CTLA4 Message Reflects Pathway Disruption in Monogenic Disorders and Under Therapeutic Blockade

CTLA-4 is essential for immune tolerance. Heterozygous CTLA4 mutations cause immune dysregulation evident in defective regulatory T cells with low levels of CTLA-4 expression. Biallelic mutations in LRBA also result in immune dysregulation with low levels of CTLA-4 and clinical presentation indistinguishable from CTLA-4 haploinsufficiency. CTLA-4 has become an immunotherapy target whereby its blockade with a monoclonal antibody has resulted in improved survival in advanced melanoma patients, amongst other malignancies. However, this therapeutic manipulation can result in autoimmune/inflammatory complications reminiscent of those seen in genetic defects affecting the CTLA-4 pathway. Despite efforts made to understand and establish disease genotype/phenotype correlations in CTLA-4-haploinsufficiency and LRBA-deficiency, such relationships remain elusive. There is currently no specific immunological marker to assess the degree of CTLA-4 pathway disruption or its relationship with clinical manifestations. Here we compare three different patient groups with disturbances in the CTLA-4 pathway—CTLA-4-haploinsufficiency, LRBA-deficiency, and ipilimumab-treated melanoma patients. Assessment of CTLA4 mRNA expression in these patient groups demonstrated an inverse correlation between the CTLA4 message and degree of CTLA-4 pathway disruption. CTLA4 mRNA levels from melanoma patients under therapeutic CTLA-4 blockade (ipilimumab) were increased compared to patients with either CTLA4 or LRBA mutations that were clinically stable with abatacept treatment. In summary, we show that increased CTLA4 mRNA levels correlate with the degree of CTLA-4 pathway disruption, suggesting that CTLA4 mRNA levels may be a quantifiable surrogate for altered CTLA-4 expression

Asthma in inner city children: recent insights: United States

PURPOSE OF REVIEW: Children living in US inner cities experience disparate burdens of asthma, especially in severity, impairment, exacerbations, and morbidity. Investigations seeking to better understand the factors and mechanisms underlying asthma prevalence, severity, and exacerbation in children living in these communities can lead to interventions that can narrow asthma disparities and potentially benefit all children with asthma. This update will focus on recent (i.e. late 2016-2017) advances in the understanding of asthma in US inner city children. RECENT FINDINGS: Studies published in the past year expand understanding of asthma prevalence, severity, exacerbation, and the outcomes of guidelines-based management of these at-risk children, including: asthma phenotypes in US inner city children that are severe and difficult-to-control; key environmental determinants and mechanisms underlying asthma severity and exacerbations (e.g. allergy-mediated exacerbation susceptibility to rhinovirus); the importance of schools as a place for provocative exposures (e.g. mouse allergen, nitrogen dioxide) as well as a place where asthma care and outcomes can be improved; and the development and validation of clinically useful indices for gauging asthma severity and predicting exacerbations. SUMMARY: These recent studies provide a trove of actionable findings that can improve asthma care and outcomes for these at-risk children

Follow-Up for an Abnormal Newborn Screen for Severe Combined Immunodeficiencies (NBS SCID): A Clinical Immunology Society (CIS) Survey of Current Practices

Severe combined immunodeficiency (SCID) includes a group of monogenic disorders presenting with severe T cell lymphopenia (TCL) and high mortality, if untreated. The newborn screen (NBS) for SCID, included in the recommended universal screening panel (RUSP), has been widely adopted across the US and in many other countries. However, there is a lack of consensus regarding follow-up testing to confirm an abnormal result. The Clinical Immunology Society (CIS) membership was surveyed for confirmatory testing practices for an abnormal NBS SCID result, which included consideration of gestational age and birth weight, as well as flow cytometry panels. Considerable variability was observed in follow-up practices for an abnormal NBS SCID with 49% confirming by flow cytometry, 39% repeating TREC analysis, and the remainder either taking prematurity into consideration for subsequent testing or proceeding directly to genetic analysis. More than 50% of respondents did not take prematurity into consideration when determining follow-up. Confirmation of abnormal NBS SCID in premature infants continues to be challenging and is handled variably across centers, with some choosing to repeat NBS SCID testing until normal or until the infant reaches an adjusted gestational age of 37 weeks. A substantial proportion of respondents included naïve and memory T cell analysis with T, B, and NK lymphocyte subset quantitation in the initial confirmatory panel. These results have the potential to influence the diagnosis and management of an infant with TCL as illustrated by the clinical cases presented herein. Our data indicate that there is clearly a strong need for harmonization of follow-up testing for an abnormal NBS SCID result

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

Mepolizumab for urban children with exacerbation-prone eosinophilic asthma in the USA (MUPPITS-2): a randomised, double-blind, placebo-controlled, parallel-group trial

BACKGROUND: Black and Hispanic children living in urban environments in the USA have an excess burden of morbidity and mortality from asthma. Therapies directed at the eosinophilic phenotype reduce asthma exacerbations in adults, but few data are available in children and diverse populations. Furthermore, the molecular mechanisms that underlie exacerbations either being prevented by, or persisting despite, immune-based therapies are not well understood. We aimed to determine whether mepolizumab, added to guidelines-based care, reduced the number of asthma exacerbations during a 52-week period compared with guidelines-based care alone. METHODS: This is a randomised, double-blind, placebo-controlled, parallel-group trial done at nine urban medical centres in the USA. Children and adolescents aged 6-17 years, who lived in socioeconomically disadvantaged neighbourhoods and had exacerbation-prone asthma (defined as ≥two exacerbations in the previous year) and blood eosinophils of at least 150 cells per μL were randomly assigned 1:1 to mepolizumab (6-11 years: 40 mg; 12-17 years: 100 mg) or placebo injections once every 4 weeks, plus guideline-based care, for 52 weeks. Randomisation was done using a validated automated system. Participants, investigators, and the research staff who collected outcome measures remained masked to group assignments. The primary outcome was the number of asthma exacerbations that were treated with systemic corticosteroids during 52 weeks in the intention-to-treat population. The mechanisms of treatment response were assessed by study investigators using nasal transcriptomic modular analysis. Safety was assessed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT03292588. FINDINGS: Between Nov 1, 2017, and Mar 12, 2020, we recruited 585 children and adolescents. We screened 390 individuals, of whom 335 met the inclusion criteria and were enrolled. 290 met the randomisation criteria, were randomly assigned to mepolizumab (n=146) or placebo (n=144), and were included in the intention-to-treat analysis. 248 completed the study. The mean number of asthma exacerbations within the 52-week study period was 0·96 (95% CI 0·78-1·17) with mepolizumab and 1·30 (1·08-1·57) with placebo (rate ratio 0·73; 0·56-0·96; p=0·027). Treatment-emergent adverse events occurred in 42 (29%) of 146 participants in the mepolizumab group versus 16 (11%) of 144 participants in the placebo group. No deaths were attributed to mepolizumab. INTERPRETATION: Phenotype-directed therapy with mepolizumab in urban children with exacerbation-prone eosinophilic asthma reduced the number of exacerbations. FUNDING: US National Institute of Allergy and Infectious Diseases and GlaxoSmithKline

Clinical spectrum and outcome of treatment for autoimmune cytopenias in rag deficiency

Univ Debrecen, Fac Med, Dept Immunol, Debrecen, HungaryHarvard Univ, Massachusetts Gen Hosp, Sch Med, Pediat Allergy & Immunol, Boston, MA USAHarvard Univ, Massachusetts Gen Hosp, Sch Med, Ctr Immunol & Inflammatory Dis, Boston, MA USAMassachusetts Gen Hosp Children, Div Pediat Allergy Immunol, Boston, MA USAUniv Tehran Med Sci, Childrens Med Ctr, Pediat Ctr Excellence, Res Ctr Immunodeficiencies, Tehran, IranMayo Clin, Lab Med & Pathol, Rochester, MN USAWeill Cornell Med Coll Qatar, Pediat, Doha, QatarSidra Med & Res Ctr, Allergy & Immunol, Doha, QatarHamad Med Corp, Doha, QatarKuwait Univ, Fac Med, Dept Pediat, Safat 13060, KuwaitAmer Univ Beirut, Ctr Infect Dis Res, Dept Pediat & Adolescent Med, Beirut, LebanonBambino Gesu Pediat Hosp, Dept Oncohematol, Stem Cell Transplant Unit, Rome, ItalyCincinnati Childrens Hosp Med Ctr, Div Bone Marrow Transplantat & Immune Deficiency, Cincinnati, OH 45229 USACincinnati Childrens Hosp Med Ctr, Cincinnati, OH 45229 USAGreat Ormond St Hosp Sick Children, Dept Paediat Immunol, London, EnglandGreat Ormond St Hosp Sick Children, Dept Paediat Immunol, London, North IrelandUC Irvine, CHOC Childrens Hosp, Pediat Hematol, Orange, CA USAChildrens Hosp Bambino Gesu, Dept Pediat, Rome, ItalyUniv Roma Tor Vergata, Sch Med, Rome, ItalyUniv Utah, Dept Pediat, Div Allergy Immunol & Rheumatol, Salt Lake City, UT USAHarvard Univ, Sch Med, Dept Pediat, Immunol Div,Boston Childrens Hosp, Boston, MA 02115 USAUniv Fed Sao Paulo, Dept Allergy Clin Immunol & Rheumatol, Sao Paulo, BrazilNIAID, Host Def Lab, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USABoston Childrens Hosp, Dept Immunol, Boston, MA USAHarvard Univ, Sch Med, Boston, MA USAUniv Colorado, Sch Med, Childrens Hosp Colorado, Div Allergy & Immunol, Boulder, CO 80309 USAImmunol Outpatient Clin, Vienna, AustriaUniv Iowa, Dept Pediat, Carver Coll Med, Iowa City, IA 52242 USANatl Jewish Hlth, Dept Pediat, Div Pediat Allergy & Clin Immunol, Denver, CO USANIAID, Lab Clin Infect Dis, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USAMayo Clin, Div Pediat Allergy Immunol, Rochester, MN USAAghia Sophia Childrens Hosp, Specialized Ctr, Dept Immunol Histocompatibil, Athens, GreeceAghia Sophia Childrens Hosp, Referral Ctr Primary Immunodeficiencies Pediat Im, Athens, GreeceOsped Pediat Bambino Gesu, Dept Pediat Hematol & Oncol, Rome, ItalyIRCCS Bambino Gesu Childrens Hosp, Dept Pediat Hematol & Oncol, Rome, ItalyBaylor Coll Med, Dept Pediat, Houston, TX 77030 USATexas Childrens Hosp, Sect Allergy & Immunol, Houston, TX 77030 USAErciyes Univ, Sch Med, Dept Pediat Hematol & Oncol, Kayseri, TurkeyErciyes Univ, Sch Med, Dept Pediat Immunol, Kayseri, TurkeyUniv Calif San Fransisco, Pediat Immunol & Bone Marrow Transplantat, San Francisco, CA USAChildrens Hosp Los Angeles, USC Keck Sch Med, Los Angeles, CA 90027 USAUniv Hosp Ulm, Dept Pediat & Adolescent Med, Ulm, GermanyDuke Univ, Sch Med, Div Allergy & Immunol, Durham, NC USAHarvard Univ, Sch Med, Boston Childrens Hosp, Div Immunol, Boston, MA USAUniv Fed Sao Paulo, Dept Allergy Clin Immunol & Rheumatol, Sao Paulo, BrazilWeb of Scienc

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