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Objective: Bi-allelic pathogenic variants in the MVK gene, which encodes mevalonate kinase (MK), an essential enzyme in isoprenoid biosynthesis, cause the autoinflammatory metabolic disorder mevalonate kinase deficiency (MKD). We generated and characterized MK-deficient monocytic THP-1 cells to identify molecular and cellular mechanisms that contribute to the pro-inflammatory phenotype of MKD. Methods: Using CRISPR/Cas9 genome editing, we generated THP-1 cells with differentMK deficiencies mimicking the severe (MKD-MA) andmild end (MKD-HIDS) of the MKD disease spectrum. Following confirmation of previously established disease-specific biochemical hallmarks, we studied the consequences of the different MK deficiencies on LPS-stimulated cytokine release, glycolysis versus oxidative phosphorylation rates, cellular chemotaxis and protein kinase activity. Results: Similar to MKD patients' cells, MK deficiency in the THP-1 cells caused a pro-inflammatory phenotype with a severity correlating with the residual MK protein levels. In the MKD-MA THP-1 cells, MK protein levels were barely detectable, which affected protein prenylation and was accompanied by a profound pro-inflammatory phenotype. This included a markedly increased LPS-stimulated release of pro-inflammatory cytokines and a metabolic switch from oxidative phosphorylation towards glycolysis. We also observed increased activity of protein kinases that are involved in cell migration and proliferation, and in innate and adaptive immune responses. The MKD-HIDS THP-1 cells had approximately 20% residual MK activity and showed a milder phenotype, which manifested mainly upon LPS stimulation or exposure to elevated temperatures. Conclusion: MK-deficient THP-1 cells show the biochemical and proinflammatory phenotype of MKD and are a good model to study underlying disease mechanisms and therapeutic options of this autoinflammatory disorder. [ABSTRACT FROM AUTHOR]

ObjectiveBi-allelic pathogenic variants in the MVK gene, which encodes mevalonate kinase (MK), an essential enzyme in isoprenoid biosynthesis, cause the autoinflammatory metabolic disorder mevalonate kinase deficiency (MKD). We generated and characterized MK-deficient monocytic THP-1 cells to identify molecular and cellular mechanisms that contribute to the pro-inflammatory phenotype of MKD.MethodsUsing CRISPR/Cas9 genome editing, we generated THP-1 cells with different MK deficiencies mimicking the severe (MKD-MA) and mild end (MKD-HIDS) of the MKD disease spectrum. Following confirmation of previously established disease-specific biochemical hallmarks, we studied the consequences of the different MK deficiencies on LPS-stimulated cytokine release, glycolysis versus oxidative phosphorylation rates, cellular chemotaxis and protein kinase activity.ResultsSimilar to MKD patients’ cells, MK deficiency in the THP-1 cells caused a pro-inflammatory phenotype with a severity correlating with the residual MK protein levels. In the MKD-MA THP-1 cells, MK protein levels were barely detectable, which affected protein prenylation and was accompanied by a profound pro-inflammatory phenotype. This included a markedly increased LPS-stimulated release of pro-inflammatory cytokines and a metabolic switch from oxidative phosphorylation towards glycolysis. We also observed increased activity of protein kinases that are involved in cell migration and proliferation, and in innate and adaptive immune responses. The MKD-HIDS THP-1 cells had approximately 20% residual MK activity and showed a milder phenotype, which manifested mainly upon LPS stimulation or exposure to elevated temperatures.ConclusionMK-deficient THP-1 cells show the biochemical and pro-inflammatory phenotype of MKD and are a good model to study underlying disease mechanisms and therapeutic options of this autoinflammatory disorder.

Objective: This study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD). Methods: A total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR. Results: Three patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25–4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p < 0.05). The erythrocyte sedimentation rate normalized in 2 patients with AGS. The interferon score (IS) was remarkably decreased in 2 patients with SPENCD (p < 0.01). Catch-ups with growth and weight gain were observed in 3 and 2 patients, respectively. Lung lesions improved in 1 patient with SAVI and remained stable in 3 patients. Lymphopenia was found in 3 patients during the treatment without severe infections. Conclusion: The JAK inhibitors baricitinib and tofacitinib are promising therapeutic agents for patients with SAVI, AGS, and SPENCD, especially for the improvement of cutaneous lesions and febrile attacks. However, further cohort studies are needed to assess the efficacy and safety. [ABSTRACT FROM AUTHOR]

ObjectiveThis study aimed to assess the efficacy and safety of 2 Janus kinase (JAK) inhibitors (jakinibs) tofacitinib and ruxolitinib in the treatment of type I interferonopathies patients including STING-associated vasculopathy with onset in infancy (SAVI), Aicardi-Goutières syndrome (AGS), and spondyloenchondrodysplasia with immune dysregulation (SPENCD).MethodsA total of 6 patients were considered in this study: 2 patients with SAVI, 1 patient with AGS1, 1 patient with AGS7, and 2 patients with SPENCD. Clinical manifestations, laboratory investigations, radiology examinations, treatment, and outcomes were collected between November 2017 and November 2021 in Peking Union Medical College Hospital. The disease score for patients with SAVI and AGS scale for patients with AGS were documented. The expression of 6 interferon-stimulated genes (ISGs) was assessed by real-time PCR.ResultsThree patients (1 patient with SAVI, 2 patients with AGS) were treated with ruxolitinib and 3 patients (1 patient with SAVI, 2 patients with SPENCD) were treated with tofacitinib. The mean duration of the treatment was 2.5 years (1.25–4 years). Upon treatment, cutaneous lesions and febrile attacks subsided in all affected patients. Two patients discontinued the corticoid treatment. Two patients with SAVI showed an improvement in the disease scores (p

Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20.Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption.Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively).Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders.

Background: Haploinsufficiency A20 (HA20) is a newly described monogenic disease characterized by a wide spectrum of manifestations and caused by heterozygous mutations in TNFAIP3 which encodes A20 protein. TNFAIP3 mutation leads to disruption of the A20 ovarian tumor (OTU) domain and/or the zinc finger (ZnF) domain. This study aims at exploring the association between the various manifestations of HA20 and different domains disruption of A20. Methods: We reviewed the HA20 cases in previous literature and summarized the clinical features, TNFAIP3 mutation loci and the disrupted domains caused by different sites and patterns of mutations. Patients were classified into three groups according to the A20 domains disruption. Results: A total of 89 patients from 39 families with a genetic diagnosis of HA20 were included. Overall, the age at onset of HA20 was early (median:5.92, IQR:1-10). Patients in the ZnF group showed the earliest onset (median:2.5, IQR:0.6-5), followed by patients in the OTU+ZnF group (median:6, IQR:1-10) and patients in the OTU group (median:10, IQR:8-14). The main manifestations of HA20 patients were recurrent oral ulcers (70%), recurrent fever (42%), gastrointestinal ulcers (40%), skin lesion (38%), genital ulcers (36%), and musculoskeletal disorders (34%). The percentage of patients with musculoskeletal disorders was significantly different among the three groups (p = 0.005). Patients in the OTU+ZnF group and ZnF group were more likely to develop musculoskeletal disorders than patients in the OTU group (p = 0.002 and p = 0.035, respectively). Besides, forty-three percent of HA20 patients were initially diagnosed as Behcet's disease (BD). Compared to the ZnF group, the OTU+ZnF group and OTU group had a higher percentage of patients initially diagnosed as BD (p = 0.006 and p < 0.001, respectively). Conclusion: HA20 is characterized by early-onset and the most common symptoms of HA20 are recurrent oral ulcers, fever and gastrointestinal ulcers. The onset of HA20 in patients with the ZnF domain disruption is earlier than patients with the OTU domain disruption. Compared to the OTU domain, the ZnF domain may be more closely related to musculoskeletal disorders. [ABSTRACT FROM AUTHOR]

Autoinflammatory diseases were originally defined as a group of monogenic disorders associated with seemingly unprovoked inflammatory episodes mediated mainly by the innate immune system and without direct involvement of adaptive immunity. The renewed concept encompasses a larger group of disorders including multifactorial diseases, which share the same inflammatory and clinical features with the monogenic disorders. Coining of the “auto” prefix to these inflammatory diseases suggests a constitutively active and self-augmenting innate immune response, but only a subgroup of them including cryopyrin-associated periodic syndrome (CAPS), associated with dominantly inherited gain-of-function NLRP3 variants, fits well with the definition of the “autonomous” inflammatory conditions. However, the “autoinflammation” concept also includes another group of disorders characterized by episodes of exaggerated inflammatory response only when challenged by certain triggers. The dynamics of this latter group can be better defined as a “hyperinflammatory” state, which shares similar characteristics with the innate memory or trained immunity. Differentiation of “autonomous” and “hyperinflammatory” states of autoinflammatory disorders can provide additional insights to understand their pathogenesis and develop better management strategies since both conditions may have different inflammatory dynamics affecting the severity and frequency of clinical findings and treatment responses.

Autoinflammatory diseases were originally defined as a group of monogenic disorders associated with seemingly unprovoked inflammatory episodes mediated mainly by the innate immune system and without direct involvement of adaptive immunity. The renewed concept encompasses a larger group of disorders including multifactorial diseases, which share the same inflammatory and clinical features with the monogenic disorders. Coining of the "auto" prefix to these inflammatory diseases suggests a constitutively active and self-augmenting innate immune response, but only a subgroup of them including cryopyrin-associated periodic syndrome (CAPS), associated with dominantly inherited gain-of-function NLRP3 variants, fits well with the definition of the "autonomous" inflammatory conditions. However, the "autoinflammation" concept also includes another group of disorders characterized by episodes of exaggerated inflammatory response only when challenged by certain triggers. The dynamics of this latter group can be better defined as a "hyperinflammatory" state, which shares similar characteristics with the innate memory or trained immunity. Differentiation of "autonomous" and "hyperinflammatory" states of autoinflammatory disorders can provide additional insights to understand their pathogenesis and develop better management strategies since both conditions may have different inflammatory dynamics affecting the severity and frequency of clinical findings and treatment responses. [ABSTRACT FROM AUTHOR]