Phosphatases in Mouse Mast Cell Rapid IgE Desensitization: The Role of SHIP-1

Rapid Drug Desensitization (RDD) is a widely used and effective clinical approach to enable allergic individuals to temporary tolerate various drugs to which they have an IgE-mediated hypersensitivity reaction. Latest studies have found mast cells (MCs) as the primary target cells for Desensitization (DS). Studies on both in vitro and in vivo murine rapid IgE/MCs DS showed impairment of all MC activation hallmarks such as receptor internalization, calcium mobilization, degranulation, production of lipid mediators and cytokines. However, the molecular targets and underlying mechanisms behind this process remain unclear. Previous studies have shown that the inositol phosphatase SHIP acts as a “gatekeeper” and negatively regulate MC degranulation over all antigen doses. Thus, we hypothesize that the multiple subthreshold doses of antigen during DS might result in recruitment of SHIP-1. Here, we focused on assessing the role of phosphatases specifically SHIP-1 in FcεRI signal regulation during DS. We have used SiRNA and SHIP-1 inhibitor, 3-a-aminocholestane (3AC) to knock down (KD) the protein expression and inhibit its biological activity respectively. Our preliminary data showed more degranulation response at the end of the DS in SHIP-1 KD BMMCs compare to the WT BMMCs, indicating an inhibitory response of SHIP-1. Although 3AC at a range of concentrations between 2 to 100M did not shown an inhibitory response, we found more phospho-SHIP1 in the early steps of DS compare to later steps; indicating its critical role in turning the inhibitory pathway. Our future direction is to measure other parameters of MCs activation such as Ca+2 flux, receptor internalization, lipid mediators and cytokine production. In addition, we intend to replicate the DS protocol in RBL cells (an adherent MCs) to visualize SHIP-1 co-localization with FcRI during DS

Anaphylaxis in the 21st century: phenotypes, endotypes, and biomarkers

Anaphylaxis is the most serious of all allergic reactions and can be fatal. The diagnosis is frequently delayed, and misdiagnosis often occurs with asthma or urticaria. Biomarkers such as tryptase are not routinely checked, and appropriate treatment with epinephrine is not administered in a majority of cases, increasing the risk of poor outcomes. The objective of this review is to provide a better understanding of the pathophysiology of anaphylaxis with a description of phenotypes, endotypes, and biomarkers available in both the clinical and research settings. Expanding knowledge with regard to the presentation, causes, and triggers for anaphylaxis among health care providers will improve its diagnosis and management, increase patient safety, and decrease morbidity and mortality

Glycogenic Hepatopathy: A Rare Hepatic Complication of Poorly Controlled Type 1 DM

Glycogen hepatopathy (GH) is a rare complication of type 1 diabetes mellitus that leads to an abnormal accumulation of glycogen in the hepatocytes. The exact mechanism of GH remains unknown, but fluctuations in blood glucose and insulin levels play important roles in promoting glycogen accumulation. We report a case of a 16-year-old female diagnosed with poorly controlled type 1 diabetes mellitus with hepatomegaly and elevated liver enzymes. The patient experienced multiple admissions for diabetic ketoacidosis, and she also had celiac disease diagnosed 2 years previously based on serology and a duodenal biopsy. The laboratory analyses results were compatible with acute hepatitis, and the celiac serology was positive. Other investigations ruled out viral hepatitis and autoimmune and metabolic liver diseases. Ultrasound and computerized tomography (CT) scans of the abdomen revealed liver enlargement with diffuse fatty infiltration. A liver biopsy revealed the presence of abundant glycogen in the cytoplasm of the hepatocytes. PAS staining was strongly positive, which confirmed the diagnosis of GH. There were no features of autoimmune hepatitis or significant fibrosis. Duodenal biopsy results were consistent with celiac disease. Despite our efforts, which are supported by a multidisciplinary team approach that included a hepatologist, a diabetic educator, a dietitian, and an endocrinologist, we have encountered difficulties in controlling the patient’s diabetes, and she persistently maintains symptomatic hepatomegaly and abnormal liver biochemistry. Given the patient’s age, we assumed that these abnormalities were related to patient noncompliance. In conclusion, GH remains an under-recognized complication of type 1 DM that is potentially reversible with adequate glycemic control. The awareness of GH should prevent diagnostic delay and its implications for management and the outcome

Drug Hypersensitivity and Desensitizations: Mechanisms and New Approaches

Drug hypersensitivity reactions (HSRs) are increasing in the 21st Century with the ever expanding availability of new therapeutic agents. Patients with cancer, chronic inflammatory diseases, cystic fibrosis, or diabetes can become allergic to their first line therapy after repeated exposures or through cross reactivity with environmental allergens. Avoidance of the offending allergenic drug may impact disease management, quality of life, and life expectancy. Precision medicine provides new tools for the understanding and management of hypersensitivity reactions (HSRs), as well as a personalized treatment approach for IgE (Immunoglobuline E) and non-IgE mediated HSRs with drug desensitization (DS). DS induces a temporary hyporesponsive state by incremental escalation of sub-optimal doses of the offending drug. In vitro models have shown evidence that IgE desensitization is an antigen-specific process which blocks calcium flux, impacts antigen/IgE/FcεRI complex internalization and prevents the acute and late phase reactions as well as mast cell mediator release. Through a “bench to bedside” approach, in vitro desensitization models help elucidate the molecular pathways involved in DS, providing new insights to improved desensitization protocols for all patients. The aim of this review is to summarize up to date information on the drug HSRs, the IgE mediated mechanisms of desensitization, and their clinical applications