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Background: TNFα inhibitors are regularly used to treat autoimmune diseases. Tuberculosis (TB) and viral hepatitis B are considered potential infectious complications, and screening and surveillance are therefore recommended. Current guidelines do not take into account regional differences in endemicity of these infections. Methods: A systematic literature review of TB and viral hepatitis in patients receiving TNFα-inhibitors was performed, searching in PubMed, Embase, MEDLINE and Web of Science databases. Studies were selected against predefined eligibility criteria and assessed using the Newcastle-Ottawa scale. The number of TB and viral hepatitis cases/1,000 TNFα-inhibitor patients were evaluated, and regional variation compared. Results: 105 observational studies involving over 140,000 patients were included. Overall, 1% of patients developed TB or viral hepatitis B. TB cases/1,000 TNFα-inhibitor patients were 4-fold higher in Asia, Africa, and South America than in Europe, North America, and Australasia where only 0%–0.4% of patients developed TB. Hepatitis B cases/1,000 patients were over 15-fold higher in countries with high prevalence (China, Taiwan, South Korea, Thailand) compared with low prevalence ( p < 0.00001) where only 0.4% of patients developed hepatitis B. Only three of 143 patients developed viral hepatitis C, and there was insufficient data to allow regional sub-analysis. Conclusion: TB and viral hepatitis B infections in patients treated with TNFα inhibitors are largely confined to countries with high prevalence of these infections. As only 1/2,500 patients in low prevalence countries treated with TNFα inhibitors develop TB or viral hepatitis B, we suggest an individualized, risk-based approach, rather than universal screening for all patients.

Loss-of-function mutations in the human CTP synthase 1 gene cause an immunodeficiency disease with impaired T cell proliferation after antigen stimulation, revealing a potential new target for immunosuppressive drugs. A novel immune deficiency A study of several unrelated families susceptible to recurrent viral diseases but in whom known primary immunodeficiencies had been excluded has led to the identification of a novel human inherited immunodeficiency, and the recognition of a molecular pathway required to mount an efficient immune response against pathogens. Loss-of-function mutations in the gene for cytidine 5′ triphosphate synthase 1 ( CTPS1 ) are associated with severe and selective impairment of T-cell proliferation after antigen stimulation, identifying the enzyme as a critical checkpoint in adaptive immunity. CTPS1 deficiency does not induce other phenotype abnormalities, so these findings suggest that CTPS1 could be a viable target for therapeutics to inhibit unwanted adaptive responses. Lymphocyte functions triggered by antigen recognition and co-stimulation signals are associated with a rapid and intense cell division, and hence with metabolism adaptation 1 . The nucleotide cytidine 5′ triphosphate (CTP) is a precursor required for the metabolism of DNA, RNA and phospholipids 2 , 3 , 4 . CTP originates from two sources: a salvage pathway and a de novo synthesis pathway that depends on two enzymes, the CTP synthases (or synthetases) 1 and 2 (CTPS1 with CTPS2); the respective roles of these two enzymes are not known 5 , 6 , 7 . CTP synthase activity is a potentially important step for DNA synthesis in lymphocytes 8 , 9 . Here we report the identification of a loss-of-function homozygous mutation (rs145092287) in CTPS1 in humans that causes a novel and life-threatening immunodeficiency, characterized by an impaired capacity of activated T and B cells to proliferate in response to antigen receptor-mediated activation. In contrast, proximal and distal T-cell receptor (TCR) signalling events and responses were only weakly affected by the absence of CTPS1. Activated CTPS1-deficient cells had decreased levels of CTP. Normal T-cell proliferation was restored in CTPS1-deficient cells by expressing wild-type CTPS1 or by addition of exogenous CTP or its nucleoside precursor, cytidine. CTPS1 expression was found to be low in resting T cells, but rapidly upregulated following TCR activation. These results highlight a key and specific role of CTPS1 in the immune system by its capacity to sustain the proliferation of activated lymphocytes during the immune response. CTPS1 may therefore represent a therapeutic target of immunosuppressive drugs that could specifically dampen lymphocyte activation.

The rising prevalence of allergic diseases over the last century has been linked to smaller families and the shift of populations from countryside to cities, leading to reduced exposure to environmental bacteria. We previously demonstrated that Staphylococcus aureus -derived Second immunoglobulin-binding protein (Sbi) drives type 2 immune responses and atopic dermatitis (AD). Here we show that contrary to current dogma, soluble lipopeptides, particularly diacylated lipopeptides released by Gram-positive bacteria in their stationary phase suppress type 2 immune responses in vitro and eczema in the NC/Tnd mouse model. The immunomodulatory activity of these lipopeptides is destroyed by lipoprotein lipase. Their mechanism of immunomodulation is independent of CD14 and toll-like receptor (TLR) signaling but rather associated with inhibition of caspase/gasdermin D (GSDMD)-mediated release of the interleukin (IL)-33 alarmin from the nucleus. Our findings help to explain why exposure to environmental bacteria and topical application of bacterial commensals suppresses AD. We suggest that soluble bacterial lipopeptides could be developed into a novel class of therapeutics for treatment of allergic diseases. Here, the authors show that bacteria release immunosuppressive lipopeptides that suppress eczema and may serve as a potential therapy. This activity is independent of toll-like receptor signalling but involves gasdermin D-induced release of IL-33.

Christoph Klein and colleagues identify loss-of-function mutations in SMARCD2 ( BAF60b ) that lead to neutropenia, specific granule deficiency and myelodysplasia. They show that SMARCD2 controls differentiation of myeloid–erythroid progenitor cells through interaction with CEBPɛ and that reduced SMARCD2 levels cause transcription and chromatin alterations in acute myeloid leukemia cells. We identify SMARCD2 (SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily D, member 2), also known as BAF60b (BRG1/Brahma-associated factor 60b), as a critical regulator of myeloid differentiation in humans, mice, and zebrafish. Studying patients from three unrelated pedigrees characterized by neutropenia, specific granule deficiency, myelodysplasia with excess of blast cells, and various developmental aberrations, we identified three homozygous loss-of-function mutations in SMARCD2 . Using mice and zebrafish as model systems, we showed that SMARCD2 controls early steps in the differentiation of myeloid–erythroid progenitor cells. In vitro , SMARCD2 interacts with the transcription factor CEBPɛ and controls expression of neutrophil proteins stored in specific granules. Defective expression of SMARCD2 leads to transcriptional and chromatin changes in acute myeloid leukemia (AML) human promyelocytic cells. In summary, SMARCD2 is a key factor controlling myelopoiesis and is a potential tumor suppressor in leukemia.

RAS-associated lymphoproliferative disorder (RALD), caused by acquired gain-of-function mutations in Kirsten rat sarcoma KRAS or Neuroblastoma rat sarcoma NRAS, is an orphan disease with very few cases reported worldwide. The most common presenting feature is autoimmune cytopenia, which is generally documented to be responsive to immunosuppression. We describe two cases of RALD in which associated autoimmunity proved refractory to multiagent immunosuppression. We also share our experience of haematopoietic stem cell transplantation (HSCT) in the two patients with recalcitrant autoimmunity, adding valuable insight into the distinctive complications and transplant course in this rare disorder. Furthermore, we review the published literature on HSCT in RALD, which includes three other patients, primarily transplanted for malignant transformation of RALD. In addition, we report our experience with targeted therapy, specifically the MEK inhibitor, in this disease and reflect on its role within the treatment paradigm of RALD.

Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a negative immune regulator on the surface of T cells. In humans, heterozygous germline mutations in can cause an immune dysregulation syndrome. The phenotype comprises a broad spectrum of autoinflammatory, autoimmune, and immunodeficient features. An increased frequency of malignancies in primary immunodeficiencies is known, but their incidence in CTLA-4 insufficiency is unknown. Clinical manifestations and details of the clinical history were assessed in a worldwide cohort of 184 mutation carriers. Whenever a malignancy was reported, a malignancy-specific questionnaire was filled. Among the 184 mutation carriers, 131 were considered affected, indicating a penetrance of 71.2%. We documented 17 malignancies, which amounts to a cancer prevalence of 12.9% in affected mutation carriers. There were ten lymphomas, five gastric cancers, one multiple myeloma, and one metastatic melanoma. Seven lymphomas and three gastric cancers were EBV-associated. Our findings demonstrate an elevated cancer risk for patients with CTLA-4 insufficiency. As more than half of the cancers were EBV-associated, the failure to control oncogenic viruses seems to be part of the CTLA-4-insufficient phenotype. Hence, lymphoproliferation and EBV viral load in blood should be carefully monitored, especially when immunosuppressing affected mutation carriers.

Background For children aged 6–11 years with uncontrolled severe atopic dermatitis (AD), 16 weeks of treatment with dupilumab resulted in substantial clinical benefit compared with placebo with an acceptable safety profile. However, longer-term safety and efficacy data are important to inform longitudinal AD management. Objectives This analysis of data from an open-label extension study (LIBERTY AD PED-OLE, NCT02612454) reports the long-term safety, efficacy, and pharmacokinetics of dupilumab in children with severe AD who had participated in the pivotal dupilumab LIBERTY AD PEDS study (NCT03345914). Methods Enrolled patients initially received subcutaneous dupilumab 300 mg every 4 weeks (q4w). The q4w regimen could be uptitrated to dupilumab dose regimens of 200 or 300 mg every 2 weeks (q2w; for body weight < 60 or ≥ 60 kg, respectively) for patients who did not achieve an Investigator’s Global Assessment (IGA) score of 0/1 (clear/almost clear skin) at week 16, or prior to week 16 as rescue treatment. Additional patients were uptitrated to a weight-tiered q2w regimen following a protocol amendment. Patients who maintained an IGA score of 0/1 continuously for a 12-week period after week 40 discontinued dupilumab. They were monitored for relapse and were reinitiated on dupilumab if required. Results Data for 321 patients (mean age 8.6 years) were analyzed, 254 (79%) of whom had completed the scheduled 52-week visit at the database lock. Most treatment-emergent adverse events were mild/moderate. By week 52, 41% of patients achieved an IGA score of 0/1, and 97%, 82%, and 50%, respectively, had at least a 50%, 75%, and 90% improvement from the parent study baseline in Eczema Area and Severity Index (EASI). By week 52, 29% of patients in the overall population had clear/almost clear skin sustained for 12 weeks and had stopped medication; of these, 40% relapsed and were subsequently reinitiated on treatment, with a mean time to reinitiation of 13.5 (standard deviation 5.2) weeks. Following reinitiation of dupilumab, 41% of the patients with evaluable data at the time of database lock had regained an IGA 0/1 clinical response. Conclusions Consistent with results seen in adults and adolescents, long-term treatment with dupilumab in children aged 6–11 years with severe AD showed an acceptable safety profile and incremental clinical benefit. A substantial proportion of children who stopped dupilumab treatment after achieving clear/almost clear skin subsequently experienced disease recurrence, and required reinitiation of dupilumab, suggesting that continuous treatment may be necessary for maintenance of clinical benefit. Trial Registration ClinicalTrials.gov Identifier NCT02612454. Plain Language Summary Atopic dermatitis (AD) is a chronic disease that causes recurrent inflamed and rough skin rashes with itching and often soreness. In children with AD, treatment with a medication called dupilumab has shown improvements in their disease and quality of life. But most clinical trials of dupilumab in children have only lasted for 16 weeks. We investigated the effect of dupilumab in children treated for a longer time. The 321 children (aged 6–11 years) who were included in this study had taken part in a clinical trial of dupilumab because they had severe AD. They were treated with either dupilumab or a placebo (a dummy treatment) for 16 weeks. When that trial ended, they were then all treated with dupilumab for up to a year. Their average AD severity continued to get steadily better over a year of extended treatment, with almost all children reaching 50% skin improvement compared with their AD before treatment. Many children reached a point where their skin was clear or almost clear of AD for a period, and following the rules of the study they stopped taking dupilumab. In many of them, their AD slowly returned without treatment. But if they started to take dupilumab again, their AD improved, and some could even achieve skin clearance again. Over the longer term, the safety of dupilumab was similar to what was seen with short-term treatment. This study showed that children with AD aged 6–11 years benefited from receiving dupilumab for a longer period of time.

Inducible co-stimulator (ICOS) deficiency was the first monogenic defect reported to cause common variable immunodeficiency (CVID)-like disease in 2003. Since then, 16 patients have been reported worldwide with an increasing range of clinical phenotypes. We sought to compare the clinical and immunological phenotype and provide clinical follow-up and therapeutic approaches for treating ICOS-deficient patients. We describe the clinical and laboratory data of 15 patients with available clinical data. Previous publications and clinical assessment were used as data sources. The observed ICOS gene mutations were all deletions leading to undetectable protein expression. The clinical phenotype of ICOS deficiency is much broader than initially anticipated and includes not only CVID-like disease but an increased susceptibility to viral and opportunistic infections, as well as cancer. Impaired B-cell development led to decreased memory B-cells in all patients, and hypogammaglobulinemia in all but one patient. Circulating CXCR5 CD4 follicular T-helper-cell numbers were also reduced in all patients. Treatment included immunoglobulin replacement, regular antibiotic prophylaxis, corticosteroids, and steroid-sparing agents. Three patients underwent hematopoietic stem cell transplantation; one of them died due to capillary leak syndrome on day 5 posttransplantation. The disease spectrum of ICOS deficiency is expanding from solely B-cell to combined B- and T-cell immunodeficiency, suggesting genetic and environmental modifiers. Genetic diagnosis is the only tool to distinguish ICOS deficiency from other immunological defects. Patients with antibody deficiency, autoimmunity, and combined immunodeficiency should be screened for mutations.

We recently reported the genetic cause of autosomal dominant chronic mucocutaneous candidiasis (AD-CMC) as a mutation in the STAT1 gene. In the present study we show that STAT1 Arg274Trp mutations in the coiled-coil (CC) domain is the genetic cause of AD-CMC in three families of patients. Cloning and transfection experiments demonstrate that mutated STAT1 inhibits IL12R/IL-23R signaling, with hyperphosphorylation of STAT1 as the likely underlying molecular mechanism. Inhibition of signaling through the receptors for IL-12 and IL-23 leads to strongly diminished Th1/Th17 responses and hence to increased susceptibility to fungal infections. The challenge for the future is to translate this knowledge into novel strategies for the treatment of this severe immunodeficiency.