Pathogenesis, and Outcome of Autoinflammatory Diseases, NOMID/CAPS, DIRA, CANDLE, SAVI, NLRC4-MAS, Still's-like Diseases, and other Undifferentiated Autoinflammatory Diseases

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A. CHARACERIZATION OF THE NATURAL HISTROY OF SAIDs: 1. We follow patient cohorts with NOMID, DIRA, CANDLE and SAVI and are assessing biomarker changes on currently recommended treatment. 2. We continue to characterize the genetics and pathogenesis of NEMO-NDAS. 3. Our studies contributed to the development of treatment guidance documents for IL-1 mediated diseases, autoinflammatory interferonopathies including CANDLE and SAVI. B. DEVELOPMENT AND VALIDATION OF OUTCOME CRITERIA: We are developing modular outcomes for the treatment of autoinflammatory diseases with the goals to generate standardized outcomes that will be accepted for regulatory approval of targeted treatments. C. LONG-TERM OUTCOME AND SAFETY EVALUATION ON TARGETED TREATMENTS WE INITIATED. 1. NOMID is at the most severe spectrum of CAPS and the often-severe inflammatory CNS disease requires chronic high-dose treatment with anakinra to suppress inflammation. We observed the development of anakinra amyloidosis in patients on high dose treatment. The amyloidosis that develops locally at the site of injection can disseminate over time and involve the kidney. Patients need to be monitored and we are exploring alternatives to lower chronic anakinra doses. 2. We have described the benefit of JAK inhibition with the small molecule baricitinib in patients with CANDLE and SAVI (Sanchez GAM et al JCI 2019) and followed patients long-term to characterize the safety profile on ongoing treatment with baricitinib (Gedic K Arthritis Rheum abstract 2020). As we previously described the development of BK viruria and viremia, we monitor kidney function and hematologic parameters and have described disease flares with significant dose reductions thus validating the clinical regimen we proposed for the treatment of these patients (Gedic K Arthritis Rheum abstract 2021). D. CLINICAL AND GENETIC EVALUATION OF PATIENTS WITH EARLY-ONSET AUTOINFLAMMATORY DISEASES INCLUDING THE CHARACTERIZATION OF NOVEL AUTOINFLAMMATORY DISEASES Using trio whole exome sequencing: 1. We identified 3 patients with disease-causing mutations in Lyn kinase who presented with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation and two patients developed liver fibrosis in their first year of life. Functional studies revealed increased induced endothelial cells (iECs) activation and neutrophil adhesion and increased 2-integrin expression on patient neutrophils that resulted in increased neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis (De Jesus Nature Communications 2023) and expand the clinical spectrum of disease manifestations that cause autoinflammation. 2. We identified additional CANDLE-causing mutations in PSMA5 and POMP that cause CANDLE (Papendorf et al Frontiers Immunol. 2023). 3. We continue to evaluate and treat patients with severe inflammatory diseases that present early in infancy with highly elevated interferon signatures but yet unknown genetic mutations. All patients undergo a detailed immune evaluation that includes assessment of their assessed their IFN response gene signature, genetic analyses using next generation sequencing, (whole exome sequencing (WES) and/or whole genome sequencing (WGS). E. DEVELOPMENT AND VALIDATION OF BIOMARKERS THAT CHARACTERIZE THE IMMUNE DYSREGULATION AT BASELINE AND OVER TIME. 1. Our effort to identify the cellular sources of IFN production in blood and in human lesional biopsies is ongoing. We validated our 28 gene Type-I IFN gene expression profile in other monogenic and complex diseases including in pediatric patients with COVID-19 and expanded our ability to characterize and quantify NFKB activation and Type II IFN mediated inflammation (Sacco et al 2022). 2. In collaboration, our patient samples aided in unraveling the that linked proteasome mutations to type-I IFN production by establishing protein kinase R (PKR) as an innate immune sensor for proteotoxic stress by sensing the accumulation of cytoplasmic of IL-24 which is during stress is misfolded and egressed into the cytosol through the endoplasmic reticulumassociated degradation pathway (ERAD) and thus acts as danger-associated molecular pattern (DAMP) (Davidson et al. Science Immunol 2022). PKR also acts as rheostat for proteotoxic stress by triggering phosphorylation of eIF2, which can prevent the translation of new proteins to restore homeostasis. F. ASESSMENT OF THE IMPACT OF MONOCYTE AND MACROPHAGE DIFFERENTIATION ON PROINFLAMMATORY CYTOKINE PRODUCTION 1. We are profiling and assessing the immune dysregulation in monocytes from active NOMID and SAVI patients with the goal to identify markers of inflammasome and STING gain-of function mediated impacts on monocyte differentiation and function. G. USE OF IN VITRO CELL CULTURE SYSTEMS TO MODEL ORGAN-SPECIFIC IMMUNE DYSREGULATION AND ORGAN DAMAGE IN SELECTED AUTOINFLAMMATORY DISEASES. 1. In collaboration with Dr. Manfred Boehms group at NHLBI we model endothelial dysfunction in Lyn kinase-mediated inflammation in LAVLI (Harper R et al. Stem Cell Res 2022).