クリオピリン関連周期熱症候群

Cryopyrin-associated periodic syndromes (CAPS) are autoinflammatory disorders caused by gain-of-function NLRP3 variants. Although NLRP3 inflammasomes mediate IL-1β secretion through Gasdermin D (GSDMD), we show that GSDMD deletion did not prevent autoinflammation in mice ubiquitously expressing the Nlrp3A350V variant. Inflamed skin of Nlrp3A350V-expressing GSDMD-deficient mice displayed citrullinated histone 3-containing neutrophil extracellular traps (CitH3-NETs). CitH3-NETs induced IL-1β secretion from murine Nlrp3A350V-expressing GSDMD-deficient macrophages as well as from human CAPS patient monocytes and macrophages. Blocking protein arginine deiminase-4 (PAD4) prevented CitH3 release and disabled the IL-1β-inducing NET effects, identifying CitH3 as crucial trigger. Mechanistically, CitH3-NETs activated GSDME in GSDMD-deficient Nlrp3A350V macrophages, and GSDME deletion prevented pathology in Nlrp3A350V-expressing GSDMD-deficient mice. In addition to this GSDME-dependent autoinflammation axis, PAD4 deletion also prevented autoinflammation in mice with neutrophil-specific Nlrp3A350V expression that develop CAPS in a GSDMD-dependent manner. These observations support a CAPS model in which PAD4-mediated CitH3-NET release can trigger both GSDMD-dependent and GSDME-dependent autoinflammation.

The human immune system maintains a delicate balance between protective immunity and self-tolerance. Disruption of this equilibrium leads to immune-mediated diseases (IMDs), a heterogeneous group of disorders including autoimmune, allergy, and autoinflammatory conditions [examples include familial Mediterranean fever (FMF) and cryopyrin-associated periodic syndromes (CAPS)]. Traditionally viewed as organ-specific pathologies, IMDs are now recognized as systemic disorders driven by chronic, self-sustaining low-grade inflammation. The microbiome, a key regulator of immune development and barrier function, acts as a central driver of this systemic inflammatory circuit. Dysbiosis impairs epithelial integrity, promotes microbial translocation, and triggers aberrant activation of pattern-recognition receptors, inflammasomes, and inflammatory signaling pathways. It skews cytokine networks toward pro-inflammatory phenotypes and disrupts the differentiation and function of critical immune cell populations, establishing a vicious cycle that propagates systemic inflammation and multi-organ comorbidities via gut-skin, gut-joint, and gut-lung axes. This review summarizes the roles of microbiome dysbiosis in IMD pathogenesis, highlights related biomarkers, and evaluates emerging therapeutic strategies targeting the host-microbiota axis. We advocate a systems immunology paradigm that integrates the microbiome as a core therapeutic target to restore immune homeostasis, achieve durable remission, and reduce the systemic comorbidity burden in patients with IMDs.

The NLRP3 inflammasome is a critical component of innate immunity, and its aberrant activation is implicated in the pathogenesis of various inflammatory diseases, including cryopyrin-associated periodic syndrome (CAPS), sepsis, inflammatory bowel disease, and type 2 diabetes. Although several NLRP3 inhibitors have entered clinical trials, none have been approved by the FDA to date, highlighting an urgent need for novel, safe, and efficient drug candidates. AZD-7762 is a well-known inhibitor of checkpoint kinase 1/2 (Chk1/2) primarily investigated for its role in enhancing cancer chemosensitivity; however, its function in inflammation remains unknown. Here, we identify AZD-7762 as a highly potent and selective direct inhibitor of the NLRP3 inflammasome. Mechanistically, AZD-7762 directly binds to the ATP-binding site of the NLRP3 NACHT domain, thereby inhibiting NLRP3 ATPase activity, oligomerization, and subsequent inflammasome assembly. Importantly, pharmacological administration of AZD-7762 significantly ameliorated disease severity in mouse models of NLRP3-driven diseases, including lipopolysaccharide (LPS)-induced systemic inflammation and dextran sulfate sodium (DSS)-induced colitis. Our findings reveal a novel function for AZD-7762 and suggest that it is a promising therapeutic candidate for the treatment of NLRP3-related inflammatory disorders.

Interleukin-1 (IL-1) plays a key role in inflammasome activation, keratinocyte signaling and neutrophil recruitment, and is a driving force behind many neutrophil-rich and suppurative dermatoses. There is robust evidence supporting the use of IL-1 blockade as a disease-modifying therapy in cryopyrin-associated periodic syndromes and other monogenic periodic fever syndromes, as well as in the treatment of Schnitzler syndrome, where it can rapidly control urticarial and neutrophilic eruptions. Cohort- and series-level data demonstrate high efficacy in IL-1 receptor antagonist deficiency and steroid-refractory pyoderma gangrenosum, whereas benefits appear more heterogeneous in hidradenitis suppurativa, pustular psoriasis and proline-serine-threonine phosphatase-interacting protein 1-associated autoinflammatory diseases. In contrast, conditions such as IL-36 receptor antagonist deficiency, synovitis acne pustulosis hyperostosis osteitis syndrome, Sweet syndrome and vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome are supported only by scattered case reports or theoretical rationale, with highly variable or uncertain responses to IL-1 blockade, highlighting the importance of careful clinical and, where possible, genetic phenotyping. We summarize practical considerations for selecting agents, pediatric and adult dosing and safety. IL-1 antagonists are indispensable for a subset of IL-1-driven disorders and represent a rational rescue option for selected neutrophilic dermatoses.

BACKGROUND: Cryopyrin-associated periodic syndromes (CAPS) are rare but treatable autoinflammatory disorders, including familial cold autoinflammatory syndrome (FCAS), Muckle-Wells syndrome (MWS), and chronic infantile neurologic cutaneous articular syndrome (CINCA), also known as neonatal-onset multisystem inflammatory disease (NOMID). These conditions can lead to severe complications such as AA amyloidosis, potentially resulting in renal failure. To date, the youngest reported case of CAPS-associated amyloidosis was 10 years old, and no cases with overlapping FCAS/MWS/CINCA features have been described. The coexistence of CAPS and psoriasis is extremely rare, with only one prior report. CASE PRESENTATION: We report a 10-year-old boy with features of cryopyrinopathy who developed early-onset AA amyloidosis. Clinical manifestations included bilateral sensorineural hearing loss, severe headaches due to chronic aseptic meningitis, splenomegaly, lymphadenopathy, and progressive renal insufficiency, along with a history of recurrent urticarial-like rashes and arthralgias. Genetic testing revealed a heterozygous pathogenic variant in the NLRP3 gene (NM_001079821.3:c.907G > A; p.Asp303Asn). Variant interpretation, based on ACMG/AMP guidelines, classified this variant as pathogenic (PS1, PS2, PS3, PM1, PM2, PM5, PP1, PP3, PP5). Treatment with the IL-1 receptor antagonist anakinra led to resolution of symptoms, stabilization of renal function, and partial improvement in hearing. During follow-up, the patient developed psoriasis, confirmed by skin biopsy, which was successfully managed with topical therapy. CONCLUSION: To our knowledge, this represents one of the youngest reported cases of AA amyloidosis secondary to CAPS with an overlapping FCAS/MWS/CINCA phenotype. The subsequent co-occurrence of psoriasis highlights the rarity of this case and suggests potential shared pathogenic mechanisms, including dysregulation of inflammatory pathways such as the NLRP3 inflammasome.