Dominant activating RAC2 mutation with lymphopenia, immunodeficiency, and cytoskeletal defects.

Ras-related C3 botulinum toxin substrate 2 (RAC2), through interactions with reduced NAD phosphate oxidase component p67 phox , activates neutrophil superoxide production, whereas interactions with p21-activated kinase are necessary for fMLF-induced actin remodeling. We identified 3 patients with de novo RAC2[E62K] mutations resulting in severe T- and B-cell lymphopenia, myeloid dysfunction, and recurrent respiratory infections. Neutrophils from RAC2[E62K] patients exhibited excessive superoxide production, impaired fMLF-directed chemotaxis, and abnormal macropinocytosis. Cell lines transfected with RAC2[E62K] displayed characteristics of active guanosine triphosphate (GTP)-bound RAC2 including enhanced superoxide production and increased membrane ruffling. Biochemical studies demonstrated that RAC2[E62K] retains intrinsic GTP hydrolysis; however, GTPase-activating protein failed to accelerate hydrolysis resulting in prolonged active GTP-bound RAC2. Rac2+/E62K mice phenocopy the T- and B-cell lymphopenia, increased neutrophil F-actin, and excessive superoxide production seen in patients. This gain-of-function mutation highlights a specific, nonredundant role for RAC2 in hematopoietic cells that discriminates RAC2 from the related, ubiquitous RAC1.

Acute Respiratory Failure Associated With Vaping.

The use of e-cigarettes to deliver aerosolized nicotine has gained popularity in recent years. Numerous reports have cited the development of acute pulmonary disease linked to vaping nicotine as well as marijuana-based products. As cultural attitudes evolve and policies shift toward the legalization of marijuana, its use has become more prevalent. Given the increased prevalence of marijuana consumption and e-cigarette usage, better insight into its potential to cause lung toxicity is warranted. The clinical, radiographic, and histopathologic characteristics of lung injury associated with vaping, particularly with marijuana-based products, have yet to be well described in the literature. We present eight patients, most of whom were admitted recently to our institution with acute respiratory failure following vaping. The majority of patients were young, with a median age of 31.5 years (range, 24-62 years) and with no known underlying lung disease. This case series highlights common clinical findings as well as the varied radiographic and histopathologic features of acute respiratory failure associated with vaping predominantly marijuana-based products. As more cases of vaping-associated pulmonary injury unfold, data will be available to further characterize this emerging disease entity. Improved understanding of disease pathogenesis and its clinical course will help clinicians determine optimal management and follow-up strategies for this patient population.