Hyper-IgE and Carcinoma in CADINS Disease.

Background: Atopic dermatitis (AD) affects up to 25% of children and 10% of adults in Western countries. When severe or recurrent infections and exceedingly elevated serum IgE levels occur in AD patients, an inborn error of immunity (IEI) may be suspected. The International Union of Immunological Societies classification lists variants in different genes responsible for so-called Hyper-IgE syndromes. Diagnosing an underlying IEI may influence treatment strategies. Methods: Clinical and diagnostic workup of family members are presented including a detailed immunological description and histology of the carcinoma. Functional testing of the novel variant in CARD11 underlying 'CARD11-associated atopy with dominant interference of NF-kB signaling' (CADINS) was performed. Results: We report on an 18-year-old patient with a long-standing history of infections, accompanied by hypogammaglobulinemia, intermittent agranulocytosis, atopy, eosinophilia and colitis. The working diagnosis of common variable immunodeficiency was revised when a novel heterozygous CARD11 variant [c.223C>T; p.(Arg75Trp)] was identified. Functional studies confirmed this variant to have a dominant negative (DN) effect, as previously described in patients with CADINS. Five other family members were affected by severe atopy associated with the above variant, but not hypogammaglobulinemia. Malignancies occurred in two generations: an HPV-positive squamous cell carcinoma and a cutaneous T-cell lymphoma. So far, one patient is under treatment with dupilumab, which has shown marked benefit in controlling severe eczema. Conclusion: The phenotypic spectrum associated with heterozygous CARD11 DN mutations is broad. Partial T-cell deficiency, diminished IFN-γ cytokine and increased IL-4 production, were identified as disease-causing mechanisms. Malignant disease associated with germline CARD11 DN variants has only been reported sporadically. HPV vaccination in teenage years, and cytology screening analogous with routine cervical swabs may be recommended. Treatment with dupilumab, a monoclonal antibody blocking interleukin-4- and interleukin-13 signaling, may be of benefit in controlling severe and extended AD for some patients as reported for STAT3 loss-of-function.

One Gene, Many Facets: Multiple Immune Pathway Dysregulation in SOCS1 Haploinsufficiency.

Background: Inborn errors of immunity (IEI) present with a large phenotypic spectrum of disease, which can pose diagnostic and therapeutic challenges. Suppressor of cytokine signaling 1 (SOCS1) is a key negative regulator of cytokine signaling, and has recently been associated with a novel IEI. Of patients described to date, it is apparent that SOCS1 haploinsufficiency has a pleiotropic effect in humans. Objective: We sought to investigate whether dysregulation of immune pathways, in addition to STAT1, play a role in the broad clinical manifestations of SOCS1 haploinsufficiency. Methods: We assessed impacts of reduced SOCS1 expression across multiple immune cell pathways utilizing patient cells and CRISPR/Cas9 edited primary human T cells. Results: SOCS1 haploinsufficiency phenotypes straddled across the International Union of Immunological Societies classifications of IEI. We found that reduced SOCS1 expression led to dysregulation of multiple intracellular pathways in immune cells. STAT1 phosphorylation is enhanced, comparably with STAT1 gain-of-function mutations, and STAT3 phosphorylation is similarly reduced with concurrent reduction of Th17 cells. Furthermore, reduced SOCS1 E3 ligase function was associated with increased FAK1 in immune cells, and increased AKT and p70 ribosomal protein S6 kinase phosphorylation. We also found Toll-like receptor responses are increased in SOCS1 haploinsufficiency patients. Conclusions: SOCS1 haploinsufficiency is a pleiotropic monogenic IEI. Dysregulation of multiple immune cell pathways may explain the variable clinical phenotype associated with this new condition. Knowledge of these additional dysregulated immune pathways is important when considering the optimum management for SOCS1 haploinsufficient patients.

Perioperative risk analysis for acute respiratory distress syndrome after elective oesophagectomy.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a major contributor to respiratory morbidity and mortality after oesophagectomy. Several pre-, intra- and post-operative factors are thought to predispose to its development in the post-oesophagectomy period. The aim of this study was to determine factors predisposing to ARDS in the post-oesophagectomy period. METHODS: A total of 112 patients who underwent elective oesophagectomy for oesophageal cancer (gastro-oesophageal adenocarcinoma and high-grade dysplasia, 93; oesophageal squamous cell carcinoma, 16; oesophageal oat cell tumour, 1; oesophageal anaplastic carcinoma, 1; oesophageal colloid carcinoma, 1) between 1 January 2003 and 31 December 2006 formed the study group in this retrospective study. The pre-, intra and post-operative data for these patients (male : female = 89:23, mean age 60.8 years) were collected from an oesophagectomy database and hospital medical records. RESULTS: The incidence of ARDS was 13%. The in-hospital mortality among ARDS cases was 20% and 1-year mortality was 40%. Various factors such as preoperative chronic respiratory disease (P-value = 0.000, odds ratio = 17.76), smoking pack-years (P-value = 0.045, odds ratio = 1.02), abnormal preoperative forced expiratory volume in 1 s (P-value = 0.009, odds ratio = 7.97), high percentage of oxygen in inspired air (P-value = 0.041, odds ratio = 1.24) and use of perioperative inotropes (P-value = 0.021, odds ratio = 4.26) were associated with ARDS. CONCLUSIONS: Preoperative physiological status as indicated by a preoperative history of chronic respiratory disease and preoperative pulmonary function influenced the post-operative outcome in our patients. The use of perioperative inotropes suggests perioperative cardiorespiratory instability, and could also predispose to the development of ARDS in the post-operative period.