The autoinflammation-associated NLRC4V341A mutation increases microbiota-independent IL-18 production but does not recapitulate human autoinflammatory symptoms in mice.

Background: Autoinflammation with infantile enterocolitis (AIFEC) is an often fatal disease caused by gain-of-function mutations in the NLRC4 inflammasome. This inflammasomopathy is characterized by macrophage activation syndrome (MAS)-like episodes as well as neonatal-onset enterocolitis. Although elevated IL-18 levels were suggested to take part in driving AIFEC pathology, the triggers for IL-18 production and its ensuing pathogenic effects in these patients are incompletely understood. Methods: Here, we developed and characterized a novel genetic mouse model expressing a murine version of the AIFEC-associated NLRC4V341A mutation from its endogenous Nlrc4 genomic locus. Results: NLRC4V341A expression in mice recapitulated increased circulating IL-18 levels as observed in AIFEC patients. Housing NLRC4V341A-expressing mice in germfree (GF) conditions showed that these systemic IL-18 levels were independent of the microbiota, and unmasked an additional IL-18-inducing effect of NLRC4V341A expression in the intestines. Remarkably, elevated IL-18 levels did not provoke detectable intestinal pathologies in NLRC4V341A-expressing mice, even not upon genetically ablating IL-18 binding protein (IL-18BP), which is an endogenous IL-18 inhibitor that has been used therapeutically in AIFEC. In addition, NLRC4V341A expression did not alter susceptibility to the NLRC4-activating gastrointestinal pathogens Salmonella Typhimurium and Citrobacter rodentium. Conclusion: As observed in AIFEC patients, mice expressing a murine NLRC4V341A mutant show elevated systemic IL-18 levels, suggesting that the molecular mechanisms by which this NLRC4V341A mutant induces excessive IL-18 production are conserved between humans and mice. However, while our GF and infection experiments argue against a role for commensal or pathogenic bacteria, identifying the triggers and mechanisms that synergize with IL-18 to drive NLRC4V341A-associated pathologies will require further research in this NLRC4V341A mouse model.

Enfermedades autoinflamatorias sistémicas, entidades en auge: generalidades, principales síndromes monogénicos y aproximación al manejo terapéutico / Systemic autoinflammatory diseases, entities on the rise: basic concepts, main monogenic syndromes and approach to therapeutic management

Systemic autoinflammatory diseases are relatively recent entities caused by dysregulation of the innate immune system. They are mainly caused by monogenic mutations, although there are entities produced by polygenic mutations or of multifactorial origin. Traditionally, they have been classified based on the presence or absence of fever, however, thanks to the advancement of knowledge of their Pathogenic mechanisms and the signaling pathways involved, recently it has been advocated to classify them based on the latter. The three more important groups of monogenic autoinflammatory diseases are type 1 interferonopathies, inflammasomopathies and dysregulation in the nuclear factor kappa light chain enhancer of activated B cells [NFkB] pathway (relopahies). In this review, the main pathways involved, the main syndromes of each of these groups and the therapeutic approach are addressed. (AU)

Las enfermedades autoinflamatorias sistémicas son entidades relativamente recientes ocasionadas por disregulación del sistema inmune innato. Están ocasionadas fundamentalmente por mutaciones monogénicas, aunque existen entidades producidas por mutaciones poligénicas o de origen multifactorial. Tradicionalmente se han clasificadoen función de la presencia o ausencia de fiebre, sin embargo, con el avance en el conocimiento de sus mecanismos patogénicos y de las vías de señalización involucradas, recientemente se aboga por clasificarlas en base a esto último, siendo los tres grupos más importantes de entidades autoinflamatorias monogénicas las interferonopatías tipo 1,las inflamasomopatías y las ocasionadas por disregulación en la vía del factor nuclear potenciador de las cadenas ligeras kappa de las células B activadas [NF-KB] (relopatías). En la presente revisión se aborda de forma general las principales vías implicadas, los principales síndromes de cada uno de estos grupos y el abordaje terapéutico. (AU)

Clinical and genetic spectrum of 14 cases of NLRP3-associated autoinflammatory disease (NLRP3-AID) in China and a review of the literature.

BACKGROUND: NLRP3-associated autoinflammatory disease (NLRP3-AID), caused by mutations of NLRP3, is one of the autoinflammatory diseases affecting inflammasomes. Since there are little cases of Chinese NLRP3-AID, we reported 14 Chinese NLRP3-AID patients in our center and summarized the clinical features of all Chinese patients by reviewing the literature. RESULTS: Fourteen patients had been diagnosed as NLRP3-AID in our center. 12 different NLRP3 variants were identified, among which one is novel: p.Leu361Trp. Rash, recurrent fever, arthritis/arthralgia, uveitis, sensorineural deafness, symptoms of central neural systems (CNS), and increased inflammatory markers (including CRP, ESR, except Ferritin) were the common findings in Chinese patients. The frequencies of fever, neurological symptoms, musculoskeletal manifestations and ocular manifestations in Chinese patients might differ from that of patients from other regions. Besides, we also found clubbing fingers and optic neuritis in some NLRP3-AID patients, which were not commonly mentioned in previous reports. CONCLUSION: In our study, we expanded the clinical spectrum as well as the genetic pathogenic variants of NLRP3-AID. We also found that there were some differences between Chinese patients and patients from other regions, and that Chinese patients were more likely to develop severe symptoms.

Pathogenic insights from genetic causes of autoinflammatory inflammasomopathies and interferonopathies.

A number of systemic autoinflammatory diseases arise from gain-of-function mutations in genes encoding IL-1-activating inflammasomes or cytoplasmic nucleic acid sensors including the receptor and sensor STING and result in increased IL-1 and type I interferon production, respectively. Blocking these pathways in human diseases has provided proof-of-concept, confirming the prominent roles of these cytokines in disease pathogenesis. Recent insights into the multilayered regulation of these sensor pathways and insights into their role in amplifying the disease pathogenesis of monogenic and complex genetic diseases spurred new drug development targeting the sensors. This review provides insights into the pathogenesis and genetic causes of these "prototypic" diseases caused by gain-of function mutations in IL-1-activating inflammasomes (inflammasomopathies) and in interferon-activating pathways (interferonopathies) including STING-associated vasculopathy with onset in infancy, Aicardi-Goutieres syndrome, and proteasome-associated autoinflammatory syndromes that link activation of the viral sensors STING, "self" nucleic acid metabolism, and the ubiquitin-proteasome system to "type I interferon production" and human diseases. Clinical responses and biomarker changes to Janus kinase inhibitors confirm a role of interferons, and a growing number of diseases with "interferon signatures" unveil extensive cross-talk between major inflammatory pathways. Understanding these interactions promises new tools in tackling the significant clinical challenges in treating patients with these conditions.

[What is confirmed in the treatment of autoinflammatory fever diseases?] / Was ist gesichert in der Therapie von autoinflammatorischen Fiebererkrankungen?

In the last 20 years the clarification of monogenic periodic febrile diseases has led to the independent concept of autoinflammation. In this heterogeneous group polygenic complex diseases are also now included. The spectrum of symptoms is continuously growing. The main difference to autoimmunity is an excessive activation of the innate immune system without formation of autoantibodies or antigen-specific T­cells. The cardinal symptom is recurrent fever episodes accompanied by signs of inflammation, which in the periodic manifestations alternate with intervals of general well-being. The classical monogenic diseases are also known as hereditary recurrent fever (HRF). Examples are familial Mediterranean fever (FMF), cryopyrin-associated periodic syndrome (CAPS), tumor necrosis factor receptor 1­associated periodic syndrome (TRAPS), adenosine deaminase 2 (ADA2) deficiency and mevalonate kinase deficiency (MKD, hyper-IgD syndrome). The polygenic diseases are also known as nonhereditary fever syndromes. These include adult-onset Still's disease (AoSD), Adamantiades-Behçet disease, the PFAPA syndrome (periodic fever, aphthous stomatitis, pharyngitis and cervical adenitis) and gouty arthritis. All autoinflammatory fever syndromes are accompanied by a long-term risk of development of amyloid A amyloidosis, depending on the individual severity and treatment success. In some diseases severe complications can sometimes occur.

Monogenic Autoinflammatory Diseases: State of the Art and Future Perspectives.

Systemic autoinflammatory diseases are a heterogeneous family of disorders characterized by a dysregulation of the innate immune system, in which sterile inflammation primarily develops through antigen-independent hyperactivation of immune pathways. In most cases, they have a strong genetic background, with mutations in single genes involved in inflammation. Therefore, they can derive from different pathogenic mechanisms at any level, such as dysregulated inflammasome-mediated production of cytokines, intracellular stress, defective regulatory pathways, altered protein folding, enhanced NF-kappaB signalling, ubiquitination disorders, interferon pathway upregulation and complement activation. Since the discover of pathogenic mutations of the pyrin-encoding gene MEFV in Familial Mediterranean Fever, more than 50 monogenic autoinflammatory diseases have been discovered thanks to the advances in genetic sequencing: the advent of new genetic analysis techniques and the discovery of genes involved in autoinflammatory diseases have allowed a better understanding of the underlying innate immunologic pathways and pathogenetic mechanisms, thus opening new perspectives in targeted therapies. Moreover, this field of research has become of great interest, since more than a hundred clinical trials for autoinflammatory diseases are currently active or recently concluded, allowing us to hope for considerable acquisitions for the next few years. General paediatricians need to be aware of the importance of this group of diseases and they should consider autoinflammatory diseases in patients with clinical hallmarks, in order to guide further examinations and refer the patient to a specialist rheumatologist. Here we resume the pathogenesis, clinical aspects and diagnosis of the most important autoinflammatory diseases in children.

[Classification of autoinflammatory diseases based on pathophysiological mechanisms]. / Klassifikation autoinflammatorischer Erkrankungen anhand pathophysiologischer Mechanismen.

Monogenic autoinflammatory diseases present with systemic inflammation with the involvement of multiple organs. With the help of modern molecular genetic techniques a large number of diseases with previously unknown pathomechanisms have been described in recent years. This knowledge can be utilized to group autoinflammatory diseases according to the signalling pathways involved and thus provide a better understanding of these entities.

Vasculitis in Systemic Autoinflammatory Diseases.

Autoinflammatory diseases (AID) are diseases of the innate immune system, characterized by recurrent episodes of localized or systemic inflammation. Vasculitis may accompany AID. The causes of the association of vasculitis with monogenic AID are still debated. Among the monogenic AID, Familial Mediterranean Fever (FMF) is the most common. IgA-related vasculitis (IgAV) and Polyarteritis Nodosa (PAN) involving small and/or medium-sized vessels have an increased frequency among FMF patients. There are also case reports revealing vasculitic features in Cryopyrin-Associated Periodic Fever Syndrome (CAPS), Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS), Mevalonate Kinase Deficiency (MKD), also known as Hyper IgD syndrome (HIDS), Deficiency of IL-1 Receptor Antagonist (DIRA) and Pyogenic Arthritis, Pyoderma gangrenosum, and Acne (PAPA) patients. Central nervous system vasculitis and vasculopathy have been reported in DIRA and PAPA patients whereas small vessel involvement affecting skin has been reported in CAPS, TRAPS, and MKD patients. Alternatively, vasculitis can also be a leading feature especially in the recently defined monogenic AID (Otulipenia, Deficiency of Adenosine Deaminase 2-DADA2, Haploinsufficiency of A20) and interferonopathies (STING-associated vasculopathy with onset in infancy-SAVI). DADA2 often presents as a PAN-like disease. In otulipenia, patients have painful subcutaneous nodules caused by septal panniculitis with small and medium vessel vasculitis. Haploinsufficiency of A20 (also called Familial Behcet-like Autoinflammatory Syndrome) results in a phenotype very similar to the variable vessel vasculitis of Behcet's disease with recurrent oral-genital ulcers, in addition to, skin rash, uveitis, and polyarthritis. SAVI is an autoinflammatory vasculopathy with increased Interferon (IFN) signature, causing severe skin lesions resulting in ulceration, necrosis, and in some cases, amputation. Behcet's Disease (BD) is a multifactorial polygenic AID characterized by recurrent attacks of oral-genital ulcers, skin lesions, uveitis and a unique vasculitis affecting both arteries and veins of all sizes. Many clinical features overlap with other autoinflammatory diseases and overexpression of proinflammatory cytokines is an important feature of the disease.

What do we know about the inflammasome in humans?

The inflammasome complex is part of the innate immune system, which serves to protect the host against harm from pathogens and damaged cells. It is a term first proposed by Tschopp's group in 2002, with numerous original research articles and reviews published on the topic since. There have been many types of inflammasome identified, but all result in the common pathway of activation of caspases and interleukin 1ß along with possible cell death called pyroptosis. Despite a growing body of research investigating the structure and function of the inflammasome in animal models, there is still limited evidence identifying inflammasome components in human physiology and disease. In this review, we explore the molecular structure and mechanism of activation of the inflammasome with a particular focus on inflammasome complexes expressed in humans. Inflammasome components have been identified in several human peripheral and brain tissues using both in vivo and ex vivo work, and the inflammasome complex has been shown to be associated with several genetic and acquired inflammatory and neoplastic disorders. We discuss the strengths and weaknesses of the information available on the inflammasome with an emphasis on the importance of prioritizing work on human tissue. There is a huge demand for more effective treatments for a number of inflammatory and neurodegenerative diseases. Modulation of the inflammasome has been proposed as a novel treatment for several of these diseases and there are currently clinical trials ongoing to test this theory.

Enfermedades Autoinflamatorias / Autoinflammatory Diseases

Presentamos un artículo de revisión sobre las enfermedades autoinflamatorias, narrando su origen histórico y describiendo la estructura proteica y molecular del Inflamosoma, la clasificación actual de los trastornos autoinflamatorios y una descripción de las características inmunogenéticas y clínicas más sobresalientes de cada enfermedad.

We present a review article on the autoinflammatory diseases, narrating its historical origin and describing the protein and molecular structure of the Inflammasome, the current classification of the autoinflammatory diseases and a description of the immunogenetics and clinical characteristics more important of every disease.