Pathogenesis Of Novel Autoinflammatory Diseases Caused By Mutations In IL-1R1 And PSMD12

Autoinflammatory diseases（AIDs）are a group of heterogeneous disorders characterized by systemic inflammation and primarily driven by the innate immune system.Genetic factors play a significant role in their development,leading to the classification of AIDs into monogenic and polygenic forms.Since the identification of MEFV that caused familial Mediterranean fever,the causative genes for over 50 AIDs have been reported,which broaden our understandings of AIDs.However,due to their clinical heterogeneity,including periodic fever,rash,hepatosplenomegaly,arthritis,vasculitis,there is a lack of clear diagnostic features,leading to many patients been undiagnosed or misdiagnosed.The discovery of causative genes and their pathogenesis for undiagnosed AIDs have always been the research focus,as well as the prerequisite for precision diagnosis and treatment.Through bioinformatics analysis,our research discovered new pathogenic genes and clinical phenotypes of undiagnosed AIDs.We investigated the pathogenesis,and applied targeted therapy for the patient,which can provide guidance for genetic diagnosis for more undiagnosed AIDs patients.In project one,we identified a novel IL-1R1 Lys131Glu mutation that caused chronic recurrent multifocal osteomyelitis（CRMO）.IL-1R1 is a key molecule that transmits IL-1 signals and mediates systemic inflammation.We observed increased expression levels of inflammatory cytokines in the patient’s serum and peripheral blood mononuclear cells（PBMCs）,as well as significant activation of NF-κB and MAPK pathways mediated by IL-1R1.We demonstrated that the mutation disrupted the binding of IL-1R1 to its antagonist ligand IL-1Ra,without affecting IL-1α/βbinding,leading to sustained activation of IL-1 signaling pathway.The Il1r1^R134E/R134Emice were sensitive to collagen antibody-induced arthritis,with elevated osteoclast differentiation and disrupted bone metabolism.We applied anti-IL-1βtreatment canakinumab to the patient based on the pathogenesis,and achieved significant therapeutic effects.In project two,we identified a PSMD12 Arg289*mutation that caused PSMD12haploinsufficiency in a family with neurodevelopmental diseases and AIDs.The two patients mainly showed growth retardation,intellectual disability,as well as uveitis and rash.Abnormal proteasome assembly and activity were observed in both patients’PBMCs and PSMD12 knock-down cells.Proteasome defects were reported to cause activation of type I IFN.And the patints’monocytes were identified as pro-inflammatory source with high expression of IFN-related genes,suggesting the clinical feasibility of using JAK inhibitors to treat inflammations in the patients.In summary,we identified a novel AID caused by IL-1R1 K131E and applied successful targeted therapy,and the first case of an AID resulting from PSMD12haploinsufficiency.These discoveries broaden our knowledge of AIDs,which are expected to improve the clinical diagnostic efficiency,guide the implementation of targeted therapy,and provide novel insights for future AID diagnosis and treatment.Highlights:1.Identified pathogenic genes and deciphered molecular mechanisms in two families,enabling targeted treatment for one patient and inspiring potential therapies for similar patient populations,completing a research cycle that benefits patients from a patient-centric perspective.2.Discovered an IL-1R1 K131 E mutation that caused a novel AID.Elucidated the mechanism of CRMO phenotype in the patient resulting from the inability of IL-1R1 and IL-1Ra interaction.And applied successful targeted treatment with canakinumab based on the pathogenesis.3.Identified the first case of an AID with elevated IFN that caused by haploinsufficiency of the 19 S proteasome subunit PSMD12,which broadened the spectrum of human disease phenotypes associated with PSMD12 mutations.