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

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

A. CHARACERIZATION OF THE NATURAL HISTROY OF SAIDs: 1. DIRA, CANDLE, SAVI: We have summarized the natural history of untreated DIRA and assessed long-term outcome on IL-1 inhibiting treatments. We are completing the long-term cohort study of CANDLE and SAVI patients to characterize the spectrum of inflammatory disease manifestations and accumulating organ damage, the impact on perinatal morbidity and mortality. We are assessing biomarker changes on currently recommended treatment. 2. We have identified female patients with NEMO-NDAS and are validating a bioinformatics pipeline to identify these patients whose mutations are masked by a pseudogene and remain undetected by WES. B. DEVELOPMENT AND VALIDATION OF OUTCOME CRITERIA: We have assessed various parameters as outcome in autoinflammatory diseases and have developed and validated the outcomes in the following areas for patients with DIRA and CANDLE: 1. parents/ patient outcomes, 2. remission, and 3. low disease activity. 4. Maintenance of a outcome inclusion of 5. growth and development parameters and 6. Ability to wean systemic glucocorticoids. These outcomes are used in the assessment of disease activity. C. LONG-TERM OUTCOME AND SAFETY EVALUATION ON TARGETED TREATMENT WITH JAK INHIBITROR BARICITINIB. 1. SAVI and CANDLE/PRAAS are genetically defined rare autoinflammatory interferonopathies that are caused by gain-of-function mutations in STING1 and in genes encoding proteasome components or proteasome assembly genes (PSMB8, PSMB4, PSMA3, PSMB9, PSMB10, PSMG2 and POMP). We have described the benefit of JAK inhibition with the small molecule baricitinib in patients with CANDLE and SAVI; patients require life-long treatment (Sanchez GAM et al JCI 2019). We follow 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 infections 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 All patients seen under this program undergo trio whole exome sequencing. 1. We identified 9 female patients with disease-causing mutations in the X-linked gene IKBKG encoding NEMO that result in NEMO exon5 deleted autoinflammatory syndrome (NEMO-NDAS) and developed a bioinformatics screening tool to identify disease-causing mutations that are undetected in current clinical WES/WGS analyses (De Jesus Arthritis Rheumatol Abstract 2021) and expand the clinical spectrum of disease manifestations. 2. We identified additional SAVI-causing mutations in STING1 that cause a milder disease phenotype and suggest novel disease-activating model of STING activation that may aid in the design of STING inhibiting treatments (Bin Lin et al Frontiers Immunol. 2021). 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). In that context we have identified novel Proteasome mutations that lead to severe forms of PRAAS. E. DEVELOPMENT AND VALIDATION OF BIOMARKERS THAT CHARACTERIZE THE IMMUNE DYSREGULATION AT BASELINE AND OVER TIME AND IDENTIFICATION OF THE CELLUAR SOURCES OF IFN OUR PATIENT COHORT. 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 patients with COVID-19 and expanded our ability to characterize and quantify NFKB activation and Type II IFN mediated inflammation (Abers et al 2020). 2. We are collaborating with Dr. Pascual on assessing the role of proteasome dysfunction on mitochondrial DNA retention in maturing erythrocytes as a source of IFN in severe SAVI patients. Caielli et al. described that the ubiquitin proteasome system (UPS), is necessary for the autophagic removal of mitochondria from maturing red blood cells. The retention of mitochondria in red blood cells triggers IFN production through STING sensing pathways in phagocytosing monocytes (Caielli et al. Cell 2021). While the source of interferon activation is likely complex, dissecting the various components to the IFN response is critical in understanding the sterile inflammation significantly contributed by IFN production. F. ASESSMENT OF THE IMPACT OF MONOCYTE AND MACROPHAGE DIFFERENTIATION ON PROINFLAMMATORY CYTOKINE PRODUCTION 1. We established a monocyte stimulation and monocyte derived macrophage differentiation assay in the IL-1 mediated diseases, Majeed syndrome, DIRA and NOMID and found that M2 differentiated cells from Majeed patient produce pro-inflammatory cytokines and chemokines that drive osteoclastogenesis and provide a model for bone inflammation in CRMO (Bhuyan et al Arthritis Rheumatol. 2021). 2. 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 and development of interstitial lung disease in patients with SAVI, who present with variable severity of interstitial lung disease ranging from being absent to severe. Complications from interstitial lung disease are the major cause of childhood mortality in SAVI. In addition to genetic modifying regions that are associated with the severity of lung disease, we characterize the complex downstream pathways that cause lung fibrosis with the goal to identify targets for the treatment of severe lung disease. THE NATURAL HISTORY PROTOCOL was developed for initial and follow-up evaluations of patients with autoinflammatory diseases. Affected participants (enrollment ceiling of n = 1000) are clinically evaluated and phenotyped at the NIH CC which includes state of the art radiologic molecular imaging. Research samples are collected and include blood, skin, saliva, urine, and CSF. Unaffected relatives and unrelated healthy volunteers (n = 500 of each) are enroll for the collection of control biological samples. All affected patients and their parents undergo genetic evaluation. The frequency of the follow-up visits is based on the participants clinical status and the scientific objective related to the patient's disease. We collect and store samples including DNA for comprehensive genetic analyses, RNA for gene expression profiling, serum, plasma and cells for biomarker analysis and biopsy material if left over from clinically indicated procedures. We generate fibroblast cells lines from selected patients, and we may generate iPSCs to model disease pathogenesis in organs and tissues. We obtain imaging to evaluate organs that are inflamed or damaged. THE COMPASSIONATE USE PROGRAM to treat CANDLE, SAVI and with other autoinflammatory interferonopathies with the JAK1/2 inhibitor baricitinib has been concluded, but safety assessment in all patients are ongoing.