Deficiency Of IL-1 Receptor Antagonist Research Articles

Blocking of interleukin-1 suppresses both angiotensin II-induced renal inflammation and hypertension

Abstract Background Clinical hypertension is associated with renal inflammation and elevated circulating levels of proinflammatory cytokines. IL-1 receptor antagonist (IL-1Ra) is one of the most important anti-inflammatory cytokines and plays a crucial role in inflammation. Inhibition of IL-1 may contribute to modulation of the Angiotensin II (AngII)-induced hypertension response. This study aimed to elucidate the effects of IL-1Ra and anti-IL-1beta antibody (01BSUR) on AngII-induced hypertension and renal inflammation. Methods and results To determine the contribution of IL-1Ra to AngII-induced renal inflammation, male wild-type (WT) and IL-1Ra-deficient (IL-1Ra−/−) mice were infused with AngII (1000ng/kg/min) using subcutaneous osmotic pumps for 14 days. We checked blood pressure, histological change, and several mRNA expressions 14 days after infusion. Fourteen days after infusion, systolic blood pressure (197±5 vs 169±9 mmHg, p<0.05) in IL-1Ra−/− mice significantly increased compared with WT mice. Furthermore, on day 14 of AngII infusion, plasma IL-6 was 5.9-fold higher in IL-1Ra−/− versus WT mice (p<0.001); renal preproendothelin-1 mRNA expression was also significantly higher in IL-1Ra−/− mice (p<0.05). To examine renal function, we analyzed 24-hour urinary protein excretion and serum levels of blood urea nitrogen, creatinine, and uric acid in IL-1Ra−/− and WT mice. On day 14 of Ang II infusion, all levels increased significantly in IL-1Ra−/− mice compared with WT mice, suggesting that IL-1Ra deficiency reduced renal function following Ang II infusion. In addition, renal histology revealed that glomerular injury (Figure upper panels: PAS staining) and tubulointerstitial fibrosis (Figure lower panels: Elastica Masson staining) increased significantly in Ang II-infused IL-1Ra−/− versus Ang II-infused WT mice. Finally, we administrated 01BSUR to both IL-1Ra−/− and WT mice, and 01BSUR treatment decreased AngII-induced hypertension (162±17 vs 204±6 mmHg, p<0.05) and renal damage (glomerular injury and fibrosis of the tubulointerstitial area) in both IL-1Ra−/− and WT mice compared with IgG2a treatment. These findings suggest that 01BSUR suppresses Ang II-induced inflammation and renal injury. Conclusions Inhibition of interleukin-1 by both endogenous IL-1Ra and exogenous 01BSUR decreased AngII-induced hypertension and renal damage in mice, suggesting suppression of IL-1 may provide an additional strategy to protect against renal damage in hypertensive patients. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): JSPS KAKENHI

Recurrent inflammatory disease caused by a heterozygous mutation in CD48

Recurrent inflammatory disease caused by a heterozygous mutation in CD48

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.

Bone involvement in monogenic autoinflammatory syndromes

Until recently the most common autoinflammatory diseases (AIDs) associated with bone disease in childhood included a few genetically complex (chronic non-bacterial osteomyelitis, synovitis, acne, pustulosis, hyperostosis and osteitis syndrome) and monogenic (Majeed syndrome, deficiency of IL-1 receptor antagonist, cherubism) AIDs. However, the spectrum of monogenic AIDs associated with bone manifestations has markedly expanded to include both recently identified diseases such as the type I interferonopathies and also newly recognized bone dysplasias in already established AIDs. In addition, we propose that some known bone dysplasia syndromes, especially those presenting with hyperostosis and associated systemic inflammation, be classified as AIDs. Collectively, we provide an overview of the diverse bone manifestations identified in the genetically defined AIDs, discuss the hypotheses of the underlying pathophysiological mechanisms and highlight potential novel therapeutic strategies.

Rilonacept maintains long-term inflammatory remission in patients with deficiency of the IL-1 receptor antagonist.

Deficiency of IL-1 receptor antagonist (DIRA) is a rare autoinflammatory disease that presents with life-threatening systemic inflammation, aseptic multifocal osteomyelitis, and pustulosis responsive to IL-1-blocking treatment. This study was performed (a) to investigate rilonacept, a long-acting IL-1 inhibitor, in maintaining anakinra-induced inflammatory remission in DIRA patients, (b) to determine doses needed to maintain remission, and (c) to evaluate the safety and pharmacokinetics of rilonacept in young children (<12 years). Six mutation-positive DIRA patients (children, ages 3-6 years), treated with daily anakinra, were enrolled into an open-label pilot study of subcutaneous rilonacept for 24 months. Clinical symptoms and inflammatory blood parameters were measured at all visits. A loading dose (4.4 mg/kg) was administered, followed by once weekly injections (2.2 mg/kg) for 12 months. Dose escalation (4.4 mg/kg) was allowed if inflammatory remission was not maintained. Subjects in remission at 12 months continued rilonacept for an additional 12 months. Five of six patients required dose escalation for findings of micropustules. Following dose escalation, all patients were in remission on weekly rilonacept administration, with stable laboratory parameters for the entire study period of 24 months. All children are growing at normal rates and have normal heights and weights. Quality of life improved while on rilonacept. No serious adverse events were reported. Rilonacept was found to maintain inflammatory remission in DIRA patients. The once weekly injection was well tolerated and correlated with increased quality of life, most likely related to the lack of daily injections. ClinicalTrials.gov NCT01801449. NIH, NIAMS, and NIAID.

Potential of IL-1, IL-18 and Inflammasome Inhibition for the Treatment of Inflammatory Skin Diseases.

In 2002, intracellular protein complexes known as the inflammasomes were discovered and were shown to have a crucial role in the sensing of intracellular pathogen- and danger-associated molecular patterns (PAMPs and DAMPs). Activation of the inflammasomes results in the processing and subsequent secretion of the pro-inflammatory cytokines IL-1β and IL-18. Several autoinflammatory disorders such as cryopyrin-associated periodic syndromes and Familial Mediterranean Fever have been associated with mutations of genes encoding inflammasome components. Moreover, the importance of IL-1 has been reported for an increasing number of autoinflammatory skin diseases including but not limited to deficiency of IL-1 receptor antagonist, mevalonate kinase deficiency and PAPA syndrome. Recent findings have revealed that excessive IL-1 release induced by harmful stimuli likely contributes to the pathogenesis of common dermatological diseases such as acne vulgaris or seborrheic dermatitis. A key pathogenic feature of these diseases is IL-1β-induced neutrophil recruitment to the skin. IL-1β blockade may therefore represent a promising therapeutic approach. Several case reports and clinical trials have demonstrated the efficacy of IL-1 inhibition in the treatment of these skin disorders. Next to the recombinant IL-1 receptor antagonist (IL-1Ra) Anakinra and the soluble decoy Rilonacept, the anti-IL-1α monoclonal antibody MABp1 and anti-IL-1β Canakinumab but also Gevokizumab, LY2189102 and P2D7KK, offer valid alternatives to target IL-1. Although less thoroughly investigated, an involvement of IL-18 in the development of cutaneous inflammatory disorders is also suspected. The present review describes the role of IL-1 in diseases with skin involvement and gives an overview of the relevant studies discussing the therapeutic potential of modulating the secretion and activity of IL-1 and IL-18 in such diseases.

Inflammasomes and dermatology.

Inflammasomes are intracellular multiprotein complexes that comprise part of the innate immune response. Since their definition, inflammasome disorders have been linked to an increasing number of diseases. Autoinflammatory diseases refer to disorders in which local factors lead to the activation of innate immune cells, causing tissue damage when in the absence of autoantigens and autoantibodies. Skin symptoms include the main features of monogenic inflammasomopathies, such as Cryopyrin-Associated Periodic Syndromes (CAPS), Familial Mediterranean Fever (FMF), Schnitzler Syndrome, Hyper-IgD Syndrome (HIDS), PAPA Syndrome, and Deficiency of IL-1 Receptor Antagonist (DIRA). Concepts from other pathologies have also been reviewed in recent years, such as psoriasis, after the recognition of a combined contribution of innate and adaptive immunity in its pathogenesis. Inflammasomes are also involved in the response to various infections, malignancies, such as melanoma, autoimmune diseases, including vitiligo and lupus erythematosus, atopic and contact dermatitis, acne, hidradenitis suppurativa, among others. Inhibition of the inflammasome pathway may be a target for future therapies, as already occurs in the handling of CAPS, through the introduction of IL-1 inhibitors. This study presents a literature review focusing on the participation of inflammasomes in skin diseases.

Eurofever-lesons from last year

Autoinflammatory diseases are rare disorders secondary to mutation of genes involved in the regulation of innate immunity. The main limitation to a better knowledge of Autoinflammatory diseases is related to the extreme fragmentation of the diagnosed cases that are spread over different centers and countries. The general aim of the Eurofever Project was to build an international registry on Autoinflammatory diseases. A web-based registry collecting baseline and cross-sectional clinical information on Autoinflammatory diseases is available in the member area of the PRINTO web-site (http://www.printo.it). The registry is open to all pediatric and adult Centers with a specific interest in Autoinflammatory diseases. The following monogenic autoinflammatory diseases were considered: Familial Mediterranean Fever (FMF), Cryopyrin-associated periodic syndromes (CAPS), TNF receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency (MKD), Blau syndrome, pyogenic arthritis, pioderma and acne (PAPA) syndrome, deficiency of IL-1 receptor antagonist (DIRA), NLRP12-mediated periodic fever. Information on CRMO, Behcet’s disease, PFAPA and undefined periodic fevers were also collected. 2916 patients, from 95 centers in 53 countries, have been enrolled in the registry during the first 36 months. Baseline demographic data (country of residence, disease onset, disease duration, mutations, family history ect) from all patients are now available. In 2275 (81%) complete information on clinical manifestations and responses to treatments is also available. The disease distribution of enrolled patients is: FMF 787 (621 with complete clinical data); TRAPS 237 (211 with complete clinical data); CAPS 207 (186 with complete clinical data); MKD 153 (133 with complete clinical data); Blau syndrome 62 (21 with complete clinical data); PAPA 19 (18 with complete clinical data); NLRP-12 mediated periodic fever 8 (6 with complete clinical data); DIRA and Majeed 3 and 2 patients, respectively (all with complete clinical data). Among multifactorial autoinflammatory diseases: PFAPA 564 (402 with complete clinical data); CRMO 392 (370 with complete clinical data); pediatric Behcet disease 84 (68 with complete clinical data) and 205 patients with undefined periodic fever (174 with complete clinical data). So far 8 papers involving 56 different authors and 32 centers have been published in high-rank international journals and other papers are in preparation. A large registry of patients with Autoinflammatory diseases is available and, despite the expiring of the initial grant, the enrolment is still ongoing with an increasing number of centers involved. Eurofever represents a good example of how a disease-oriented registry can provide relevant scientific answers to many unknown clinical aspects of ultra-rare diseases. This aspects was the main reason of the relevant success of the enrolment we have observed.

SP0072 Lessons Learned from the Eurofever Project

Autoinflammatory diseases are rare disorders secondary to mutation of genes involved in the regulation of innate immunity. The main limitation to a better knowledge of Autoinflammatory diseases is related to...

SP0039 Immunological and genetic basis of CRMO

Chronicnon-bacterial osteomyelitis (CNO) is an inflammatory bone disorder of yet unknown origin. The clinical spectrum ranges from relatively benign, self-limiting, mono-focal symptoms to destructive, multi-focal involvement (known as chronic recurrent...

IL-1 blockade in inherited fever syndromes - what have we learnt?

The inherited periodic fever syndromes are single gene disorders of innate immunity which have provided invaluable insights into the regulation of inflammation. They are all extremely rare but are clinically important as they cause very significant day to day symptoms and carry a high risk of early death due to AA amyloidosis. With the exception of familial Mediterranean fever treatment was essentially ineffective until this century. The discovery in 2002 that specific IL-1 blockade completely prevented all symptoms in cryopyrin associated periodic syndrome (CAPS) transformed treatment of this rare genetic disease. Isolation of the responsible gene, NLRP3, followed by rapid advances in molecular biology and identification of the inflammasome has made it clear that CAPS is purely a disease of IL-1 dysregulation. These discoveries combined with the availability of specific anti IL-1 agents have resulted in new insights into the regulation of IL-1 beta production in humans and its long term consequences. IL-1 is now recognised to be an important mediator of inflammation in other inherited autoinflammatory diseases such as Familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), deficiency of IL-1 receptor antagonist (DIRA) and mevalonate kinase deficiency and has transformed patient prognosis and quality of life. In addition the recognition that IL-1 blockade provides complete disease control in acquired diseases of uncertain aetiology particularly Schnitzler’s syndrome and systemic onset juvenile chronic arthritis (SoJIA), adult onset Stills disease and recurrent idiopathic pericarditis has made it clear that these too are autoinflammatory disorders. One of the most striking features of these diseases is that IL-1 blocking agents have been used for prolonged periods as monotherapy without serious side effects or breakthrough of inflammatory activity thus differentiating them from the commoner autoimmune disorders such as rheumatoid arthritis and vasculitis.

Síndrome CINCA/NOMID

CINCA/NOMID syndrome was first reported in 1981, identified as a new disease in 1987 and the main cause discovered in 2001, when mutations in the CIAS1 gene modifying the structure of the protein cryopirin were found in those patients (although other factors seem to play a role). Together with the major symptoms that characterized the syndrome, neurological, cutaneous and articular manifestations, others have been added which seem to be quite constant among CINCA/NOMID diagnosed patients: pre and perinatal symptoms, morfological changes, outbreaks of fever and biological abnormalities which reveal a persistent inflammatory background. The radiological studies have been able to identify the physis as the origin of the osteoarticular malformations seen in this syndrome. Diferential diagnosis includes diseases with similar onset at the neonatal period or infancy: systemic onset juvenile idiopathic athritis, periodic fever associated with mevalonate kinase deficiency, deficiency of IL-1 receptor antagonist (DIRA) and Muckle-Wells syndrome.

Inflammasomes and related diseases

Although inflammation is important for host defense, excessive inflammation sometimes causes serious consequences. IL-1β is one of major proinflammatory cytokines. Dysregulation of IL-1β promotes development of several diseases. Mature IL-1β is produced by cleavage of its proform by a protein complex named inflammasome. Inflammasome consists of NOD-LRRs containing family (NLR proteins), an adaptor protein, and a cysteine protease caspase-1. Several NLRs can be assembled into inflammasome in response to various stimulatory signals. Genetic disorder of inflammasome-IL-1 system cause autoinflammatory diseases such as cryopyrin-associated autoinflammatory disease, familial Mediterranean fever, deficiency of IL-1 receptor antagonist, and PAPA syndrome. This article reviews recent advances in the study of inflammasome and related diseases.

IL-1 pathways in inflammation and human diseases

Interleukin (IL)-1 was first cloned in the 1980s, and rapidly emerged as a key player in the regulation of inflammatory processes. The term IL-1 refers to two cytokines, IL-1alpha and IL-1beta, which are encoded by two separate genes. The effects of IL-1 are tightly controlled by several naturally occurring inhibitors, such as IL-1 receptor antagonist (IL-1Ra), IL-1 receptor type II (IL-1RII), and other soluble receptors. Numerous IL-1 inhibitors have been developed and tested primarily in rheumatoid arthritis, with only modest effects. By contrast, the use of IL-1 antagonists has been uniformly associated with beneficial effects in patients with hereditary autoinflammatory conditions associated with excessive IL-1 signaling, such as cryopyrinopathies and IL-1Ra deficiency. Successful treatment with IL-1 blockers has also been reported in other hereditary autoinflammatory diseases, as well as in nonhereditary inflammatory diseases, such as Schnizler syndrome, systemic-onset juvenile idiopathic arthritis and adult Still disease. The role of microcrystals in the regulation of IL-1beta processing and release has provided the rationale for the use of IL-1 inhibitors in crystal-induced arthritis. Finally, preliminary results indicating that IL-1 targeting is efficacious in type 2 diabetes and smoldering myeloma have further broadened the spectrum of IL-1-driven diseases.

Abstract 1208: Deficiency of Interleukin-1 receptor antagonist in T cells promotes Aortic Valve Stenosis by releasing Tumor Necrosis Factor-α

The cytokine interleukin (IL)-1 is an important mediator of inflammation and cardiovascular disease. Activity of this cytokine is modulated endogenously via IL-1 receptor antagonist (IL-1Ra). We have shown that IL-1Ra-deficient (IL-1Ra −/− ) mice develop degenerative aortic valve stenosis (AS) that is the most common valvular disease in Western countries. The objective of this study is to determine the mechanisms by which deficiency of IL-1Ra may promote AS. Method and Results : IL-1Ra −/− mice (backcrossed 8 generations to the BALB/c background) and wild-type (WT) mice did not differ with regard to body weight, heart weight, and systolic arterial pressure. Furthermore, no significant differences in plasma lipid levels were observed between IL-1Ra −/− and WT mice. However histological analysis revealed that IL-1Ra −/− mice developed aortitis and showed increased aortic valve leaflet thickness compared to WT mice at the age of 12 weeks (p&lt;0.001). Echo cardiograms also revealed that IL-1Ra −/− mice displayed higher transvalvular velocities than WT mice at the age of 40 weeks (p&lt;0.01). These findings showed that IL-1Ra−/− mice spontaneously developed AS. In this study, we examined the role of T cells in development of AS by peripheral T cell transplantation. Transplantation of T cells from WT mice induced mild swelling of aortic valve leaflet in nu/nu mice. In contrast, T cells from IL-1Ra −/− mice induced an increase in aortic valve thickness in nu/nu mice. We next checked T cell function. After anti-CD3 antibody stimulation, IL-1Ra −/− T cells produced much higher levels of tumor necrosis factor (TNF)-α in culture supernatants compared to those from WT mice (p&lt;0.001). Furthermore, in IL-1Ra −/− mice, TNF-α protein levels were higher than in WT mice (106.2±12.5 vs. 216.5±12.5 pg/mL, p&lt;0.001) in vivo. Finally, we studied the roles of TNF-α in the development of AS in IL-1Ra −/− mice by generating double gene deficient (TNF-α −/− / IL-1Ra −/− ) mice. Interestingly, TNF-α −/− /IL-1Ra −/− mice did not develop AS. Conclusions : These findings suggest that IL-1Ra deficiency in T cells disrupts homeostasis of the immune system and TNF-α plays an important role in the development of AS in IL-1Ra −/− mice. These novel findings provide a clue for the development of new therapies for AS.

TNF-α is crucial for the development of autoimmune arthritis in IL-1 receptor antagonist–deficient mice

IL-1 receptor antagonist-deficient (IL-1Ra(-/-)) mice spontaneously develop autoimmune arthritis. We demonstrate here that T cells are required for the induction of arthritis; T cell-deficient IL-1Ra(-/-) mice did not develop arthritis, and transfer of IL-1Ra(-/-) T cells induced arthritis in nu/nu mice. Development of arthritis was also markedly suppressed by TNF-alpha deficiency. We found that TNF-alpha induced OX40 expression on T cells and blocking the interaction between either CD40 and its ligand or OX40 and its ligand suppressed development of arthritis. These findings suggest that IL-1 receptor antagonist deficiency in T cells disrupts homeostasis of the immune system and that TNF-alpha plays an important role in activating T cells through induction of OX40.