Th17/1 and ex-Th17 cells are detected in patients with polyarticular juvenile arthritis and increase following treatment.

BACKGROUND: A better understanding of the pathogenesis of polyarticular juvenile idiopathic arthritis (polyJIA) is needed to aide in the development of data-driven approaches to guide selection between therapeutic options. One inflammatory pathway of interest is JAK-STAT signaling. STAT3 is a transcription factor critical to the differentiation of inflammatory T helper 17 cells (Th17s). Previous studies have demonstrated increased STAT3 activation in adult patients with rheumatoid arthritis, but less is known about STAT3 activation in polyJIA. We hypothesized that Th17 cells and STAT3 activation would be increased in treatment-naïve polyJIA patients compared to pediatric controls. METHODS: Blood from 17 patients with polyJIA was collected at initial diagnosis and again if remission was achieved (post-treatment). Pediatric healthy controls were also collected. Peripheral blood mononuclear cells were isolated and CD4 + T cell subsets and STAT activation (phosphorylation) were evaluated using flow cytometry. Data were analyzed using Mann-Whitney U and Wilcoxon matched-pairs signed rank tests. RESULTS: Treatment-naïve polyJIA patients had increased Th17 cells (CD3 + CD4 + interleukin(IL)-17 +) compared to controls (0.15% v 0.44%, p < 0.05), but Tregs (CD3 + CD4 + CD25 + FOXP3 +) from patients did not differ from controls. Changes in STAT3 phosphorylation in CD4 + T cells following ex vivo stimulation were not significantly different in patients compared to controls. We identified dual IL-17 + and interferon (IFN)γ + expressing CD4 + T cells in patients, but not controls. Further, both Th17/1 s (CCR6 + CD161 + IFNγ + IL-17 +) and ex-Th17s (CCR6 + CD161 + IFNγ + IL-17neg) were increased in patients' post-treatment (Th17/1: 0.3% v 0.07%, p < 0.05 and ex-Th17s: 2.3% v 1.4%, p < 0.05). The patients with the highest IL-17 expressing cells post-treatment remained therapy-bound. CONCLUSIONS: Patients with polyJIA have increased baseline Th17 cells, potentially reflecting higher tonic STAT3 activation in vivo. These quantifiable immune markers may identify patients that would benefit upfront from pathway-focused biologic therapies. Our data also suggest that inflammatory CD4 + T cell subsets not detected in controls but increased in post-treatment samples should be further evaluated as a tool to stratify patients in remission on medication. Future work will explore these proposed diagnostic and prognostic biomarkers.

CADHERIN-11 regulation of myeloid phagocytes and autoimmune inflammation in murine lupus.

BACKGROUND AND OBJECTIVE: Understanding the regulation of efferocytosis by myeloid phagocytes is important in identifying novel targets in systemic lupus erythematosus (SLE). Cadherin-11 (CDH11), a cell adhesion molecule, is implicated in inflammatory arthritis and fibrosis and recently been shown to regulate macrophage phagocytosis. The extent and mechanism of this regulation is unknown. Our objective was to examine the extent to which CDH11 regulates myeloid phagocytes and contributes to autoimmunity and tissue inflammation. METHODS: We analyzed efferocytosis in macrophages and dendritic cells (DCs) from WT and Cdh11-/- mice and investigated the mechanisms in vitro. We investigated the role of CDH11 in disease development in vivo using the pristane induced lupus model. To translate the clinical relevance of CDH11 in human disease, we measured serum CDH11 levels in two independent pediatric SLE (pSLE) cohorts and healthy controls. RESULTS: Using bone marrow derived macrophages (BMDMs) and DCs (BMDCs), we found impaired efferocytosis in phagocytes from Cdh11-/- mice, mediated by downregulated efferocytosis receptor expression and RhoGTPase activation. Specifically, loss of CDH11 downregulated Mertk expression and Rac1 activation in BMDMs, and integrin αVß3 expression and Cdc42 activation in BMDCs, highlighting distinct pathways. In vivo, Cdh11-/- mice displayed defective efferocytosis and increased accumulation of apoptotic debris in pristane-induced lupus. Further, Cdh11-/- mice had enhanced systemic inflammation and autoimmune inflammation with increased anti-dsDNA autoantibodies, splenomegaly, type I interferons, and inflammatory cytokines. Paradoxically, at the tissue level, Cdh11-/- mice were protected against glomerulonephritis, indicating a dual role in murine lupus. Finally, SLE patients had increased serum CDH11 compared to controls. CONCLUSION: This study highlights a novel role of CDH11 in regulating myeloid cells and efferocytosis and its potential as a contributor to development in autoimmunity murine lupus. Despite the increase in autoimmunity, Cdh11-/- mice developed decreased tissue inflammation and damage.

COPA Syndrome from Diagnosis to Treatment: A Clinician's Guide.

COPA syndrome is a recently described autosomal dominant inborn error of immunity characterized by high titer autoantibodies and interstitial lung disease, with many individuals also having arthritis and nephritis. Onset is usually in early childhood, with unique disease features including alveolar hemorrhage, which can be insidious, pulmonary cyst formation, and progressive pulmonary fibrosis in nonspecific interstitial pneumonia or lymphocytic interstitial pneumonia patterns. This review explores the clinical presentation, genetics, molecular mechanisms, organ manifestations, and treatment approaches for COPA syndrome, and presents a diagnostic framework of suggested indications for patient testing.

Imaging findings of COPA Syndrome.

BACKGROUND: Autosomal dominant mutations in the coatomer-associated protein alpha (COPA) gene cause an immune dysregulation disorder associated with pulmonary hemorrhage, lymphoid hyperplasia, arthritis, and glomerulonephritis. OBJECTIVE: To describe the thoracic, musculoskeletal, and renal imaging findings of COPA syndrome with a focus on the evolution of the pulmonary findings. MATERIALS AND METHODS: With approval of the Institutional Review Board, consensus retrospective review of findings on chest radiography and computed tomography (CT), musculoskeletal radiography and magnetic resonance imaging (MRI), and renal ultrasound (US) was performed for pediatric COPA syndrome patients. COPA syndrome patients < 18 years of age presenting between 1992 and 2019 were identified from an institutional rheumatology registry. RESULTS: Twelve pediatric COPA syndrome patients (mean age of 6.5 years at first imaging exam; 6 females) were identified. Imaging exams available for review included 45 chest CT exams on 12 patients, 37 musculoskeletal exams on 4 patients, and 10 renal US exams on 5 patients. All 12 had abnormal chest CT exams, with findings including ground-glass opacities (12/12), cysts (8/12), septal thickening (9/12), nodules (8/12), fibrosis (7/12), crazy-paving (2/12), consolidation (1/12), hilar/mediastinal lymphadenopathy (11/12), and chest wall deformity (5/12). Nine had at least one follow-up chest CT, which showed improvement in nodules (7/9), ground-glass opacities (4/9), and lymphadenopathy (9/9), but worsening of septal thickening (3/9), cyst formation (3/9), and fibrosis (3/9). Four had musculoskeletal imaging revealing synovitis (2/4), bone erosions (1/4), tenosynovitis (1/4), enthesitis (1/4), and subcutaneous nodules (1/4). Five had at least one renal US, revealing renal size abnormalities (4/5) and cortical hyperechogenicity (3/5). CONCLUSION: The most prevalent imaging finding of COPA syndrome is diffuse lung disease related to early childhood-onset recurrent pulmonary hemorrhage and lymphoid hyperplasia that may progress to pulmonary fibrosis. Other imaging findings manifesting later in childhood or adolescence relate to arthritis and glomerulonephritis.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

2022 American College of Rheumatology Guideline for Vaccinations in Patients With Rheumatic and Musculoskeletal Diseases.

OBJECTIVE: To provide evidence-based recommendations on the use of vaccinations in children and adults with rheumatic and musculoskeletal diseases (RMDs). METHODS: This guideline follows American College of Rheumatology (ACR) policy guiding management of conflicts of interest and disclosures and the ACR guideline development process, which includes the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. It also adheres to the Appraisal of Guidelines for Research and Evaluation (AGREE) criteria. A core leadership team consisting of adult and pediatric rheumatologists and a guideline methodologist drafted clinical population, intervention, comparator, outcomes (PICO) questions. A review team performed a systematic literature review for the PICO questions, graded the quality of evidence, and produced an evidence report. An expert Voting Panel reviewed the evidence and formulated recommendations. The panel included adult and pediatric rheumatology providers, infectious diseases specialists, and patient representatives. Consensus required ≥70% agreement on both the direction and strength of each recommendation. RESULTS: This guideline includes expanded indications for some vaccines in patients with RMDs, as well as guidance on whether to hold immunosuppressive medications or delay vaccination to maximize vaccine immunogenicity and efficacy. Safe approaches to the use of live attenuated vaccines in patients taking immunosuppressive medications are also addressed. Most recommendations are conditional and had low quality of supporting evidence. CONCLUSION: Application of these recommendations should consider patients' individual risk for vaccine-preventable illness and for disease flares, particularly if immunosuppressive medications are held for vaccination. Shared decision-making with patients is encouraged in clinical settings.

Monogenic early-onset lymphoproliferation and autoimmunity: Natural history of STAT3 gain-of-function syndrome.

BACKGROUND: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity. OBJECTIVE: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants. METHODS: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3. RESULTS: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate. CONCLUSION: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome.

STAT3 gain-of-function mutations connect leukemia with autoimmune disease by pathological NKG2Dhi CD8+ T cell dysregulation and accumulation.

The association between cancer and autoimmune disease is unexplained, exemplified by T cell large granular lymphocytic leukemia (T-LGL) where gain-of-function (GOF) somatic STAT3 mutations correlate with co-existing autoimmunity. To investigate whether these mutations are the cause or consequence of CD8+ T cell clonal expansions and autoimmunity, we analyzed patients and mice with germline STAT3 GOF mutations. STAT3 GOF mutations drove the accumulation of effector CD8+ T cell clones highly expressing NKG2D, the receptor for stress-induced MHC-class-I-related molecules. This subset also expressed genes for granzymes, perforin, interferon-γ, and Ccl5/Rantes and required NKG2D and the IL-15/IL-2 receptor IL2RB for maximal accumulation. Leukocyte-restricted STAT3 GOF was sufficient and CD8+ T cells were essential for lethal pathology in mice. These results demonstrate that STAT3 GOF mutations cause effector CD8+ T cell oligoclonal accumulation and that these rogue cells contribute to autoimmune pathology, supporting the hypothesis that somatic mutations in leukemia/lymphoma driver genes contribute to autoimmune disease.

A human STAT3 gain-of-function variant confers T cell dysregulation without predominant Treg dysfunction in mice.

Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) and found these mice developed T cell dysregulation, lymphoproliferation, and CD4+ Th1 cell skewing. Surprisingly, Treg numbers, phenotype, and function remained largely intact; however, mice had a selective deficiency in the generation of iTregs. In parallel, we performed single-cell RNA-Seq on T cells from STAT3 GOF patients. We demonstrate only minor changes in the Treg transcriptional signature and an expanded, effector CD8+ T cell population. Together, these findings suggest that Tregs are not the primary driver of disease and highlight the importance of preclinical models in the study of disease mechanisms in rare PIRD.

Comparison of Laboratory and Hemodynamic Time Series Data Across Original, Alpha, and Delta Variants in Patients With Multisystem Inflammatory Syndrome in Children.

OBJECTIVES: To compare the clinical, laboratory, and hemodynamic parameters during hospitalization for patients with multisystem inflammatory syndrome in children (MIS-C), across the Original/Alpha and the Delta variants of severe acute respiratory syndrome coronavirus 2 infection. DESIGN: Retrospective cohort study. SETTING: Single-center quaternary children's hospital. PATIENTS: Children with MIS-C admitted from May 2020 to February 2021(Original and Alpha variant cohort) and August 2021 to November 2021 (Delta variant cohort). MEASUREMENTS AND MAIN RESULTS: Continuous vital sign measurements, laboratory results, medications data, and hospital outcomes from all subjects were evaluated. Of the 134 patients (102 with Original/Alpha and 32 with Delta), median age was 9 years, 75 (56%) were male, and 61 (46%) were Hispanics. The cohort with Original/Alpha variant had more males (61% vs 41%; p = 0.036) and more respiratory/musculoskeletal symptoms on presentation compared with the Delta variant ( p < 0.05). More patients in the Original/Alpha variant cohort received mechanical ventilation (16 vs 0; p = 0.009). Median hospital length of stay (LOS) was 7 days, and ICU LOS was 3 days for the entire cohort. ICU LOS was shorter in cohort with the Delta variant compared with the Original/Alpha variant (4 vs 2 d; p = 0.001). Only one patient had cardiac arrest, two needed extracorporeal membrane oxygenation, and two needed left ventricular assist device (Impella, Danvers, MA), all in the Original/Alpha variant cohort; no mortality occurred in the entire cohort. MIS-C cohort associated with the Delta variant had lower INR, prothrombin time, WBCs, sodium, phosphorus, and potassium median values ( p < 0.05) during hospitalization compared with the Original/Alpha variants. Hemodynamic assessment showed significant tachycardia in the Original/Alpha variants cohort compared with the Delta variant cohort ( p < 0.05). INTERVENTIONS: None. CONCLUSIONS: Patients with MIS-C associated with the Delta variants had lower severity during hospitalization compared with the Original/Alpha variant. Analysis of distinct trends in clinical and laboratory parameters with future variants of concerns will allow for potential modification of treatment protocol.

Vasoplegic Shock Represents a Dominant Hemodynamic Profile of Multisystem Inflammatory Syndrome Following COVID-19 in Children and Adolescents.

OBJECTIVES: The hemodynamic profile of multisystem inflammatory syndrome in children (MIS-C)-related shock remains poorly defined and, therefore, challenging to support with pharmacotherapy in the ICU. We aimed to evaluate the hemodynamic profile and vasoactive medication management used in MIS-C patients presenting to the ICU in shock and provide data from high-fidelity continuous cardiac output monitoring. DESIGN: Single-center retrospective case-cohort study. SETTING: Pediatric and cardiac ICU in a quaternary-care hospital. PATIENTS: All patients who met U.S. Centers for Disease Control and Prevention criteria for MIS-C and who were admitted to the ICU between March 2020 and May 2021 required vasoactive support and were placed on continuous cardiac index (CCI) monitoring. Patients requiring extracorporeal life support were excluded. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among 52 children with MIS-C presenting in shock and requiring vasoactive support, 14 patients (27%) were placed on CCI monitoring. These 14 patients had hyperdynamic cardiac index (CI) and low indexed systemic vascular resistance (SVRi) in the first 24 hours with normalization of CI and improved SVRi within the subsequent 24 hours. CONCLUSIONS: Further studies are needed to evaluate the difference between the use of vasoconstrictor versus vasodilators in pediatric patients with MIS-C because a phenotype with high CI and low SVRi may be important.

Severe Pediatric COVID-19 Pneumonia Treated With Adjuvant Anakinra.

BACKGROUND AND OBJECTIVES: To compare previous hemophagocytic lymphohistiocytosis criteria with adult coronavirus disease 2019 (COVID-19)-associated hyperinflammatory syndrome (cHIS) criteria for the diagnosis of hyperinflammation in pediatric patients with COVID-19. The secondary objective was to assess treatment response to intravenous (IV) anakinra in these patients. METHODS: This case series included children admitted to the PICU for COVID-19 pneumonia with hyperinflammation and treated with IV anakinra between July 2020 to April 2021. Hyperinflammatory criteria were determined for each patient. Clinical course, chest imaging, and inflammatory marker trends were assessed pre- and post-anakinra treatment. RESULTS: All patients had a cHIS criteria score of ≥5. Two patients met 2004-hemophagocytic lymphohistiocytosis criteria. Only the patient that required extracorporeal membrane oxygenation met the H-Score cut-off value. All but one patient had a decrease in their inflammatory markers and improvement in clinical status with early initiation of adjunctive IV anakinra. CONCLUSIONS: In this case series, adult cHIS criteria were successfully used to identify pediatric COVID-19 patients with hyperinflammation. Ferritin levels decreased after the early initiation of IV anakinra.

STAT3 gain-of-function syndrome.

STAT3 gain-of-function (GOF) syndrome is a multi-organ primary immune regulatory disorder characterized by early onset autoimmunity. Patients present early in life, most commonly with lymphoproliferation, autoimmune cytopenias, and growth delay. However, disease is often progressive and can encompass a wide range of clinical manifestations such as: enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, and rarely neurologic disease, vasculopathy, and malignancy. Treatment of the autoimmune and immune dysregulatory features of STAT3-GOF patients relies heavily on immunosuppression and is often challenging and fraught with complications including severe infections. Defects in the T cell compartment leading to effector T cell accumulation and decreased T regulatory cells may contribute to autoimmunity. While T cell exhaustion and apoptosis defects likely contribute to the lymphoproliferative phenotype, no conclusive correlations are yet established. Here we review the known mechanistic and clinical characteristics of this heterogenous PIRD.

Genetic errors of immunity distinguish pediatric nonmalignant lymphoproliferative disorders.

BACKGROUND: Pediatric nonmalignant lymphoproliferative disorders (PLPDs) are clinically and genetically heterogeneous. Long-standing immune dysregulation and lymphoproliferation in children may be life-threatening, and a paucity of data exists to guide evaluation and treatment of children with PLPD. OBJECTIVE: The primary objective of this study was to ascertain the spectrum of genomic immunologic defects in PLPD. Secondary objectives included characterization of clinical outcomes and associations between genetic diagnoses and those outcomes. METHODS: PLPD was defined by persistent lymphadenopathy, lymph organ involvement, or lymphocytic infiltration for more than 3 months, with or without chronic or significant Epstein-Barr virus (EBV) infection. Fifty-one subjects from 47 different families with PLPD were analyzed using whole exome sequencing. RESULTS: Whole exome sequencing identified likely genetic errors of immunity in 51% to 62% of families (53% to 65% of affected children). Presence of a genetic etiology was associated with younger age and hemophagocytic lymphohistiocytosis. Ten-year survival for the cohort was 72.4%, and patients with viable genetic diagnoses had a higher survival rate (82%) compared to children without a genetic explanation (48%, P = .03). Survival outcomes for individuals with EBV-associated disease and no genetic explanation were particularly worse than outcomes for subjects with EBV-associated disease and a genetic explanation (17% vs 90%; P = .002). Ascertainment of a molecular diagnosis provided targetable treatment options for up to 18 individuals and led to active management changes for 12 patients. CONCLUSIONS: PLPD defines children at high risk for mortality, and whole exome sequencing informs clinical risks and therapeutic opportunities for this diagnosis.

Extracorporeal Membrane Oxygenation Support for Antineutrophil Cytoplasmic Antibody-associated Vasculitides: An ELSO Registry Analysis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitides with pulmonary involvement include granulomatosis with polyangiitis, microscopic polyangiitis, and eosinophilic granulomatosis with polyangiitis, and can present with life-threatening pulmonary hemorrhage in up to 40% of patients. Mortality in those patients who require intubation and mechanical ventilation can reach 77%. Extracorporeal membrane oxygenation (ECMO) can be used to support these patients through definitive diagnosis and treatment, although minimizing the risk of ventilator-induced lung injury. We aimed to determine factors associated with favorable outcomes in patients with (ANCA)-associated vasculitides supported on ECMO. We performed a retrospective observational study using the Extracorporeal Life Support Organization registry of pediatric and adult patients with ANCA-associated vasculitis supported on ECMO from 2010 to 2020. One hundred thirty-five patients were included for analysis. Many patients had renal involvement (39%) in addition to pulmonary involvement (93%). Survival was 73% in AAV patients supported on ECMO. The presence of pulmonary hemorrhage was not associated with worse outcomes in our cohort. Older age, the use of venoarterial ECMO, ECMO-cardiopulmonary resuscitation, or sustaining a cardiac arrest before ECMO was associated with decreased survival. In conclusion, venovenous ECMO should be considered as a supportive bridge to definitive diagnosis and treatment in (ANCA)-associated vasculitides, regardless if pulmonary hemorrhage is present.

STAT3 Gain-of-Function Mutations Underlie Deficiency in Human Nonclassical CD16+ Monocytes and CD141+ Dendritic Cells.

Genetic analysis of human inborn errors of immunity has defined the contribution of specific cell populations and molecular pathways in the host defense against infection. The STAT family of transcription factors orchestrate hematopoietic cell differentiation. Patients with de novo activating mutations of STAT3 present with multiorgan autoimmunity, lymphoproliferation, and recurrent infections. We conducted a detailed characterization of the blood monocyte and dendritic cell (DC) subsets in patients with gain-of-function (GOF) mutations across the gene. We found a selective deficiency in circulating nonclassical CD16+ and intermediate CD16+CD14+ monocytes and a significant increase in the percentage of classical CD14+ monocytes. This suggests a role for STAT3 in the transition of classical CD14+ monocytes into the CD16+ nonclassical subset. Developmentally, ex vivo-isolated STAT3GOF CD14+ monocytes fail to differentiate into CD1a+ monocyte-derived DCs. Moreover, patients with STAT3GOF mutations display reduced circulating CD34+ hematopoietic progenitors and frequency of myeloid DCs. Specifically, we observed a reduction in the CD141+ DC population, with no difference in the frequencies of CD1c+ and plasmacytoid DCs. CD34+ hematopoietic progenitor cells from patients were found to differentiate into CD1c+ DCs, but failed to differentiate into CD141+ DCs indicating an intrinsic role for STAT3 in this process. STAT3GOF-differentiated DCs produced lower amounts of CCL22 than healthy DCs, which could further explain some of the patient pathological phenotypes. Thus, our findings provide evidence that, in humans, STAT3 serves to regulate development and differentiation of nonclassical CD16+ monocytes and a subset of myeloid DCs.

Case Report: Hyper IgE, but Not the Usual Suspects-Kimura Disease in an Adolescent Female.

Elevated immunoglobulin E (IgE) levels can be associated with infectious, allergic and inflammatory disorders, and rarely as a manifestation of an inborn error of immunity. Here we report the case of an adolescent female who presented with a gradually enlarging neck mass, lymphadenopathy, eosinophilia and highly elevated IgE levels. Laboratory and histopathologic evaluation revealed an unlikely diagnosis of Kimura Disease. We discuss the differential diagnosis of a neck mass with prominent eosinophils on histology, and review support for T-helper type 2 (Th2) cell activation and hyper-IgE in Kimura Disease.