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Anna Simon - One of the best experts on this subject based on the ideXlab platform.
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systemic Autoinflammatory Syndromes
Clinical Immunology (Fourth Edition), 2019Co-Authors: Catharina M Muldersmanders, Jeroen Van Der Hilst, J W M Van Der Meer, Anna SimonAbstract:Abstract Autoinflammatory diseases are characterized by recurrent episodes of inflammation, accompanied by a wide range of inflammatory symptoms, including fever, abdominal pain, skin rash, arthralgias, and myalgias. There can be frank signs of peritonitis, pericarditis, or arthritis. Many Autoinflammatory diseases have a genetic background, and major progress has been made in identifying specific disease-inducing mutations. The common pathophysiological feature of Autoinflammatory Syndromes is the increased production of interleukin-1 (IL-1), making drugs targeting this cytokine the treatment of choice. The exception to this is familial Mediterranean fever, where anti–IL-1-therapy is only indicated when treatment with colchicine is ineffective. Adequate control of inflammation is necessary to prevent amyloid A (AA) amyloidosis.
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Clinical Immunology (Fourth Edition) - Systemic Autoinflammatory Syndromes
2018Co-Authors: Catharina M. Mulders-manders, J W M Van Der Meer, Jeroen Van Der Hilst, Anna SimonAbstract:Abstract Autoinflammatory diseases are characterized by recurrent episodes of inflammation, accompanied by a wide range of inflammatory symptoms, including fever, abdominal pain, skin rash, arthralgias, and myalgias. There can be frank signs of peritonitis, pericarditis, or arthritis. Many Autoinflammatory diseases have a genetic background, and major progress has been made in identifying specific disease-inducing mutations. The common pathophysiological feature of Autoinflammatory Syndromes is the increased production of interleukin-1 (IL-1), making drugs targeting this cytokine the treatment of choice. The exception to this is familial Mediterranean fever, where anti–IL-1-therapy is only indicated when treatment with colchicine is ineffective. Adequate control of inflammation is necessary to prevent amyloid A (AA) amyloidosis.
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the challenge of Autoinflammatory Syndromes with an emphasis on hyper igd syndrome
Rheumatology, 2016Co-Authors: J W M Van Der Meer, Anna SimonAbstract:Autoinflammatory Syndromes are disorders with an exaggerated inflammatory response, mostly in the absence of an appropriate trigger. Prototypic Autoinflammatory Syndromes are FMF, hyper-IgD syndrome (also known as mevalonate kinase deficiency), TNF receptor-associated periodic syndrome and cryopyrin-associated periodic syndrome. The clinical phenotypes partly overlap (with fever and acute phase response), but also differ between the various Syndromes (e.g. regarding fever pattern, episodic vs chronic inflammation and accompanying clinical signs). In recent years, the genetic basis of quite a number of these relatively rare and mostly hereditary disorders has been elucidated. These genetic defects lead to either enhanced production of inflammatory mediators or to a lack of inhibition of these components of the innate immune system. Among these dysregulated inflammatory mediators, the pro-inflammatory cytokine IL-1beta stands out. Hence, targeted treatment with blockers of IL-1 action, such as recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) and mAb against IL-1beta has met with impressive clinical results. In this article, hyper-IgD syndrome is discussed in more detail, based on 30 years of experience with this syndrome.
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treating inflammation by blocking interleukin 1 in a broad spectrum of diseases
Nature Reviews Drug Discovery, 2012Co-Authors: Charles A Dinarello, Anna Simon, Jos W M Van Der MeerAbstract:Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in Autoinflammatory Syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1β antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1α antibody are in clinical trials.
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Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases
Nature Reviews Drug Discovery, 2012Co-Authors: Charles A Dinarello, Anna Simon, J W M Van Der MeerAbstract:Interleukin-1 (IL-1) is a highly active pro-inflammatory cytokine that lowers pain thresholds and damages tissues. Monotherapy blocking IL-1 activity in Autoinflammatory Syndromes results in a rapid and sustained reduction in disease severity, including reversal of inflammation-mediated loss of sight, hearing and organ function. This approach can therefore be effective in treating common conditions such as post-infarction heart failure, and trials targeting a broad spectrum of new indications are underway. So far, three IL-1-targeted agents have been approved: the IL-1 receptor antagonist anakinra, the soluble decoy receptor rilonacept and the neutralizing monoclonal anti-IL-1beta antibody canakinumab. In addition, a monoclonal antibody directed against the IL-1 receptor and a neutralizing anti-IL-1alpha antibody are in clinical trials.
J W M Van Der Meer - One of the best experts on this subject based on the ideXlab platform.
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systemic Autoinflammatory Syndromes
Clinical Immunology (Fourth Edition), 2019Co-Authors: Catharina M Muldersmanders, Jeroen Van Der Hilst, J W M Van Der Meer, Anna SimonAbstract:Abstract Autoinflammatory diseases are characterized by recurrent episodes of inflammation, accompanied by a wide range of inflammatory symptoms, including fever, abdominal pain, skin rash, arthralgias, and myalgias. There can be frank signs of peritonitis, pericarditis, or arthritis. Many Autoinflammatory diseases have a genetic background, and major progress has been made in identifying specific disease-inducing mutations. The common pathophysiological feature of Autoinflammatory Syndromes is the increased production of interleukin-1 (IL-1), making drugs targeting this cytokine the treatment of choice. The exception to this is familial Mediterranean fever, where anti–IL-1-therapy is only indicated when treatment with colchicine is ineffective. Adequate control of inflammation is necessary to prevent amyloid A (AA) amyloidosis.
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Clinical Immunology (Fourth Edition) - Systemic Autoinflammatory Syndromes
2018Co-Authors: Catharina M. Mulders-manders, J W M Van Der Meer, Jeroen Van Der Hilst, Anna SimonAbstract:Abstract Autoinflammatory diseases are characterized by recurrent episodes of inflammation, accompanied by a wide range of inflammatory symptoms, including fever, abdominal pain, skin rash, arthralgias, and myalgias. There can be frank signs of peritonitis, pericarditis, or arthritis. Many Autoinflammatory diseases have a genetic background, and major progress has been made in identifying specific disease-inducing mutations. The common pathophysiological feature of Autoinflammatory Syndromes is the increased production of interleukin-1 (IL-1), making drugs targeting this cytokine the treatment of choice. The exception to this is familial Mediterranean fever, where anti–IL-1-therapy is only indicated when treatment with colchicine is ineffective. Adequate control of inflammation is necessary to prevent amyloid A (AA) amyloidosis.
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the challenge of Autoinflammatory Syndromes with an emphasis on hyper igd syndrome
Rheumatology, 2016Co-Authors: J W M Van Der Meer, Anna SimonAbstract:Autoinflammatory Syndromes are disorders with an exaggerated inflammatory response, mostly in the absence of an appropriate trigger. Prototypic Autoinflammatory Syndromes are FMF, hyper-IgD syndrome (also known as mevalonate kinase deficiency), TNF receptor-associated periodic syndrome and cryopyrin-associated periodic syndrome. The clinical phenotypes partly overlap (with fever and acute phase response), but also differ between the various Syndromes (e.g. regarding fever pattern, episodic vs chronic inflammation and accompanying clinical signs). In recent years, the genetic basis of quite a number of these relatively rare and mostly hereditary disorders has been elucidated. These genetic defects lead to either enhanced production of inflammatory mediators or to a lack of inhibition of these components of the innate immune system. Among these dysregulated inflammatory mediators, the pro-inflammatory cytokine IL-1beta stands out. Hence, targeted treatment with blockers of IL-1 action, such as recombinant IL-1 receptor antagonist (IL-1Ra, anakinra) and mAb against IL-1beta has met with impressive clinical results. In this article, hyper-IgD syndrome is discussed in more detail, based on 30 years of experience with this syndrome.
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sp0213 clinical and pathogenetic aspects of Autoinflammatory Syndromes
Annals of the Rheumatic Diseases, 2014Co-Authors: J W M Van Der MeerAbstract:Some 15 years ago, the term Autoinflammatory syndrome has been coined to delineate a group of disorders in which patients suffer from recurrent or chronic inflammation without an obvious exogenous trigger. In earlier days, these Syndromes were described as periodic or episodic fevers; the most prominent among these are Familial Mediterranean fever (FMF), TNF receptor associated periodic syndrome (TRAPS), Hyper-IgD syndrome (HIDS) and Cryopyrin-associated periodic syndrome (CAPS). Today, some 15 different Autoinflammatory disorders have been recognised as Autoinflammatory Syndromes. Elucidation of the genetic background, using modern genetic techniques, has taught a lot about the inflammatory pathways in many these disorders. Baseline activation of inflammasomes (hetero- and homo-multimeric protein complexes that trigger cytokine activation) appears to play a role in many of these disorders. Among the cytokines that are activated, especially interleukin-1beta (IL-1beta) stands out. This is further corroborated by a beneficial effect of therapeutic interventions directed towards IL-1beta, using either recombinant IL-1 receptor antagonist (anakinra), soluble decoy receptor construct (rilonacept) or neutralising monoclonal antibody against IL-1beta. We are now at a stage where it is realised that not all Autoinflammatory Syndromes respond in the same way to IL-1 blockade, pointing to the complexity of the cytokine network and the role of pro-inflammatory cytokines other than IL-1beta. Originally, a sharp distinction was made between Autoinflammatory Syndromes and autoimmune disorders. In the former, autoreactive T- and/or B-lymphocytes, which are a hallmark of autoimmunity, were thought to be absent. By the recognition of Syndromes with Autoinflammatory and autoimmune traits, this distinction has become less strict. This also implies that not all Autoinflammatory Syndromes are pure disorders of an overactive innate immune system. Disclosure of Interest None declared DOI 10.1136/annrheumdis-2014-eular.6325
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effects of the histone deacetylase inhibitor itf2357 in Autoinflammatory Syndromes
Molecular Medicine, 2011Co-Authors: Evelien J Bodar, Anna Simon, J W M Van Der MeerAbstract:We explored the effects of the oral histone deacetylase (HDAC) Inhibitor ITF2357 In patients with Autoinflammatory syndrome. In this prospective open-label pilot study, eight patients were enrolled; one patient with tumor necrosis factor receptor-associated periodic syndrome (TRAPS), three patients with hyper-IgD and periodic fever syndrome (HIDS) and four patients with Schnitzler syndrome were closely followed during 90 d of ITF2357 treatment. Three patients with Schnitzler syndrome and one TRAPS patient experienced a partial remission. In four patients, there was no effect. In HIDS patients, there was a tendency toward a higher attack frequency and increasing attack severity. In two patients (one TRAPS and one HIDS), we observed a decrease of acute-phase response without signs of clinical improvement. One patient with Schnitzler syndrome showed a partial response despite an ongoing acute-phase response. In conclusion, ITF2357 monotherapy was able to induce partial response only in patients with Schnitzler syndrome and no response in patients with HIDS.
Marco Gattorno - One of the best experts on this subject based on the ideXlab platform.
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urticarial vasculitis and urticarial Autoinflammatory Syndromes
Giornale italiano di dermatologia e venereologia : organo ufficiale Società italiana di dermatologia e sifilografia, 2015Co-Authors: Angelo V Marzano, Simona Tavecchio, Marina Venturini, Piergiacomo Calzavarapinton, Raffaella Sala, Marco GattornoAbstract:Abstract Urticaria is a frequent disorder classified as acute and chronic forms, which presents with wheals that can be associated with angioedema. Several entities may manifest with urticarial skin lesions, encompassing a heterogeneous group of conditions that have to be differentiated from ordinary urticaria. This review is focused on two of these urticarial Syndromes: urticarial vasculitis (UV), which represents the most important differential diagnosis with common urticaria, and Autoinflammatory diseases such as cryopyrin-associated periodic Syndromes (CAPS) and Schnitzler's Syndrome, both rare multisystem forms that may masquerade as common urticaria. UV is a small-vessel vasculitis with predominant skin involvement, characterized by wheals persisting for more than 24 hours, burning rather than itching and resolving with hyperpigmentation as well as by other cutaneous manifestations including purpura, papules, vesicles, bullae and necrotic-ulcerative lesions. Histology shows a classic pattern of leukocytoclastic vasculitis, with possible presence of upper dermal edema. CAPS are classified as three distinct entities: familial cold Autoinflammatory syndrome, Muckle-Wells Syndrome and chronic infantile neurological cutaneous and articular syndrome, which represent a spectrum of disorders caused by different mutations in a single gene, NLRP3 (NOD-like receptor 3). This gene encodes for cryopyrin, an inflammasome protein that activates interleukin-1β, leading to an overproduction of this pivotal proinflammatory cytokine. Histologically, urticarial lesions are generally characterized by a perivascular neutrophilic infiltrate. Unlike urticaria, neither UV nor urticarial Autoinflammatory Syndromes do respond to antihistamines: thus, it is important not to misdiagnose such conditions in order to give the patients specific treatments, potentially preventing serious systemic complications.
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ab1201 diversity in clinical manifestations of Autoinflammatory Syndromes in a french paediatric rheumatology referral center
Annals of the Rheumatic Diseases, 2013Co-Authors: S Boiu, Marco Gattorno, Richard Mouy, S Compeyrotlacassagne, Benedicte Neven, Carine Wouters, Pierre QuartierAbstract:Background The Autoinflammatory Syndromes (AISs) include monogenic and polygenic disorders characterized by primary dysfunction of the innate immune system. Objectives To describe the clinical spectrum, genetic background and therapy in a cohort of AIS patients followed in a reference Pediatric Rheumatology center. Methods Medical records of AIS patients followed until November 2010 and entered in the Eurofever Registry were studied. Results Fifty six patients were included: 17 CAPS, 4 TRAPS, 5 HIDS, 18 FMF, 6 CRMO, 2 SAPHO and 4 Behcet’s Disease (BD). The median follow-up was 2 years (0-14 years). The male/female ratio was 20/36. The median age was 2.5 years at disease onset and 4 years at diagnosis. Family history was positive in 34% of patients. Clinical manifestations included fever (79%), musculoskeletal (77%), gastrointestinal (63%), mucocutaneous (61%), neurological (41%), ocular (34%), cardiorespiratory (13%), and genitourinary (2%) findings, lymphadenopathy with/or hepatosplenomegaly (16%) and growth impairment (25%). The main organ system manifestations were arthralgia (70%), abdominal pain (50%), urticarial rash (34%), headache (34%), conjunctivitis (16%), generalized lymph node enlargement (13%), and chest pain (9%). Complications/sequelae developed in 45% of patients and involved the musculoskeletal (25%), neurological (21%), gastrointestinal (11%) and ocular (7%) systems. Six patients presented with severe/unusual manifestations: neonatal peritonitis (1 CAPS), pancreatitis (1 TRAPS), acute glomerulonephritis (1 FMF), complicated Henoch-Schonlein purpura (1 FMF), peritoneal adhesions with intestinal occlusion (1 FMF), periorbital pain (1 CRMO) and cerebral thrombosis (1 BD). AISs were associated with other diseases in 2 patients (FMF/Henoch-Schonlein purpura and CRMO/enthesitis-related arthritis). One mutant allele was found in 16/17 CAPS, 4/4 TRAPS and 4/18 FMF patients. Two mutant allelles were present in 5/5 HIDS and 11/18 FMF patients.The most used therapeutic agents were biologics (54%) (anakinra, canakinumab, etanercept, adalimumab), NSAIDs (48%), colchicine (45%) and corticosteroids (29%). Anti-interleukin-1 therapy and colchicine proved efficacy in CAPS and FMF patients, respectively. In addition, favorable responses demonstrated anti-interleukin-1 therapy in TRAPS, HIDS and colchicine-resistant FMF patients, as well as etanercept in TRAPS, HIDS and CRMO patients non-responsive to NSAIDs. Fifty seven% and 41% of patients were in complete and partial remission, respectively, at last visit. Conclusions AISs in children are associated with a broad spectrum of manifestations. A detailed history, thorough review of clinical manifestations and molecular testing of specific causative genes can provide early and accurate diagnosis and institution of efficient therapy. Disclosure of Interest None Declared
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pyogenic arthritis pyoderma gangrenosum acne and hidradenitis suppurativa papash a new Autoinflammatory syndrome associated with a novel mutation of the pstpip1 gene
JAMA Dermatology, 2013Co-Authors: Angelo V Marzano, Marco Gattorno, Isabella Ceccherini, V Trevisan, Clara De Simone, Carlo CrostiAbstract:The PASH triad (pyoderma gangrenosum, acne, and hidradenitis suppurativa) has recently been described in 2 unrelated patients as a new entity within the spectrum of Autoinflammatory Syndromes.1- 2 PASH syndrome is similar to PAPA syndrome (pyogenic arthritis, acne, and pyoderma gangrenosum) but differs insofar as it lacks the associated arthritis and has a different genetic basis.3 PAPA syndrome is caused by mutations in the proline-serine-threonine-phosphatase protein 1 (PSTPIP1) gene (OMIM: 606347) that is involved in regulating innate immune responses, whereas no mutations have yet been detected in PASH syndrome.
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biologic drugs in Autoinflammatory Syndromes
Autoimmunity Reviews, 2012Co-Authors: Roberta Caorsi, Silvia Federici, Marco GattornoAbstract:Abstract Purpose of the review Inherited Autoinflammatory Syndromes are conditions caused by mutations of proteins playing a pivotal role in the regulation of the innate immunity leading to an uncontrolled inflammation. The understanding of the molecular pathways involved in these disorders has shed a new light on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. In this review we give a start of the art of the use of biologics in these disorders. Main topics The dramatic response to anti IL-1 drugs in cryopyrin-associated periodic Syndromes represents the brightest example of the possibility to completely dampen inflammation in these severe disorders with the selective blockade of a single pivotal cytokine. Periodic fevers are characterized by recurrent episodes of fever, usually treated with on demand steroids. However the increasing frequency of fever episodes or the development of a chronic disease course may require a continuous long-term treatment, with anti-TNF or IL-1 blockers in mevalonate kinase deficiency and TNF-receptor associated periodic syndrome. Anti-IL-1 treatment is also effective in FMF patients resistant or partially responsive to colchicine. The deficiency of the interleukin-1‐receptor antagonist (DIRA) is caused by mutations in the gene encoding for the interleukin-1 receptor antagonist (IL-1Ra). In this case t he recombinant IL-1Ra (anakinra) is the treatment of choice. Due to their extreme rarity the response to the available biologic drugs in other Autoinflammatory diseases is still largely anecdotal.
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treatment of Autoinflammatory Syndromes
Current Opinion in Pediatrics, 2010Co-Authors: Marco Gattorno, Alberto MartiniAbstract:PURPOSE OF REVIEW: Inherited Autoinflammatory diseases are experiments in nature in which mutations of proteins playing a pivotal role in the regulation of the innate immunity lead to unprovoked episodes of inflammation. The understanding of the molecular pathways involved in these disorders has shed a new light on the pattern of activation and maintenance of the inflammatory response and disclosed new molecular therapeutic targets. In this review, we outline the more recent novelties in the treatment of Autoinflammatory diseases and their possible implications for some multifactorial pediatric conditions. RECENT FINDINGS: Cryopyrin-associated periodic syndrome (CAPS) represents the prototype of Autoinflammatory diseases. The study of the pathophysiological consequence of mutations of the cryopyrin gene (NLRP3) allowed the identification of the intracellular pathways thought to play a pivotal part in the activation and secretion of the potent inflammatory cytokine interleukin (IL)-1β. The dramatic effect of IL-1 blockade in CAPS opens new perspectives for the treatment of other inherited and multifactorial inflammatory disorders. A number of IL-1 blockers are now available on the market. SUMMARY: Studies on the pathogenesis and treatment of inherited Autoinflammatory diseases are also changing the approach to some multifactorial inflammatory conditions.
Donato Rigante - One of the best experts on this subject based on the ideXlab platform.
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a systematic approach to Autoinflammatory Syndromes a spelling booklet for the beginner
Expert Review of Clinical Immunology, 2017Co-Authors: Donato RiganteAbstract:ABSTRACTIntroduction: Hallmark of Autoinflammatory Syndromes (AIS) is the periodic recurrence of ‘sterile’ inflammatory attacks characterized by fever and organ- or tissue-specific inflammation. Basic research projects over the last two decades have boosted our understanding of pathological pathways, mainly involving interleukin (IL)-1 biosynthesis, and also revealed that their dysregulation results from genetically-heterogeneous inborn errors of innate immunity and leads to multiple inflammatory phenotypes. Starting from the evidence of poor response to IL-1 inhibitors of some patients with multi-organ inflammation, further research studies have disclosed a crucial role for nuclear factor (NF)-κB and type I interferon (IFN) in specific AIS. Presently, new genetically-defined AIS have been identified, following the in-depth analysis of molecular pathways which involve either constitutive NF-κB activation or IFN signaling.Areas covered: This review is intended as a spelling booklet to help clinicians appro...
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Lights and shadows in Autoinflammatory Syndromes from the childhood and adulthood perspective
Clinical Rheumatology, 2016Co-Authors: Donato Rigante, Marco Francesco Natale, Antonio Vitale, Luca CantariniAbstract:In a high percentage of cases, the monogenic Autoinflammatory Syndromes (AIS), caused by subversion in the inflammasome homeostasis leading to cytokine oversecretion and characterized by multiple inflammatory pictures, start in childhood. However, the description of tardive manifestations, veiled phenotypes, and atypical clinical signs beginning in adulthood has been more and more reported in recent times, requiring that many specialists become confident with concepts, details, and management strategies of AIS. Differences between child- and adult-onset Syndromes raise the question of whether pathogenic mechanisms might differ when the timetable of AIS onset diverges, but show that carefulness is needed to establish a straightforward diagnosis.
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monogenic Autoinflammatory Syndromes state of the art on genetic clinical and therapeutic issues
International Journal of Rheumatology, 2013Co-Authors: Francesco Caso, Donato Rigante, Luisa Costa, Mariangela Atteno, Adele Compagnone, Paolo Caso, Bruno Frediani, Orso Maria Lucherini, Antonio Vitale, Mauro GaleazziAbstract:Monogenic Autoinflammatory Syndromes (MAISs) are caused by innate immune system dysregulation leading to aberrant inflammasome activation and episodes of fever and involvement of skin, serous membranes, eyes, joints, gastrointestinal tract, and nervous system, predominantly with a childhood onset. To date, there are twelve known MAISs: familial Mediterranean fever, tumor necrosis factor receptor-associated periodic syndrome, familial cold urticaria syndrome, Muckle-Wells syndrome, CINCA syndrome, mevalonate kinase deficiency, NLRP12-associated Autoinflammatory disorder, Blau syndrome, early-onset sarcoidosis, PAPA syndrome, Majeed syndrome, and deficiency of the interleukin-1 receptor antagonist. Each of these conditions may manifest itself with more or less severe inflammatory symptoms of variable duration and frequency, associated with findings of increased inflammatory parameters in laboratory investigation. The purpose of this paper is to describe the main genetic, clinical, and therapeutic aspects of MAISs and their most recent classification with the ultimate goal of increasing awareness of autoinflammation among various internal medicine specialists.
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Monogenic Autoinflammatory Syndromes at a dermatological level
Archives of Dermatological Research, 2011Co-Authors: Donato Rigante, Luca CantariniAbstract:Autoinflammatory Syndromes include an expanding list of diseases characterized by unprovoked recurrent attacks of systemic inflammation with lack of autoantibodies or autoreactive T-cells. This group of conditions encompasses monogenic diseases with Mendelian inheritance which are caused by specific mutations of different genes regulating the innate immunity: familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic Syndromes, pyogenic disorders and deficiency of interleukin-1 receptor antagonist: all these diseases can present with dermatological manifestations, which often represent the prominent clinical features or, in some cases, the presenting sign. The purpose of this review is to increase the recognition among clinicians and mostly dermatologists of the monogenic Autoinflammatory Syndromes, highlighting the cutaneous signs of these conditions, in consideration of the possibility to prevent irreversible damages when their diagnosis and treatment are precociously established.
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the protean visage of systemic Autoinflammatory Syndromes a challenge for inter professional collaboration
European Review for Medical and Pharmacological Sciences, 2010Co-Authors: Donato RiganteAbstract:Systemic Autoinflammatory Syndromes are a group of inherited and ac- quired disorders of the innate immunity charac- terized by recurrence of seemingly unprovoked febrile attacks of variable duration and multi- district inflammation of different severity. The vast majority of these conditions when ob- served in pediatrics is caused by mutations in genetic systems involved in the orchestration of inflammation and apoptosis. The group in- cludes hereditary recurrent fevers, idiopathic febrile Syndromes, hereditary pyogenic disor- ders, bone Autoinflammatory diseases, immune- mediated granulomatous diseases, complement disorders, hemophagocytic and vasculitic syn- dromes. Diagnostic identification derives from the combination of genotype studies and clini- cal/bioumoral data showing the spontaneous ac- tivation of cells of the innate immunity in the ab- sence of specific ligands, although diagnosis re- mains only clinical for idiopathic febrile syn- dromes such as systemic-onset juvenile idio- pathic arthritis and PFAPA syndrome. Meeting the needs of patients with complex chronic dis- eases as systemic Autoinflammatory Syndromes requires the provision of collaborative multidis- ciplinary care and the expertise of a number of health care providers across varied health care settings.
Elke Krüger - One of the best experts on this subject based on the ideXlab platform.
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contribution of the unfolded protein response upr to the pathogenesis of proteasome associated Autoinflammatory Syndromes praas
Frontiers in Immunology, 2019Co-Authors: Frederic Ebstein, Maria Cecilia Poli Harlowe, Maja Studenckaturski, Elke KrügerAbstract:Type I interferonopathies cover a phenotypically heterogeneous group of rare genetic diseases including the recently described proteasome-associated Autoinflammatory Syndromes (PRAAS). By definition, PRAAS are caused by inherited and/or de novo loss-of-function mutations in genes encoding proteasome subunits such as PSMB8, PSMB9, PSMB7, PSMA3, or proteasome assembly factors including POMP and PSMG2, respectively. Disruption of any of these subunits results in perturbed intracellular protein homeostasis including accumulation of ubiquitinated proteins which is accompanied by a type I interferon (IFN) signature. The observation that, similarly to pathogens, proteasome dysfunctions are potent type I IFN inducers is quite unexpected and, up to now, the underlying molecular mechanisms of this process remain largely unknown. One promising candidate for triggering type I IFN under sterile conditions is the unfolded protein response (UPR) which is typically initiated in response to an accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) (also referred to as ER stress). The recent observation that the UPR is engaged in subjects carrying POMP mutations strongly suggests its possible implication in the cause-and-effect relationship between proteasome impairment and interferonopathy onset. The purpose of this present review is therefore to discuss the possible role of the UPR in the pathogenesis of PRAAS. We will particularly focus on pathways initiated by the four ER-membrane proteins ATF6, PERK, IRE1-α, and TCF11/Nrf1 which undergo activation under proteasome inhibition. An overview of the current understanding of the mechanisms and potential cross-talk between the UPR and inflammatory signaling casacades is provided to convey a more integrated picture of the pathophysiology of PRAAS and shed light on potential biomarkers and therapeutic targets.
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clinical aspects and genetics of proteasome associated Autoinflammatory Syndromes praas
Zeitschrift Fur Rheumatologie, 2017Co-Authors: Eugen Feist, Anja Brehm, T Kallinich, Elke KrügerAbstract:: Functional disorders of the proteasome can have a severe impact on the innate immune system. Characterized by an autosomal recessive mode of inheritance, this novel type of interferonopathy is considered to be a spectrum of diseases of proteasome-associated Autoinflammatory Syndromes (PRAAS). Accumulation of ubiquitinated proteins and the induction of type I interferon (IFN) genes seem to play a role in the pathogenesis. The typical clinical manifestations are lipodystrophy, skin, joint and muscle involvement accompanied by a remarkable variability of other associated symptoms. This article provides an overview on currently known molecular alterations as well as clinical similarities and differences of PRAAS. Furthermore, the reported effects of the immunosuppressive therapy approaches used so far are summarized.
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Dysfunction in protein clearance by the proteasome: impact on Autoinflammatory diseases
Seminars in Immunopathology, 2015Co-Authors: Anja Brehm, Elke KrügerAbstract:During innate immune responses, proteostasis is greatly impacted by synthesis of pathogen proteins as well as by inflammatory tissue damage through radicals or other damaging molecules released by phagocytes. An adequate adaptation of cellular clearance pathways to the increased burden of damaged proteins is thus of fundamental importance for cells and tissues to prevent protein aggregation, inclusion body formation, and ultimately cell death. We here review the current understanding of the pivotal role of the ubiquitin proteasome system (UPS) in this proteostasis network. The proteolytic capacity of the UPS can be adjusted by differential gene expression, the incorporation and maturation kinetics of alternative active sites, and the attachment of different regulators. Dysregulation of this fine-tuning is likely to induce cell death but seen more often to promote inflammation as well. The link between proteostasis impairment and inflammation may play a crucial role in autoinflammation as well as in age-related diseases and currently uncharacterized diseases. Recent studies on proteasome-associated Autoinflammatory Syndromes (PRAAS) discovered that IFN signaling drives the inflammation caused by reduction of degradation capacity. Elucidation of these Syndromes will reveal further insights in the understanding of inadequate immune responses. Knowledge related to the diversity of this degradation system will raise the awareness of potential pitfalls in the molecular diagnostics of Autoinflammatory Syndromes and may help to identify novel drug targets.