A team of researchers, under the leadership of Dr Hirotsugu Oda from the University of Cologne, has unveiled the significance of a particular protein complex in specific types of immunological dysregulation. The study, published in the journal Nature Immunology, delves into the role of LUBAC, the linear ubiquitin assembly complex consisting of proteins HOIP, HOIL-1, and SHARPIN, in maintaining immune homeostasis. While previous studies on mouse models have shown the severe consequences of SHARPIN loss, leading to dermatitis, the specific effects of SHARPIN deficiency in human health were previously unknown.
Through their research, the team identified two human individuals with SHARPIN deficiency who displayed symptoms of autoinflammation and immunodeficiency without the dermatological issues seen in animal models. These individuals exhibited a compromised canonical NF-kB response, emphasizing the importance of this pathway in immune responses. Furthermore, they demonstrated increased susceptibility to cell death mediated by TNF superfamily members, leading to the successful resolution of autoinflammation through anti-TNF therapies in one patient.
The study initiated at Dr Dan Kastner's lab at the National Institutes of Health (NIH) in the USA, focused on a patient with childhood-onset symptoms including fever episodes, arthritis, colitis, and immunodeficiency. Through exome sequencing, researchers identified a deleterious genetic variant in the SHARPIN gene, resulting in undetectable SHARPIN protein levels, leading to increased cell death in patient biopsies. This finding sheds light on the pivotal role of LUBAC in maintaining immune homeostasis in humans, highlighting the implications for human genetic inflammatory diseases.