クリオピリン関連周期熱症候群

BACKGROUND: AA amyloidosis (AAA) remains a life-threatening yet largely preventable complication of monogenic autoinflammatory diseases (AIDs). METHODS: We retrospectively described patients with AAA secondary to one of the four historical monogenic AIDs (familial Mediterranean fever [FMF], cryopyrin-associated periodic syndrome [CAPS], mevalonate kinase deficiency [MKD] and tumour necrosis factor receptor-associated periodic syndrome [TRAPS]) followed at the French National Referral Centre for Monogenic AIDs and Inflammatory Amyloidosis (2012-2025). RESULTS: Among 181 patients followed for AAA, 50 (28%) had one of the four monogenic AIDs (FMF n = 41, CAPS n = 4, MKD n = 3, TRAPS n = 2), corresponding to an overall prevalence of 5% among all patients with monogenic AIDs. AAA preceded the diagnosis of the underlying AID in 40% of patients, particularly those with non-FMF diseases. Disease burden remained high, with 46% of patients requiring kidney transplantation, whereas mortality reached 26% during follow-up. CONCLUSION: AAA continues to reflect delayed diagnosis, highlighting the need for increased awareness among adult healthcare providers, systematic genetic evaluation of unexplained AAA and early inflammatory control.

The spectrum of syndromes associated with chronic urticaria (CU) is broad, ranging from monogenic autoinflammatory diseases (a single gene defect drives disease through dysregulated innate immunity) to multifactorial and acquired conditions (urticaria arises as part of a broader, polygenic or immune-mediated systemic process). Monogenic autoinflammatory conditions presenting with urticaria include cryopyrin-associated periodic syndromes (CAPS)-encompassing familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and neonatal-onset multisystem inflammatory disease (NOMID/CINCA) and the broader group of familial cold urticarias. Monogenic conditions with well-characterized gain-of-function NLR family pyrin domain containing 3 (NLRP3) variants present with recurrent hives, a cardinal feature associated with recurrent fevers. Multifactorial and acquired autoinflammatory or immune-mediated conditions include Schnitzler syndrome, adult-onset Still's disease, hypereosinophilic syndrome, Gleich syndrome, Wells syndrome, and Sjögren syndrome. Multifactorial conditions, including Schnitzler syndrome and Still's disease, manifest similarly, with CU as an initial sign and a shared pathogenic mechanism of innate immune dysregulation, with interleukin-1β playing a central, pro-inflammatory role as a major pyrogen. Here, we also present a female patient with clinically established Andersen-Tawil syndrome (ATS) who developed recurrent hives on her extremities within minutes after vigorous exercise. To our knowledge, this is the first report of a co-occurrence of CU and ATS. The hives were successfully attenuated by oral intake of effervescent potassium chloride during physical activity. This observation raises the possibility that chronic inducible urticaria may represent a previously unrecognized cutaneous ATS manifestation and suggests a potential pathophysiological link between potassium-channel dysfunction and mast cell activation. Distinguishing whether hives are an isolated symptom or part of a broader syndrome is critically important, as it might be crucial for the patient outcome.

OBJECTIVES: Cogan's syndrome (CS) is a rare variable vessel vasculitis, describing sensorineural hearing loss (SNHL), inflammatory ocular disease and vestibular dysfunction. We hypothesized that within paediatric-onset (p)CS, a proportion would have monogenic disease, either autoinflammatory and/or associated with SNHL. METHODS: Whole exome sequencing (WES) was performed and analysed using an in-house pipeline incorporating virtual gene panels for inflammation and SNHL; copy number variant analysis (ExomeDepth); and phenotype-driven variant prioritization (Exomiser). Genetic variants were interpreted by a multi-disciplinary team according to American College of Medical Genetics and Genomics guidelines. RESULTS: Ten patients with a clinical diagnosis of pCS were enrolled. Three/10 (30%) had a monogenic contribution to the phenotype based on Class 4/5 variants: de novo NLRP3 p.T915R (n = 1) associated with Cryopyrin-associated periodic syndrome; MYO7A p.K542Qfs*5 (n = 1) causing SNHL; and HBB homozygous p.E7V causing sickle cell disease (associated with hearing loss and uveitis). A further two cases had possible monogenic contribution with the following rare variants of uncertain significance (class 3): ADGRV1 compound heterozygous variants (n = 1) associated with Usher syndrome; and a novel ALPK1 p.H735P (n = 1), associated with Retinal dystrophy Optic nerve oedema Splenomegaly Anhidrosis Headache (ROSAH) syndrome. CONCLUSIONS: In children presenting with features suggesting CS, genetic screening should be considered before conferring this rare diagnostic label since at least 30% had an alternative monogenic contribution to the phenotype rather than true pCS, with implications for treatment and prognosis. We thus advocate for genetic testing using next-generation sequencing for patients presenting with pCS.

Trained immunity, an innate immunological memory induced by epigenetic and metabolic reprogramming, has changed the paradigm of host defense and pathogenesis of chronic inflammatory disease. Unlike adaptive immunological memory, trained immunity is characterized by the ability of innate immune cells and their progenitors to respond more robustly or differently to subsequent stimulations and contributes to chronic inflammatory conditions. Emerging data suggests that this process might be essential in autoinflammatory and immune-mediated inflammatory illnesses by enhancing sterile inflammation, decreasing activation thresholds, and boosting disease chronicity. This narrative review summarizes the existing evidence relating trained immunity to monogenic and polygenic autoinflammatory diseases. The greatest evidence in monogenic disease is for mevalonate kinase deficiency, where dysregulated mevalonate metabolism directly overlaps with conventional trained immunity pathways. Moderate evidence exists for familial Mediterranean fever, cryopyrin-associated periodic syndromes, and tumor necrosis factor receptor-associated periodic syndrome. For other rare hereditary autoinflammatory diseases, data are still inadequate. There is convincing evidence for a role of trained immunity in polygenic disorders like gout, atherosclerosis, obesity-associated "metaflammation", and type 2 diabetes and increasing evidence in Behçet's disease, adult-onset Still's disease, psoriasis, hidradenitis suppurativa, inflammatory bowel disease, and related inflammatory spectrum disorders. A major conceptual finding is that autoinflammatory illnesses may be a dynamic interplay between hereditary susceptibility and dysfunctional innate immune memory, rather than isolated static inflammatory abnormalities. However, information gaps still exist in reprogramming at the progenitor level, disease-specific epigenetic markers, and the reversibility of trained states. Understanding these systems may allow the development of therapeutic techniques to de-train abnormal innate immunological memory and obtain resilience for diseases.

The NLRP3 inflammasome plays an important role in the innate immune system that mediates caspase-1 activation and the subsequent secretion of the pro inflammatory cytokines IL-1β and IL-18 in response to microbial infections and cellular stress. Aberrant activation of the NLRP3 inflammasome has been implicated in a range of inflammatory and metabolic disorders, including cryopyrin-associated periodic syndromes (CAPS), Alzheimer's disease, type 2 diabetes, and atherosclerosis. NLRP3 activation can be triggered by diverse stimuli and involves multiple cellular events, such as ionic flux, mitochondrial dysfunction, reactive oxygen species (ROS) generation, and lysosomal damage. A critical regulator of NLRP3 activation is NEK7, a serine/threonine kinase also known for its role in mitotic spindle formation and cytokinesis. Structurally, NEK7 exhibits a partially assembled regulatory spine (R-spine), consistent with an inactive kinase state. However, a mutant form of NEK7 engineered to stabilize the R-spine retains catalytic activity and has been crystallized in complex with compound 51- an ATP-competitive, small-molecule chemical inhibitor that targets both NEK2 and NEK7. Interestingly, wild-type NEK7 crystallized in both apo form and with compound 51 showed variable R-spine conformations, while NEK7 displayed a uniform, partially stacked R-spine configuration. Despite the structural similarity in compound 51 binding between NEK2 and NEK7, subtle differences in ligand orientation reveal potential avenues for designing isoform-selective inhibitors. In this review, we comprehensively examine the structural domains and subcellular localizations of NLRP3 and NEK7, and highlight how their interaction promotes inflammasome assembly. I also discuss recent insights from cryo-electron microscopy (cryo-EM), X-ray crystallography, and molecular modeling studies that illuminate the conformational dynamics of the NLRP3-NEK7 complex. Additionally, we explore the crosstalk between the STING pathway and inflammasome signaling, and address key unanswered questions that may guide future research into therapeutic modulation of these essential protein-protein interactions.