Regulation of Fc Receptor Expression and Signaling on Murine Mast Cells

Mast cells have long been appreciated as the primary effector cells in allergy and asthma, and recently have been implicated in other inflammatory diseases. Using high density oligonucleotide probe arrays, we assessed genome-wide transcriptional profiles after FcεRI aggregation for 90 minutes, 5 hours and 24 hours. We describe novel gene regulation in response to FcεRI signaling, including altered expression of CD44, Pari, osteopontin, Nur77, E4BP4, and NDRG 1. In addition, the gene encoding FcεRI β was downregulated 5 hours after mast cell activation according to both microarray analysis and RPA, and western blotting confirmed the downregulation of the beta subunit protein. Moreover, this downregulation of beta mRNA correlated with the decreased FcεRI surface expression after mast cell activation. Very little is known about the transcriptional regulation of the beta subunit of FcεRI. These transcriptome profiling experiments are revealing novel and clinically relevant insight into how FcεRI signaling may be controlled. Continuing with our focus on how mast cell activation is regulated, we examined the effects of Th2 cytokines on expression of important surface receptors. Murine mast cells co-express the activation receptor FcγRIII and the inhibitory receptor FcγRIIb and can be activated by lgG immune complexes. Using mouse bone marrow-derived mast cells, we report that IL-4 selectively increases FcγRIII expression without altering FcγRIIb. This enhanced expression could be induced by Stat6 activation alone, and appeared to be mediated in part by increased FcγRIIIα protein synthesis without significant changes in transcription. The increase in FcγRIII expression was functionally significant, as it was matched by enhanced FcγR-mediated degranulation and cytokine production. Selective regulation of mast cell FcγR by IL-4 could alter inflammatory lgG responses and subsequently disease severity and progression. Collectively, our studies have used genome-wide screening and reductionist studies to demonstrate mechanisms by which mast cell function is regulated

IgE signaling suppresses FcεRIβ expression

Activation of the high-affinity receptor for IgE, FcεRI, is known to elicit its rapid down-regulation through internalization and degradation. In keeping with this, expression of all three FcεRI subunits is decreased at the protein level after cross-linkage of IgE with antigen. However, we find that the FcεRI β-subunit is also selectively suppressed at the mRNA level, through a pathway primarily involving Fyn, Syk, PI3K, and NF-κB. IgG or calcium ionophore, stimuli known to mimic portions of the IgE signaling cascade, similarly suppressed β-subunit expression. LPS, a NF-κB-activating TLR ligand, did not alter β-subunit expression. As IgE increases FcεRI expression, we examined the coordinated regulation of FcεRI subunits during culture with IgE, followed by cross-linkage with antigen. IgE increased the expression of all three FcεRI subunits and strikingly induced expression of the antagonistic βT. The ratio of β:βT protein expression decreased significantly during culture with IgE and was reset to starting levels by antigen cross-linkage. These changes in protein levels were matched by similar fluctuations in β and βT mRNAs. FcεRIβ is a key regulator of IgER expression and function, a gene in which polymorphisms correlate with allergic disease prevalence. The ability of IgE and FcεRI signaling to coordinate expression of the β and βT subunits may comprise a homeostatic feedback loop—one that could promote chronic inflammation and allergic disease if dysregulated

COVID-19 Vaccination in Patients with Inborn Errors of Immunity Reduces Hospitalization and Critical Care Needs Related to COVID-19: a USIDNET Report.

BACKGROUND: The CDC and ACIP recommend COVID-19 vaccination for patients with inborn errors of immunity (IEI). Not much is known about vaccine safety in IEI, and whether vaccination attenuates infection severity in IEI. OBJECTIVE: To estimate COVID-19 vaccination safety and examine effect on outcomes in patients with IEI. METHODS: We built a secure registry database in conjunction with the US Immunodeficiency Network to examine vaccination frequency and indicators of safety and effectiveness in IEI patients. The registry opened on January 1, 2022, and closed on August 19, 2022. RESULTS: Physicians entered data on 1245 patients from 24 countries. The most common diagnoses were antibody deficiencies (63.7%). At least one COVID-19 vaccine was administered to 806 patients (64.7%), and 216 patients received vaccination prior to the development of COVID-19. The most common vaccines administered were mRNA-based (84.0%). Seventeen patients were reported to seek outpatient clinic or emergency room care for a vaccine-related complication, and one patient was hospitalized for symptomatic anemia. Eight hundred twenty-three patients (66.1%) experienced COVID-19 infection. Of these, 156 patients required hospitalization (19.0%), 47 required ICU care (5.7%), and 28 died (3.4%). Rates of hospitalization (9.3% versus 24.4%, p < 0.001), ICU admission (2.8% versus 7.6%, p = 0.013), and death (2.3% versus 4.3%, p = 0.202) in patients who had COVID-19 were lower in patients who received vaccination prior to infection. In adjusted logistic regression analysis, not having at least one COVID-19 vaccine significantly increased the odds of hospitalization and ICU admission. CONCLUSION: Vaccination for COVID-19 in the IEI population appears safe and attenuates COVID-19 severity

Outcomes in Newly Diagnosed Atrial Fibrillation and History of Acute Coronary Syndromes: Insights from GARFIELD-AF

BACKGROUND: Many patients with atrial fibrillation have concomitant coronary artery disease with or without acute coronary syndromes and are in need of additional antithrombotic therapy. There are few data on the long-term clinical outcome of atrial fibrillation patients with a history of acute coronary syndrome. This is a 2-year study of atrial fibrillation patients with or without a history of acute coronary syndromes

Prospective observational cohort study on grading the severity of postoperative complications in global surgery research

Background The Clavien–Dindo classification is perhaps the most widely used approach for reporting postoperative complications in clinical trials. This system classifies complication severity by the treatment provided. However, it is unclear whether the Clavien–Dindo system can be used internationally in studies across differing healthcare systems in high- (HICs) and low- and middle-income countries (LMICs). Methods This was a secondary analysis of the International Surgical Outcomes Study (ISOS), a prospective observational cohort study of elective surgery in adults. Data collection occurred over a 7-day period. Severity of complications was graded using Clavien–Dindo and the simpler ISOS grading (mild, moderate or severe, based on guided investigator judgement). Severity grading was compared using the intraclass correlation coefficient (ICC). Data are presented as frequencies and ICC values (with 95 per cent c.i.). The analysis was stratified by income status of the country, comparing HICs with LMICs. Results A total of 44 814 patients were recruited from 474 hospitals in 27 countries (19 HICs and 8 LMICs). Some 7508 patients (16·8 per cent) experienced at least one postoperative complication, equivalent to 11 664 complications in total. Using the ISOS classification, 5504 of 11 664 complications (47·2 per cent) were graded as mild, 4244 (36·4 per cent) as moderate and 1916 (16·4 per cent) as severe. Using Clavien–Dindo, 6781 of 11 664 complications (58·1 per cent) were graded as I or II, 1740 (14·9 per cent) as III, 2408 (20·6 per cent) as IV and 735 (6·3 per cent) as V. Agreement between classification systems was poor overall (ICC 0·41, 95 per cent c.i. 0·20 to 0·55), and in LMICs (ICC 0·23, 0·05 to 0·38) and HICs (ICC 0·46, 0·25 to 0·59). Conclusion Caution is recommended when using a treatment approach to grade complications in global surgery studies, as this may introduce bias unintentionally