitis based on the validation of a uveitis related JIA outcome measures from the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC).

Following publication of the original article [1], we have been notified that the author Joan Calzada should not have been included to the team of authors. The authors' team, thus, should be as follows.

Proposal for a definition for response to treatment, inactive disease and damage for JIA associated uveitis based on the validation of a uveitis related JIA outcome measures from the Multinational Interdisciplinary Working Group for Uveitis in Childhood (MIWGUC).

BACKGROUND: JIA-associated uveitis (JIAU) is a serious, sight-threatening disease with significant long-term complications and risk of blindness, even with improved contemporary treatments. The MIWGUC was set up in order to propose specific JIAU activity and response items and to validate their applicability for clinical outcome studies. METHODS: The group consists of 8 paediatric rheumatologists and 7 ophthalmologists. A consensus meeting took place on November 2015 in Barcelona (Spain) with the objective of validating the previously proposed measures. The validation process was based on the results of a prospective open, international, multi-centre, cohort study designed to validate the outcome measures proposed by the initial MIWGUC group meeting in 2012. The meeting used the same Delphi and nominal group technique as previously described in the first paper from the MIWGUC group (Arthritis Care Res 64:1365-72, 2012). Patients were included with a diagnosis of JIA, aged less than 18 years, and with active uveitis or an uveitis flare which required treatment with a disease-modifying anti-rheumatic drug. The proposed outcome measures for uveitis were collected by an ophthalmologist and for arthritis by a paediatric rheumatologist. Patient reported outcome measures were also measured. RESULTS: A total of 82 patients were enrolled into the validation cohort. Fifty four percent (n = 44) had persistent oligoarthritis followed by rheumatoid factor negative polyarthritis (n = 15, 18%). The mean uveitis disease duration was 3.3 years (SD 3.0). Bilateral eye involvement was reported in 65 (79.3%) patients. The main findings are that the most significant changes, from baseline to 6 months, are found in the AC activity measures of cells and flare. These measures correlate with the presence of pre-existing structural complications and this has implications for the reporting of trials using a single measure as a primary outcome. We also found that visual analogue scales of disease activity showed significant change when reported by the ophthalmologist, rheumatologist and families. The measures formed three relatively distinct groups. The first group of measures comprised uveitis activity, ocular damage and the ophthalmologists' VAS. The second comprised patient reported outcomes including disruption to school attendance. The third group consisted of the rheumatologists' VAS and the joint score. CONCLUSIONS: We propose distinctive and clinically significant measures of disease activity, severity and damage for JIAU. This effort is the initial step for developing a comprehensive outcome measures for JIAU, which incorporates the perspectives of rheumatologists, ophthalmologists, patients and families.

Inherited p40phox deficiency differs from classic chronic granulomatous disease.

Biallelic loss-of-function (LOF) mutations of the NCF4 gene, encoding the p40phox subunit of the phagocyte NADPH oxidase, have been described in only 1 patient. We report on 24 p40phox-deficient patients from 12 additional families in 8 countries. These patients display 8 different in-frame or out-of-frame mutations of NCF4 that are homozygous in 11 of the families and compound heterozygous in another. When overexpressed in NB4 neutrophil-like cells and EBV-transformed B cells in vitro, the mutant alleles were found to be LOF, with the exception of the p.R58C and c.120_134del alleles, which were hypomorphic. Particle-induced NADPH oxidase activity was severely impaired in the patients' neutrophils, whereas PMA-induced dihydrorhodamine-1,2,3 (DHR) oxidation, which is widely used as a diagnostic test for chronic granulomatous disease (CGD), was normal or mildly impaired in the patients. Moreover, the NADPH oxidase activity of EBV-transformed B cells was also severely impaired, whereas that of mononuclear phagocytes was normal. Finally, the killing of Candida albicans and Aspergillus fumigatus hyphae by neutrophils was conserved in these patients, unlike in patients with CGD. The patients suffer from hyperinflammation and peripheral infections, but they do not have any of the invasive bacterial or fungal infections seen in CGD. Inherited p40phox deficiency underlies a distinctive condition, resembling a mild, atypical form of CGD.

Chronic granulomatous disease as a risk factor for cutaneous lupus in childhood.

Chronic granulomatous disease (CGD) is a primaryimmunodeficiency disorder that affects the phagocyticcells of the innate immune system. It is characterizedby recurrent or persistent infections with granulomaformation. Lupus-like lesions have been reported incarriers of CGD and less frequently, in patients withCGD. Immunological study in these patients areusually negative. We describe the case of an 8-yearoldboy with CGD who developed chronic and acutecutaneous lupus erythematous with angular cheilitis,oral ulcers, Raynaud phenomenon, and positiveserologies for antinuclear, anticentromere, and anti-Saccharomyces cerevisiae antibodies.

The Diagnosing Challenge of a Positive ANCA Vasculitis in the Paediatric Age.

ANCA-positive systemic vasculitides, rare in paediatric age, present multiorganic involvement. A female teenager presented with a history of subglottic stenosis diagnosed at the age of 12. From the investigation carried out, we highlight hematoproteinuria and negative ANCAs. At 15 years old, she was admitted for gastrointestinal symptoms and respiratory distress. She presented poor peripheral perfusion, pulmonary haemorrhage, respiratory failure, and severe renal insufficiency. She was started mechanical ventilation and emergency haemodialysis. The immunological study revealed ANCA MPO positive. A presumptive diagnosis of ANCA-positive vasculitis was made, and she was started corticotherapy, cyclophosphamide, and plasmapheresis. A renal biopsy, performed later, showed crescentic glomerulonephritis with chronicity signs. Positive ANCA vasculitis may progress slowly or suddenly. The diagnosis was confirmed by a biopsy; however, we can make a presumptive diagnosis based on clinical findings and in a positive ANCA test in order to start an early treatment and decrease the associated morbimortality.

Effectiveness and long-term retention of anti-tumour necrosis factor treatment in juvenile and adult patients with juvenile idiopathic arthritis: data from Reuma.pt.

OBJECTIVES: Assess the effectiveness and safety of biologic therapy as well as predictors of response at 1 year of therapy, retention rate in biologic treatment and predictors of drug discontinuation in JIA patients in the Portuguese register of rheumatic diseases. METHODS: We prospectively collected patient and disease characteristics from patients with JIA who started biological therapy. Adverse events were collected during the follow-up period. Predictors of response at 1 year and drug retention rates were assessed at 4 years of treatment for the first biologic agent. RESULTS: A total of 812 JIA patients [65% females, mean age at JIA onset 6.9 years (s.d. 4.7)], 227 received biologic therapy; 205 patients (90.3%) were treated with an anti-TNF as the first biologic. All the parameters used to evaluate disease activity, namely number of active joints, ESR and Childhood HAQ/HAQ, decreased significantly at 6 months and 1 year of treatment. The mean reduction in Juvenile Disease Activity Score 10 (JADAS10) after 1 year of treatment was 10.4 (s.d. 7.4). According to the definition of improvement using the JADAS10 score, 83.3% respond to biologic therapy after 1 year. Fourteen patients discontinued biologic therapies due to adverse events. Retention rates were 92.9% at 1 year, 85.5% at 2 years, 78.4% at 3 years and 68.1% at 4 years of treatment. Among all JIA subtypes, only concomitant therapy with corticosteroids was found to be univariately associated with withdrawal of biologic treatment (P = 0.016). CONCLUSION: Biologic therapies seem effective and safe in patients with JIA. In addition, the retention rates for the first biologic agent are high throughout 4 years.

Chronic alveolar haemorrhage in a paediatric patient: a diagnostic and treatment challenge.

Pulmonary haemosiderosis is characterised by chronic alveolar haemorrhage, which can lead to serious cardiorespiratory complications. Although considered idiopathic in most patients, there are many possible aetiologies. We present a case of an 18-year-old woman with pulmonary haemosiderosis since 4 years of age, with an inconclusive initial study, who was treated with systemic corticosteroids and hydroxychloroquine until the age of 12 years, and azathioprine since then. Multiple exacerbations led to interstitial lung disease with restrictive functional pattern. Unilateral cochlear deafness was diagnosed at the age of 12 years and occasional polyarthralgias were recorded. When she was 16 years of age the study revealed an atypical myeloperoxidase-antineutrophil cytoplasmic antibody (MPO-ANCA) pattern. Cyclophosphamide and rituximab were administered with resolution of respiratory insufficiency and functional disability, without new episodes of alveolar haemorrhage. This case of chronic pulmonary haemorrhage was revealed to be an ANCA vasculitis, the diagnosis of which was possible only after 12 years of symptoms, with clinical and functional improvement with the association of cyclophosphamide and rituximab.

Reactive oxygen species deficiency induces autoimmunity with type 1 interferon signature.

AIMS: Chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the phagocyte reactive oxygen species (ROS)-producing NOX2 enzyme complex and characterized by recurrent infections associated with hyperinflammatory and autoimmune manifestations. A translational, comparative analysis of CGD patients and the corresponding ROS-deficient Ncf1(m1J) mutated mouse model was performed to reveal the molecular pathways operating in NOX2 complex deficient inflammation. RESULTS: A prominent type I interferon (IFN) response signature that was accompanied by elevated autoantibody levels was identified in both mice and humans lacking functional NOX2 complex. To further underline the systemic lupus erythematosus (SLE)-related autoimmune process, we show that naïve Ncf1(m1J) mutated mice, similar to SLE patients, suffer from inflammatory kidney disease with IgG and C3 deposits in the glomeruli. Expression analysis of germ-free Ncf1(m1J) mutated mice reproduced the type I IFN signature, enabling us to conclude that the upregulated signaling pathway is of endogenous origin. INNOVATION: Our findings link the previously unexplained connection between ROS deficiency and increased susceptibility to autoimmunity by the discovery that activation of IFN signaling is a major pathway downstream of a deficient NOX2 complex in both mice and humans. CONCLUSION: We conclude that the lack of phagocyte-derived oxidative burst is associated with spontaneous autoimmunity and linked with type I IFN signature in both mice and humans.

Kawasaki disease and sensorineural hearing loss: an (un)expected complication.

UNLABELLED: Kawasaki disease (KD) is an acute, self-limiting, idiopathic form of vasculitis. The preventive effect of early therapy on coronary artery aneurysms, the hallmark of the disease, is well established. The spectrum of complication includes not only cardiac involvement but also central nervous system lesions. We report a 4-year-old boy with a clinical presentation suggestive of KD treated with intravenous immunoglobulin and acetylsalicylic acid. Clinical manifestations regressed within 24 hours and cardiac anomalies were not seen. Two weeks later, the parents noticed a sudden absence of response to sound stimuli. Investigations confirmed bilateral severe sensorineural hearing loss for which oral steroid therapy was given. This resulted in an improvement only on the right side, with severe hearing loss persisting on the left. CONCLUSION: Sensorineural hearing loss is an uncommonly reported complication of KD. Pediatricians should be aware of this potential complication to allow for early intervention.

Clinical features and outcome of patients with IRAK-4 and MyD88 deficiency.

Autosomal recessive interleukin-1 receptor-associated kinase (IRAK)-4 and myeloid differentiation factor (MyD)88 deficiencies impair Toll-like receptor (TLR)- and interleukin-1 receptor-mediated immunity. We documented the clinical features and outcome of 48 patients with IRAK-4 deficiency and 12 patients with MyD88 deficiency, from 37 kindreds in 15 countries.The clinical features of IRAK-4 and MyD88 deficiency were indistinguishable. There were no severe viral, parasitic, and fungal diseases, and the range of bacterial infections was narrow. Noninvasive bacterial infections occurred in 52 patients, with a high incidence of infections of the upper respiratory tract and the skin, mostly caused by Pseudomonas aeruginosa and Staphylococcus aureus, respectively. The leading threat was invasive pneumococcal disease, documented in 41 patients (68%) and causing 72 documented invasive infections (52.2%). P. aeruginosa and Staph. aureus documented invasive infections also occurred (16.7% and 16%, respectively, in 13 and 13 patients, respectively). Systemic signs of inflammation were usually weak or delayed. The first invasive infection occurred before the age of 2 years in 53 (88.3%) and in the neonatal period in 19 (32.7%) patients. Multiple or recurrent invasive infections were observed in most survivors (n = 36/50, 72%).Clinical outcome was poor, with 24 deaths, in 10 cases during the first invasive episode and in 16 cases of invasive pneumococcal disease. However, no death and invasive infectious disease were reported in patients after the age of 8 years and 14 years, respectively. Antibiotic prophylaxis (n = 34), antipneumococcal vaccination (n = 31), and/or IgG infusion (n = 19), when instituted, had a beneficial impact on patients until the teenage years, with no seemingly detectable impact thereafter.IRAK-4 and MyD88 deficiencies predispose patients to recurrent life-threatening bacterial diseases, such as invasive pneumococcal disease in particular, in infancy and early childhood, with weak signs of inflammation. Patients and families should be informed of the risk of developing life-threatening infections; empiric antibacterial treatment and immediate medical consultation are strongly recommended in cases of suspected infection or moderate fever. Prophylactic measures in childhood are beneficial, until spontaneous improvement occurs in adolescence.

Pyogenic bacterial infections in humans with MyD88 deficiency.

MyD88 is a key downstream adapter for most Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs). MyD88 deficiency in mice leads to susceptibility to a broad range of pathogens in experimental settings of infection. We describe a distinct situation in a natural setting of human infection. Nine children with autosomal recessive MyD88 deficiency suffered from life-threatening, often recurrent pyogenic bacterial infections, including invasive pneumococcal disease. However, these patients were otherwise healthy, with normal resistance to other microbes. Their clinical status improved with age, but not due to any cellular leakiness in MyD88 deficiency. The MyD88-dependent TLRs and IL-1Rs are therefore essential for protective immunity to a small number of pyogenic bacteria, but redundant for host defense to most natural infections.

Mutations in STAT3 and IL12RB1 impair the development of human IL-17-producing T cells.

The cytokines controlling the development of human interleukin (IL) 17--producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17--producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) beta, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17--producing T cells. These data suggest that IL-12Rbeta1- and STAT-3--dependent signals play a key role in the differentiation and/or expansion of human IL-17-producing T cell populations in vivo.