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We have identified 5 children with complete USP18 deficiency (in collaboration with Dr. Manchini at Erasmus University, The Netherlands) and detailed the molecular mechanisms behind the type I IFN inflammation. Importantly these children presented with a severe perinatal onset of inflammation  (Meuwissen et. al Journal of Experimental Medicine) suggestive of intrauterine infection, yet without an infectious origin, leading to diagnosis of Pseudo-TORCH syndrome. USP18 has both enzymatic (acting as a deISGylating enzyme) and negative regulatory activity (prevent IFN mediated inflammation). In a large collaboration, we recently demonstrated that this invariably lethal condition could be cured. In a Saudi Arabian boy with essential USP18 splice site mutations that remove the negative regulatory domain of USP18, early intervention with intensive supportive care and JAK inhibitor therapy lead to prompt and sustained recovery (Alsohime et al., 2020). We continue to study these and other individuals with similar disease presentations looking to unveil novel genetic and molecular mechanisms behind this syndrome.

Interestingly, the role for ISGylation in humans remains elusive. We aim at better understanding the role for ISGylation in human setting. To do so, we utilize a number of genetic models we have discovered or generated, allowing us to mechanistically assess the questions of ISGylation, and deISGylation as they pertain to ISG15 and USP18 biology.

We have identified a novel homozygous STAT2 mutation as a genetic cause for lethal autoinflammation of infancy (Gruber Journal of Experimental Medicine). The clinical presentation and molecular mechanisms of this disorder largely phenocopy ISG15-deficiency and USP18-deficiency. This is because STAT2 not only transduces IFN signaling, but also works as an essential adapter for USP18-mediated negative regulation. The gain-of-function mutation in this patient disrupted the negative regulatory function of STAT2 while maintaining the positive regulatory functions of STAT2. This unusual combination leads to a gain-of-function mutation with autosomal recessive inheritance, an exquisitely rare phenomenon in human genetics. Ongoing work aims to characterize new variants, develop treatment strategies, and better understand the pathogenesis of clinical disease. 

SOCS1 serves as a master negative regulator of JAK-STAT signal transduction for nearly all cytokines in the human immune system. Accordingly, the initial reports of genetic haploinsufficiency of SOCS1 (including Gruber Journal of Clinical Immunology 2023) describe widespread immune upregulation leading to diverse infectious, inflammatory, and autoimmune disease. We recently demonstrated that targeted therapy against the IL4Ra, rather than broad immunosuppression, serves as a surprisingly fruitful treatment strategy. Future research aims to characterize common SOCS1 variants and their role in more typical rheumatologic disorders. 

JAK1 is an essential kinase that mediates signal transduction for a remarkably diverse set of cytokines. We first described a JAK1 gain-of-function (GoF) mutation in a patient with a severe multi-system immunodysregulatory disease presenting to our Undiagnosed Disease Program (Gruber Immunity 2020). In a striking case of personalized medicine, the patient was successfully treated with a JAK inhibitor, as a result of our mechanistic studies. The subsequent discovery of numerous patients harboring additional GoF mutations (Horesh Journal of Experimental Medicine 2024) allowed us to define a unifying clinical syndrome of JAK1-associated atopy, autoimmunity, colitis and/or dermatitis, now termed JAACD. By dissecting the mechanisms of these mutations, we have gained insight into the basic molecular and transcriptional regulation of JAK1. Namely, we have uncovered that: (1) GoF JAK1 mutants trans-activate other JAKs via their pseudokinase domain, independent of catalytic function; (2) GoF JAK1 variants adopt neomorphic functions, initiating signaling cascades not canonically mediated by JAK1; (3) JAK1 expression is randomly restricted to a single allele in any given cell (see Monoallelic Expression*). We continue to describe novel JAK1 variants and investigate the functional impact of monoallelic expression on disease penetrance and pathogenesis. 

TANK binding kinase 1 (TBK1) is a signaling intermediate involved in inducing both type I interferon (IFN-I) expression and nuclear factor-kB-mediated inflammatory cytokine production. Additionally, TBK1 has been shown to negatively regulate TNF-induced cell death through inactivation of RIPK1. Our group previously identified patients with biallelic loss-of-function mutations in TBK1 that exhibit early-onset autoinflammatory syndrome. While the loss of TBK1 expression results in reduced induction of IFN-I, these patients still maintain a sufficient antiviral response. Notably, the absence of TBK1 expression also removes the “brake” on RIPK1, favoring a RIPK1-mediated cell death that ultimately drives autoinflammation. Treating patients with complete TBK1 deficiency with anti-TNF improves clinical symptoms. We are currently identifying new patients, including children and adults, who suffer from type I interferonopathies, a distinct form of chronic autoinflammation, and autoimmunity. We aim to understand how TBK1 variations in these individuals regulate IFN-I, NF-kB and RIPK1 function to drive clinical disease.