Inborn Errors of Immunity Contribute to the Burden of Skin Disease and Create Opportunities for Improving the Practice of Dermatology.

Opportunities to improve the clinical management of skin disease are being created by advances in genomic medicine. Large-scale sequencing increasingly challenges notions about single-gene disorders. It is now apparent that monogenic etiologies make appreciable contributions to the population burden of disease and that they are underrecognized in clinical practice. A genetic diagnosis informs on molecular pathology and may direct targeted treatments and tailored prevention strategies for patients and family members. It also generates knowledge about disease pathogenesis and management that is relevant to patients without rare pathogenic variants. Inborn errors of immunity are a large class of monogenic etiologies that have been well-studied and contribute to the population burden of inflammatory diseases. To further delineate the contributions of inborn errors of immunity to the pathogenesis of skin disease, we performed a set of analyses that identified 316 inborn errors of immunity associated with skin pathologies, including common skin diseases. These data suggest that clinical sequencing is underutilized in dermatology. We next use these data to derive a network that illuminates the molecular relationships of these disorders and suggests an underlying etiological organization to immune-mediated skin disease. Our results motivate the further development of a molecularly derived and data-driven reorganization of clinical diagnoses of skin disease.

Staphylococcal phosphatidylglycerol antigens activate human T cells via CD1a.

Expressed on epidermal Langerhans cells, CD1a presents a range of self-lipid antigens found within the skin; however, the extent to which CD1a presents microbial ligands from bacteria colonizing the skin is unclear. Here we identified CD1a-dependent T cell responses to phosphatidylglycerol (PG), a ubiquitous bacterial membrane phospholipid, as well as to lysylPG, a modified PG, present in several Gram-positive bacteria and highly abundant in Staphylococcus aureus. The crystal structure of the CD1a-PG complex showed that the acyl chains were buried within the A'- and F'-pockets of CD1a, while the phosphoglycerol headgroup remained solvent exposed in the F'-portal and was available for T cell receptor contact. Using lysylPG and PG-loaded CD1a tetramers, we identified T cells in peripheral blood and in skin that respond to these lipids in a dose-dependent manner. Tetramer+CD4+ T cell lines secreted type 2 helper T cell cytokines in response to phosphatidylglycerols as well as to co-cultures of CD1a+ dendritic cells and Staphylococcus bacteria. The expansion in patients with atopic dermatitis of CD4+ CD1a-(lysyl)PG tetramer+ T cells suggests a response to lipids made by bacteria associated with atopic dermatitis and provides a link supporting involvement of PG-based lipid-activated T cells in atopic dermatitis pathogenesis.

Use of sleeve gastrectomy in adolescents and young adults with severe obesity.

PURPOSE OF REVIEW: The prevalence of pediatric obesity and its associated complications is increasing around the world. Treatment of obesity is challenging and metabolic and bariatric surgery (MBS) is currently the most effective treatment for this condition. At this time, vertical sleeve gastrectomy (VSG) is the most commonly performed bariatric procedure in adolescents. However, knowledge regarding the efficacy, safety, and durability of VSG in adolescents is still evolving. This review summarizes the most recent updates in the field of MBS particularly VSG in adolescents. RECENT FINDINGS: MBS is recommended to treat moderate to severe obesity, especially when complicated by comorbidities. The use of VSG for weight loss is increasing among adolescents and produces similar weight loss at five years in both adolescents and adults. The physiologic mechanisms causing weight loss after VSG are multifactorial and still being investigated. The complication rate after VSG ranges between 0 and 17.5%. SUMMARY: VSG appears to be a well-tolerated and effective procedure in adolescents. However, it continues to be underutilized despite the increasing prevalence of moderate to severe obesity in adolescents. It is thus important to educate providers regarding its benefits and safety profile.