The discovery of NLRP3 and its function in cryopyrin-associated periodic syndromes and innate immunity.

From studies of individual families to global collaborative efforts, the NLRP3 inflammasome is now recognized to be a key regulator of innate immunity. Activated by a panoply of pathogen-associated and endogenous triggers, NLRP3 serves as an intracellular sensor that drives carefully coordinated assembly of the inflammasome, and downstream inflammation mediated by IL-1 and IL-18. Initially discovered as the cause of the autoinflammatory spectrum of cryopyrin-associated periodic syndrome (CAPS), NLRP3 is now also known to play a role in more common diseases including cardiovascular disease, gout, and liver disease. We have seen cohesion in results from clinical studies in CAPS patients, ex vivo studies of human cells and murine cells, and in vivo murine models leading to our understanding of the downstream pathways, cytokine secretion, and cell death pathways that has solidified the role of autoinflammation in the pathogenesis of human disease. Recent advances in our understanding of the structure of the inflammasome have provided ways for us to visualize normal and mutant protein function and pharmacologic inhibition. The subsequent development of targeted therapies successfully used in the treatment of patients with CAPS completes the bench to bedside translational loop which has defined the study of this unique protein.

Isoliquiritigenin inhibits NLRP3 inflammasome activation with CAPS mutations by suppressing caspase-1 activation and mutated NLRP3 aggregation.

The nucleotide-binding oligomerization domain leucine-rich repeat and pyrin domain containing 3 (NLRP3) inflammasome contributes to the development of inflammatory diseases. Cryopyrin-associated periodic syndrome (CAPS) is an autoinflammatory disease caused by NLRP3 gene mutations that results in excessive IL-1ß production. We previously identified isoliquiritigenin (ILG), a component of Glycyrrhiza uralensis extracts, as a potent inhibitor of the NLRP3 inflammasome. Here, we aimed to investigate whether ILG inhibits the activation of NLRP3 inflammasome caused by NLRP3 gene mutations. We demonstrated that ILG significantly inhibited NLRP3 inflammasome-mediated lactate dehydrogenase (LDH) release and IL-1ß production in two CAPS model THP-1 cell lines, NLRP3-D303N and NLRP3-L353P, in a dose-dependent manner. Interestingly, the NLRP3 inhibitor MCC950 inhibited LDH release and IL-1ß production in NLRP3-D303N cells, but not in NLRP3-L353P cells. Western blotting and caspase-1 activity assays showed that ILG, as well as caspase inhibitors, including Z-VAD and YVAD, suppressed caspase-1 activation. Notably, ILG prevented cryo-sensitive foci formation of NLRP3 without affecting the levels of intracellular Ca2+. We concluded that ILG effectively prevents the constitutive activation of the inflammasome associated with NLRP3 gene mutations by inhibiting the aggregation of cryo-sensitive mutated NLRP3.

A novel Nlrp3 knock-in mouse model with hyperactive inflammasome in development of lethal inflammation.

NOD-like receptor family, pyrin domain-containing 3 (NLRP3) is a central protein contributing to human inflammatory disorders, including cryopyrin-associated periodic syndrome and sepsis. However, the molecular mechanisms and functions of NLRP3 activation in various diseases remain unknown. Here, we generated gain-of-function knock-in mice associated with Muckle-Wells syndromes using the Cre-LoxP system allowing for the constitutive T346M mutation of NLRP3 to be globally expressed in all cells under the control of tamoxifen. The mice were treated with tamoxifen for 4 days before determining their genotype by PCR and sequence analysis. In vitro, we found that bone marrow-derived macrophage from homozygous T346M mutation mice displayed a robust ability to produce IL-1ß in response to lipopolysaccharide exposure. Moreover, ASC specks and oligomerization were observed in the homozygous mutant bone marrow-derived macrophages in the presence of lipopolysaccharides alone. Mechanistically, K+ and Ca2+ depletion and mitochondrial depolarization contribute to the hyperactivation of mutant NLRP3. In vivo, homozygous mice carrying the T346M mutation exhibit weight loss and mild inflammation in the resting state. In the lipopolysaccharide-mediated sepsis model, homozygous mutant mice exhibited higher mortality and increased serum circulating cytokine levels, accompanied by serious liver injury. Furthermore, an increase in myeloid cells in the spleen has been suggested to be a risk factor for inducing sepsis sensitivity. Altogether, we describe a cryopyrin-associated syndrome animal model with the T346M mutation of NLRP3 and suggest that the hyperactivated inflammasome aggregated by the mutant NLRP3 lowers the inflammatory response threshold both in vitro and in vivo.

Refining Treat-to-Target (T2T) strategies in Cryopyrin-Associated Periodic Syndromes (CAPS): The role of inflammatory markers.

OBJECTIVES: Cryopyrin-Associated Periodic Syndromes (CAPS) encompasses a spectrum of Interleukin-1 (IL-1) driven systemic diseases with dramatic individual and societal burden. The study aimed to identify parameters and instruments to refine real-life Treat-to-Target (T2T) strategies and control CAPS disease activity. METHODS: A single-centre, longitudinal study of consecutive children and adults diagnosed with CAPS and treated with anti-IL-1 therapy was performed. Demographics, clinical phenotype and NLRP3 gene variants in addition to serial inflammatory markers and Physician and Patient/Parent Global Assessments (PGA/PPGA) were captured. Effectiveness of anti-IL-1 T2T strategies and factors associated with therapy escalation were determined. RESULTS: A total of 54 CAPS patients with 759 follow-up visits were included; 31/54 (57%) were children; the median follow-up was 108 months (12-620). The moderate CAPS phenotype was present in 89%; overall 59% had pathogenic/likely pathogenic NLRP3 variants. Therapy adjustments were documented in 50/759 visits including 35 therapy escalations and 15 reductions; 74% of the therapy escalation visits were for children. At time of visit, 63% showed moderate, 37% severe clinical disease activity. Inflammatory markers remained largely normal. Significant improvement was observed in both PGA/PPGA throughout the study (p< 0.01). At the last follow-up, 96% of patients achieved remission. CONCLUSION: Guidance for refining real-life T2T strategies in CAPS cohorts can be drawn from serial assessments of PGA and PPGA reliably reflecting changes in disease activity. Individual parameters including age and NLRP3 gene variants are important predictors, while the sensitivity of inflammatory markers is limited due to the confounding anti-IL-1 therapy.

Clinical presentation and genetic variants in patients with autoinflammatory diseases: results from the German GARROD registry.

To investigate clinical symptoms and genetic variants in patients from the German anti-IL-1 registry for autoinflammatory orphan diseases (GARROD) between 2013 and 2022. Multicentre, retrospective analysis of demographic, clinical and genetic data of patients with autoinflammatory diseases (AID) who received anti-IL-1 targeted therapy. The cohort comprised 152 patients with familial Mediterranean fever (FMF; n = 71), cryopyrin-associated periodic syndromes (CAPS; n = 43), TNF-receptor associated periodic syndrome (TRAPS; n = 19), mevalonate kinase deficiency (MKD; n = 3) and unclassified AID (uAID; n = 16). Inflammatory attacks started in 61.2% of the patients before the age of 18 years. The delay between the first AID attack and anti-IL-1 therapy was 17.8 years. Monogenetic AIDs were diagnosed by clinical symptoms. Genetic analyses confirmed the diagnosis in 87.3% of patients with FMF, 65.2% with CAPS and 94.8% with TRAPS. Among this group, heterozygous MEFV variants and variants of unknown significance (VUS) were detected in 22.5% of patients with FMF, 51.2% with CAPS and 47.4% with TRAPS. Patients with VUS were older at disease onset which is consistent with a milder phenotype. Twenty-four patients had secondary AA amyloidosis (AA) at initiation of anti-IL-1 therapy. The mean age of these patients was 16.4 years at their first attack and 44.9 years at the time of AA diagnosis. Turkish-Armenian ancestry correlated with MEFV variants and higher FMF disease activity compared to German ancestry. Molecular genetic analyses should substantiate the clinical diagnosis of a monogenetic AID. Our data support the concept of variable penetrance of VUS which can be associated with late-onset AID.

[The most frequent febrile syndromes and autoinflammatory diseases in adulthood]. / Die häufigsten Fiebersyndrome und autoinflammatorischen Erkrankungen im Erwachsenenalter.

Autoinflammatory diseases are characterized by inflammatory manifestations in various organ systems, whereby recurrent febrile episodes, musculoskeletal complaints, gastrointestinal and cutaneous symptoms frequently occur accompanied by serological signs of inflammation. Autoinflammatory diseases include rare monogenic entities and multifactorial or polygenic diseases, which can manifest as a variety of symptoms in the course of time. Examples of monogenic autoinflammatory diseases are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor (TNF) receptor-associated periodic syndrome (TRAPS) and the recently described VEXAS (vacuoles, E1 enzyme, X­linked, autoinflammatory and somatic) syndrome. For non-monogenically determined autoinflammatory diseases, the most important representatives in adulthood are adult-onset Still's disease (AOSD) and the Schnitzler syndrome, in which a polygenic susceptibility and epigenetic factors are more likely to play a role.

Phenotypic and genotypic characterization of Chinese adult patients with NLRP3­associated autoinflammatory disease with hearing loss.

OBJECTIVES: Nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3-associated autoinflammatory disease (NLRP3-AID) is a rare autosomal dominant systemic autoinflammatory disease. We aimed to summarize the phenotypic and genotypic features of Chinese adult NLRP3-AID patients with hearing loss. METHODS: A retrospective cohort study of twenty-one adult patients with NLRP3-AID was conducted in Peking Union Medical College Hospital between July 2015 and March 2023. All patients underwent whole exome sequencing and otorhinolaryngologic assessments. Clinical features and therapeutic data were collected and analyzed. RESULTS: We found that 13/21 (61.90%) of patients had hearing loss with high-frequency impairment in the majority, and most patients presented with vestibular dysfunction as a new finding. The NLRP3-AID patients with early-onset, cold or stress triggered episodes, red eyes, fatigue, hypopsia and mutations located in the NACHT domain of the NLRP3 protein were more likely to suffer from hearing loss, especially sensorineural hearing loss, perhaps as a result of pathogenic variants of high penetrance. By a series of audiological evaluations, tumor necrosis factor (TNF)-α inhibitors were confirmed to improve or reverse hearing loss. CONCLUSIONS: We reported the first cohort of Chinese adult NLRP3-AID patients with hearing loss and characterized vestibular dysfunction, highlighted the necessity for attention to high-frequency hearing, and provided potential alternative treatment.

AA amyloidosis complicating cryopyrin-associated periodic syndrome: a study of 86 cases including 23 French patients and systematic review.

OBJECTIVE: Cryopyrin-associated periodic syndrome (CAPS) is a rare but treatable inherited autoinflammatory condition including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and chronic infantile neurologic cutaneous articular syndrome (CINCA). Our objective was to describe the main features of CAPS AA amyloidosis (AA-CAPS) associated and the efficacy of IL-1 inhibitors in this indication. METHODS: Retrospective study in France associated with a systematic literature review. RESULTS: Eighty-six patients were identified: 23 new French cases and 63 from the literature, with a median age at amyloidosis diagnosis of 39 years old. CAPS subtypes were MWS (n = 62), FCAS (n = 9), frontier forms between MWS and FCAS (n = 12) and between CINCA and MWS (n = 3). NLRP3 had been sequenced in 60 patients (70%) and the most frequent mutation was R260W (60%). Three AA-CAPS patients displayed somatic NLRP3 mutations. Death occurred in 35 patients (41%), none of whom having ever received IL-1 inhibitors. Twenty-eight patients (33%) received IL-1 inhibitors, with a >50% decrease in proteinuria in 89% of cases. CONCLUSION: AA amyloidosis can occur in nearly all CAPS subtypes. IL-1 inhibitors are effective, underlining the necessity of an early diagnosis of CAPS in order to start this treatment as soon as possible among AA-CAPS patients.

Evolution, role in inflammation, and redox control of leaderless secretory proteins.

Members of the interleukin (IL)-1 family are key determinants of inflammation. Despite their role as intercellular mediators, most lack the leader peptide typically required for protein secretion. This lack is a characteristic of dozens of other proteins that are actively and selectively secreted from living cells independently of the classical endoplasmic reticulum-Golgi exocytic route. These proteins, termed leaderless secretory proteins (LLSPs), comprise proteins directly or indirectly involved in inflammation, including cytokines such as IL-1ß and IL-18, growth factors such as fibroblast growth factor 2 (FGF2), redox enzymes such as thioredoxin, and proteins most expressed in the brain, some of which participate in the pathogenesis of neurodegenerative disorders. Despite much effort, motifs that promote LLSP secretion remain to be identified. In this review, we summarize the mechanisms and pathophysiological significance of the unconventional secretory pathways that cells use to release LLSPs. We place special emphasis on redox regulation and inflammation, with a focus on IL-1ß, which is secreted after processing of its biologically inactive precursor pro-IL-1ß in the cytosol. Although LLSP externalization remains poorly understood, some possible mechanisms have emerged. For example, a common feature of LLSP pathways is that they become more active in response to stress and that they involve several distinct excretion mechanisms, including direct plasma membrane translocation, lysosome exocytosis, exosome formation, membrane vesiculation, autophagy, and pyroptosis. Further investigations of unconventional secretory pathways for LLSP secretion may shed light on their evolution and could help advance therapeutic avenues for managing pathological conditions, such as diseases arising from inflammation.

Multiple sclerosis in a patient with cryopyrin-associated autoinflammatory syndrome: Evidence that autoinflammation is the common link.

The co-existence of an autoinflammatory syndrome with a demyelinating disorder is a very rare occurrence raising the question whether there is a pathophysiological connection between them. We describe the case of a man with symptoms of cryopyrin-associated periodic syndrome (CAPS) since infancy who later developed multiple sclerosis (MS). As CAPS was genetically confirmed, the inhibition of interleukin-1 (IL-1) with anakinra led to a swift resolution of the CAPS symptoms and also, in combination with teriflunomide, to a clinical and imaging improvement of MS. In vitro studies showed that, upon a CAPS flare, the patient's peripheral neutrophils released neutrophil extracellular traps (NETs) decorated with IL-1ß, while NET release was markedly decreased following anakinra-induced remission of CAPS. Taking into account the growing evidence on the involvement of IL-1ß in experimental models of MS, this rare patient case suggests that the role of neutrophils/NETs and IL-1ß in MS should be further studied.

Otological aspects of NLRP3-related autoinflammatory disorder focusing on the responsiveness to anakinra.

OBJECTIVES: Gradually progressive sensorineural hearing loss (SNHL) is a prevalent sensory defect. It is generally untreatable, making rehabilitation by hearing aid or cochlear implantation the only option. However, SNHL as one of the symptoms of the hereditary autoinflammatory systemic disease cryopyrin-associated periodic syndrome, or as the only symptom of the cochlea-specific form (DFNA34), was suggested to respond to IL-1 antagonist (anakinra) therapy, which ameliorates NLRP3 variants-induced over-secretion of IL-1ß. We analysed genotypic and phenotypic spectrum of cryopyrin-associated periodic syndrome or DFNA34, specifically focusing on the responsiveness of SNHL to anakinra. METHODS: Seventeen families diagnosed with either cryopyrin-associated periodic syndrome or DFNA34 were recruited. Genotyping and phenotyping including audiogram, MRI findings, and in vitro IL-1ß assay were performed. RESULTS: Our cohort had an etiologic homogeneity of 94.1% to NLRP3 variants and a high de novo occurrence (84.6%). We identified the second DNFA34 pedigree worldwide with a novel NLRP3 variant supported by in vitro analysis. Significant improvement of hearing status against the natural course, showing response to anakinra, was identified in three probands, one of whom used to have severe SNHL. Hearing threshold worse than 60 dB at the start of anakinra and cochlear enhancement on brain MRI seemed to be related with poor audiologic prognosis and responsiveness to anakinra therapy despite stabilized systemic symptoms and inflammatory markers. CONCLUSION: We propose a constellation of biomarkers comprising NLRP3 genotypes, hearing status at diagnosis, and cochlear radiological findings as prognostic factors of hearing status after anakinra treatment and possibly as sensitive parameters for treatment dosage adjustment.

Validation of the new classification criteria for hereditary recurrent fever in an independent cohort: experience from the JIR Cohort Database.

OBJECTIVE: The new classification criteria for the hereditary recurrent fever (HRF) syndrome [cryopyrin-associated periodic syndrome (CAPS), TNF-α receptor-associated periodic syndrome (TRAPS), FMF and mevalonate kinase deficiency] have been published recently. These criteria define two core sets of criteria for each HRF: mixed criteria, including genetic and clinical variables, and clinical criteria, relying on clinical variables only. Our aim was to validate the criteria for HRF in an independent cohort, the JIR Cohort database, an international repository of systemic inflammatory diseases. METHODS: We enrolled patients with HRF, periodic fever, adenitis, pharyngitis and aphthous stomatitis syndrome (PFAPA) and syndrome of undefined recurrent fever (SURF). A score ranging from zero to two was attributed to their respective genotypes: zero (no mutation), one (non-confirmatory genotype) or two (confirmatory genotype). The criteria were applied to all patients based on genotype scoring. The treating physician's diagnosis served as the gold standard for the determination of specificity. RESULTS: We included 455 patients. The classification criteria showed excellent specificity for CAPS and TRAPS (98% specificity each), fair specificity for FMF (88%), but poor specificity for mevalonate kinase deficiency (58%). Sub-analysis showed excellent accuracy of the mixed criteria for all four HRFs. Misclassification was mainly attributable to clinical criteria sets, with false-positive patients in all four HRF clinical criteria sets. CONCLUSION: This study represents the final validation step of the HRF classification criteria as recommended by the ACR. Genetic data appear to be necessary to classify patients with HRF correctly.

Recognising and understanding cryopyrin-associated periodic syndrome in adults.

Cryopyrin-associated periodic syndrome (CAPS) is a group of rare hereditary autoinflammatory diseases characterised by recurrent flares of mild to severe systemic inflammation and fever. CAPS is the umbrella term for a spectrum of individual conditions, namely familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS) and neonatal-onset multisystem inflammatory disease (NOMID), also known as chronic infantile neurologic, cutaneous and articular (CINCA) syndrome. The flare symptoms include fever, fatigue, rashes, headaches, arthralgia and myalgia that can last for a few hours or for several days. These symptoms are debilitating, contributing to poor quality of life for patients if left untreated. Serious life-changing complications such as hearing loss, blindness and AA amyloidosis resulting in kidney failure can occur. Until recently, treatment of the disease was symptomatic using non-steroidal anti-inflammatory and immunosuppressant drugs with limited success. In contrast, biological treatments targeting interleukin 1 (IL-1) have proved remarkably effective, often associated with complete and sustained disease remission, vastly improved quality of life and avoidance of serious long-term complications.

Cryopyrin-associated periodic syndrome in early childhood can be successfully treated with interleukin-1 blockades.

Cryopyrin-associated periodic syndrome (CAPS) is caused by a mutation in the NLRP3 gene encoding cryopyrin production. Overproduction of interleukin-1 (IL-1) leads to symptoms that are associated with elevated inflammatory markers, including periodic fever and a rash. We provide a clinical overview of CAPS in children, including three Finnish case studies. CONCLUSION: When CAPS has been diagnosed, an IL-1 blockade with biological should be introduced to lessen the symptoms and to prevent the progression of organ damage.

Neonatal urticaria: Could it be CAPS?

A neonatal boy presented with a persistent urticarial rash. Initial investigations showed raised inflammatory markers and evidence of systemic inflammation. A working diagnosis of cryopyrin-associated periodic syndrome (CAPS) was made, and the patient responded extremely well to Anakinra. Molecular genetic testing revealed a somatic mutation (affecting 12.5% of cells) in the NLRP3 gene, accounting for the persistent inflammatory state but milder phenotype as seen in our patient.

[Renal amyloidosis revealing a cryopyrin associated periodic syndrome]. / Amylose rénale faisant découvrir un syndrome périodique associé à la cryopyrine.

INTRODUCTION: Cryopyrin associated periodic syndrome is a rare auto inflammatory disease including three clinical entities with a common genetic cause. Among these three entities, Muckle-Wells syndrome is described as an intermediate phenotype associated with a progressive sensorineural hearing loss and AA amyloidosis. The present case reports a renal AA amyloidosis associated with an IgA nephropathy, revealing a Muckle-Wells syndrome. OBSERVATION: The case is reported of a 38-years-old patient who presented a renal failure revealed concomitantly with a macroscopic hematuria exploration. Urological investigations were performed with negative results. The patient had no particular background except urticarial rashes, unlabeled inflammatory rheumatism and a grandmother's amyloidosis. Renal biopsy revealed glomerular, vascular and interstitial AA amyloidosis associated to an IgA nephropathy. This amyloidosis was known to be a part of Muckle-Wells syndrome, and a NLRP3 gene study confirmed the diagnosis. CONCLUSION: Cryopyrin associated periodic syndrome is a rare disease and the clinical diagnosis suspicion need genetic confirmation. AA amyloidosis is known to happen in Muckle-Wells syndrome. Other occasional renal impairments are described in this syndrome whereas the IgA nephropathy association remains poorly characterized.

Real-life effectiveness of canakinumab in cryopyrin-associated periodic syndrome.

OBJECTIVE: Cryopyrin-associated periodic syndrome (CAPS) is a heterogeneous group of diseases characterized by excessive IL-1ß release resulting in severe systemic and organ inflammation. Canakinumab targets IL-1ß and is approved at standard dose for children and adults with all CAPS phenotypes. Limited data are available for the real-life effectiveness of canakinumab in patients living with CAPS. Therefore the aim of the study was to evaluate the real-life dosing and effectiveness of canakinumab in CAPS. METHODS: A multi-centre study of consecutive children and adults with CAPS treated with canakinumab was performed. Demographics, CAPS phenotype and disease activity, inflammatory markers and canakinumab treatment strategy were recorded. Treatment response was assessed using CAPS disease activity scores, CRP and/or serum amyloid A levels. Comparisons between age groups, CAPS phenotypes and centres were conducted. RESULTS: A total of 68 CAPS patients at nine centres were included. All CAPS phenotypes were represented. Thirty-seven (54%) patients were females, the median age was 25 years and 27 (40%) were children, and the median follow-up was 28 months. Overall, complete response (CR) was seen in 72% of CAPS patients, significantly less often in severe (14%) than in mild CAPS phenotypes (79%). Only 53% attained CR on standard dose canakinumab. Dose increase was more commonly required in children (56%) than in adults (22%). Centres with a treat-to-target approach had significantly higher CR rates (94 vs 50%). CONCLUSION: Real-life effectiveness of canakinumab in CAPS was significantly lower than in controlled trials. Treat-to-target strategies may improve the outcome of children and adults living with CAPS.

Pathogenesis of systemic inflammatory diseases in childhood: "Lessons from clinical trials of anti-cytokine monoclonal antibodies for Kawasaki disease, systemic onset juvenile idiopathic arthritis, and cryopyrin-associated periodic fever syndrome".

Inflammation has often been considered to be a nonspecific response and to play a bridging role in the activation of adaptive immunity. However, it is now accepted that inflammation is the product of an independent innate immune system closely linked to the adaptive immune system. The key mediators of inflammation are inflammatory cytokines, as determined by multiple lines of evidence both in vitro and in vivo. Due to the crucial role of inflammatory cytokines in the pathogenesis of autoimmune disorders, anti-cytokine treatment has been developed as a therapy for rheumatoid arthritis, juvenile idiopathic arthritis (JIA), and inflammatory bowel diseases. We recently completed several clinical trials of anti-cytokine treatment for children with systemic inflammatory diseases: anti-IL-6 receptor monoclonal antibody (tocilizumab) for children with two subtypes of JIA (poly-JIA and systemic JIA), anti-TNF-α monoclonal antibody (infliximab) for children with Kawasaki disease, and anti-IL-1-ß monoclonal antibody (canakinumab) for children with cryopyrin-associated periodic syndrome. This review summarizes the basis of inflammation in terms of innate immunity and adaptive immunity in these systemic inflammatory diseases, clinical efficacy, and tolerability of these biologic agents, and attempts to determine the roles of individual inflammatory cytokines in disease pathogenesis.

Coexistence of systemic sclerosis and cryopyrin-associated periodic syndrome.

Systemic sclerosis (SSc) and cryopyrin-associated periodic syndrome (CAPS) are distinct clinical entities belonging to the autoimmune and autoinflammatory diseases, respectively. The coexistence of the two entities has rarely been reported and is poorly characterized. Here, we described a case of a 38-year-old Japanese woman diagnosed with anti-centromere antibody-positive SSc and CAPS carrying the pathogenic mutation in the NLRP3 gene, with a detailed autoantibody profile by a high-throughput comprehensive protein array covering approximately 90% of the human transcriptome. The clinical manifestations of the patient were typical of both SSc and CAPS. Comprehensive autoantibody profiling identified 65 autoantibodies in the patient's serum and 78 autoantibodies in the serum of her daughter with CAPS, who carried the same NLRP3 mutation as the patient. SSc-associated autoantibodies (anti-DBT, anti- CENP-B, and anti-CENP-A) and anti-CD320 antibody were detected at high levels only in the patient's serum, while autoantibodies to the following four proteins were detected in the sera of both the patient and her daughter: TRIM21, LIMS1, CLIP4, and KAT2A. The TRRUST enrichment analysis identified NF-κB1 and RelA as overlapping key transcription factors that regulate the genes encoding proteins to which autoantibodies were detected in the patient and her daughter, therefore the autoantibody profile of the patient cannot be solely attributed to SSc, but may also be influenced by CAPS. Although autoimmune and autoinflammatory diseases are considered to be at opposite ends of the immunological spectrum, detailed autoantibody profiling may reveal a unique immunological landscape in an overlapping case of the two entities.