IL-1β and Caspase-1 Drive Autoinflammatory Disease Independently of IL-1α or Caspase-8 in a Mouse Model of Familial Mediterranean Fever

Gastrointestinal (GI) manifestations, such as abdominal pain, nausea, vomiting, and diarrhea, are common autoinflammatory disease (AID) symptoms. The abdominal symptomatology reflecting serositis is one of the most important classification and diagnostic criteria for the classic monogenic AID (MAID) – familial Mediterranean fever (FMF). Failure to timely diagnose FMF frequently leads to unjustified surgical interventions. Other periodic fevers may also present as abdominal symptoms; however, the latter are outside their diagnostic features. These diseases include, first of all, tumor necrosis factor receptor-associated periodic syndrome (TRAPS). Interleukin 1 (IL1) inhibitors serve as the major targeted drugs for the treatment of TRAPS. Russia has registered the IL1 inhibitor canakinumab that prevents the development of organ damages, including those in the GI tract. The paper describes a clinical case of the classic manifestations of TRAPS (fever, rash, periorbital edema, arthritis, and elevated levels of acutephase inflammatory markers) concurrent with severe abdominalgia during attacks and with the development of severe peritoneal adhesions, which led to bowel perforation and emergency surgical intervention. The prolonged persistence of inflammatory attacks before the initiation of therapy, as well as violation of the IL1 inhibitor administration regimen facilitated the development of an urgent exacerbation. Thus, TRAPS should be included in the differential diagnostic circle for patients with severe gastrointestinal manifestations characterized by an attack-like course. These patients need timely prescription of targeted therapy, strict adherence to the dosing and intervals between drug administrations, and careful monitoring to prevent serious complications with the visceral organs, including the gastrointestinal tract, and their immediate correction.

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Unified Modeling of Familial Mediterranean Fever and Cryopyrin Associated Periodic Syndromes

Computational and Mathematical Methods in Medicine ◽

10.1155/2015/893507 ◽

2015 ◽

Vol 2015 ◽

pp. 1-18 ◽

Cited By ~ 6

Author(s):

Yasemin Bozkurt ◽

Alper Demir ◽

Burak Erman ◽

Ahmet Gül

Keyword(s):

Familial Mediterranean Fever ◽

Nonlinear Ordinary Differential Equations ◽

Extensive Simulation ◽

Unified Modeling ◽

Caspase 1 ◽

Hereditary Autoinflammatory Diseases ◽

Clinical Observations ◽

Genes Encoding ◽

Mediterranean Fever ◽

Simulation Results

Familial mediterranean fever (FMF) and Cryopyrin associated periodic syndromes (CAPS) are two prototypical hereditary autoinflammatory diseases, characterized by recurrent episodes of fever and inflammation as a result of mutations inMEFVandNLRP3genes encoding Pyrin and Cryopyrin proteins, respectively. Pyrin and Cryopyrin play key roles in the multiprotein inflammasome complex assembly, which regulates activity of an enzyme, Caspase 1, and its target cytokine, IL-1β. Overproduction of IL-1βby Caspase 1 is the main cause of episodic fever and inflammatory findings in FMF and CAPS. We present a unifying dynamical model for FMF and CAPS in the form of coupled nonlinear ordinary differential equations. The model is composed of two subsystems, which capture the interactions and dynamics of the key molecular players and the insults on the immune system. One of the subsystems, which contains a coupled positive-negative feedback motif, captures the dynamics of inflammation formation and regulation. We perform a comprehensive bifurcation analysis of the model and show that it exhibits three modes, capturing the Healthy, FMF, and CAPS cases. The mutations in Pyrin and Cryopyrin are reflected in the values of three parameters in the model. We present extensive simulation results for the model that match clinical observations.

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The PRY/SPRY Domain of Pyrin/TRIM20, The Familial Mediterranean Fever Protein, Interacts with β2-Microglobulin to Promote Inflammasome Formation

10.21203/rs.3.rs-212639/v1 ◽

2021 ◽

Author(s):

Sei Samukawa ◽

Ryusuke Yoshimi ◽

Yohei Kirino ◽

Hideaki Nakajima

Keyword(s):

Familial Mediterranean Fever ◽

Protein Interactions ◽

Hek293 Cells ◽

Human Neutrophils ◽

Interacting Protein ◽

Hek 293 ◽

Spry Domain ◽

Caspase 1 ◽

Associated Proteins ◽

Mediterranean Fever

Abstract Background. Pyrin/TRIM20 is expressed in the neutrophils and monocytes/macrophages and regulates caspase-1 activation and interleukin-1β maturation. Although the mutations in the PRY/SPRY domain of pyrin cause familial Mediterranean fever (FMF), the mechanism of how mutated pyrin provokes excessive inflammation in FMF patients is not well understood. This study was undertaken to explore the new pyrin PRY/SPRY domain-binding protein and to investigate how the interaction affected the pyrin function.Methods. We carried out the yeast two-hybrid screening for pyrin PRY/SPRY domain-binding proteins. Then, protein interactions were investigated using Lenti-X 293T cells expressing pyrin-associated proteins by co-immunoprecipitation analysis. We also used human embryonic kidney (HEK) 293 cells expressing pyrin-associated proteins and human neutrophils stimulated with monosodium urate crystal for immunofluorescence staining analysis.Results. β2-Microglobulin (β2MG) was identified as the novel pyrin ligand binding to the PRY/SPRY domain. β2MG was co-localized with pyrin not only in the HEK293 cells overexpressing these proteins but also in the stimulated human neutrophils in the speck-like structures. The pyrin-β2MG interaction triggered the binding of pyrin and proline-serine-threonine phosphatase interacting protein 1 (PSTPIP1) and then the subsequent recruitment of apoptosis-associated speck-like protein containing caspase recruitment domain (ASC). Caspase-1 p20 subunit, produced by pyrin inflammasome, also interacted with the pyrin PRY/SPRY domain and inhibited the pyrin-β2MG interaction. FMF-associated pyrin mutation M694V did not affect pyrin-β2MG interaction but weakened this inhibition.Conclusions. Our findings suggest that β2MG functions as the pyrin ligand inducing pyrin inflammasome formation and that the FMF-associated pyrin mutations weakened negative feedback of caspase-1 p20 subunit.

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Kawasaki disease triggered by EBV virus in a child with Familial Mediterranean Fever

Italian Journal of Pediatrics ◽

10.1186/s13052-019-0717-8 ◽

2019 ◽

Vol 45 (1) ◽

Cited By ~ 2

Author(s):

Maria Cristina Maggio ◽

Carmelo Fabiano ◽

Giovanni Corsello

Keyword(s):

Kawasaki Disease ◽

Familial Mediterranean Fever ◽

Epstein Barr Virus ◽

Autoinflammatory Disease ◽

Mefv Gene ◽

Clinical Manifestations ◽

Epstein Barr Virus Infection ◽

Barr Virus ◽

Mediterranean Fever ◽

Epstein Barr

Abstract Background Familial Mediterranean Fever is a monogenic autoinflammatory disease, secondary to mutation of MEFV gene, and typically expressed with recurrent attacks of fever, serositis, rash, aphthous changes in lips and/or oral mucosa. Kawasaki Disease, an acute systemic vasculitis with persistent fever (5 or more days), rash, stomatitis, conjunctivitis, lymphadenopathy, changes in extremities, is currently considered a multifactorial autoinflammatory disease. An infection, as Epstein Barr virus, can be the trigger of Kawasaki Disease. Case presentation We describe the clinical case of a 3-year-old boy with Kawasaki disease. Successfully treated with intravenous immune globulin, acetyl salicylate acid, he late developed anaemia and thrombocytopenia. The Epstein-Barr virus infection has been demonstrated and he showed a resolution of the clinical manifestations of Kawasaki disease with the persistence of coronaritis, without aneurisms. However, for the personal and familial history of monthly recurrent attacks of fever, pharyngitis, abdominal pain, the genetic study of MEFV was performed and demonstrated 3 heterozygous mutations of MEFV (E148Q, P369S, R408Q). Conclusions Mutations of MEFV can contribute to increase inflammatory expression in other diseases, as Kawasaki disease.

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Familial Mediterranean fever mutations lift the obligatory requirement for microtubules in Pyrin inflammasome activation

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1613156113 ◽

2016 ◽

Vol 113 (50) ◽

pp. 14384-14389 ◽

Cited By ~ 76

Author(s):

Hanne Van Gorp ◽

Pedro H. V. Saavedra ◽

Nathalia M. de Vasconcelos ◽

Nina Van Opdenbosch ◽

Lieselotte Vande Walle ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Autoinflammatory Disease ◽

Mononuclear Cells ◽

Human Peripheral Blood ◽

Microtubule Assembly ◽

Inflammasome Activation ◽

Wild Type ◽

Peripheral Blood Mononuclear ◽

Mouse Macrophages ◽

Mediterranean Fever

Familial Mediterranean fever (FMF) is the most common monogenic autoinflammatory disease worldwide. It is caused by mutations in the inflammasome adaptor Pyrin, but how FMF mutations alter signaling in FMF patients is unknown. Herein, we establish Clostridium difficile and its enterotoxin A (TcdA) as Pyrin-activating agents and show that wild-type and FMF Pyrin are differentially controlled by microtubules. Diverse microtubule assembly inhibitors prevented Pyrin-mediated caspase-1 activation and secretion of IL-1β and IL-18 from mouse macrophages and human peripheral blood mononuclear cells (PBMCs). Remarkably, Pyrin inflammasome activation persisted upon microtubule disassembly in PBMCs of FMF patients but not in cells of patients afflicted with other autoinflammatory diseases. We further demonstrate that microtubules control Pyrin activation downstream of Pyrin dephosphorylation and that FMF mutations enable microtubule-independent assembly of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) micrometer-sized perinuclear structures (specks). The discovery that Pyrin mutations remove the obligatory requirement for microtubules in inflammasome activation provides a conceptual framework for understanding FMF and enables immunological screening of FMF mutations.

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The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.0602081103 ◽

2006 ◽

Vol 103 (26) ◽

pp. 9982-9987 ◽

Cited By ~ 351

Author(s):

J. J. Chae ◽

G. Wood ◽

S. L. Masters ◽

K. Richard ◽

G. Park ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Caspase 1 ◽

Mediterranean Fever ◽

B30.2 Domain

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A Rare Cause of Lymphadenopathy in Children: Autoinflammatory Disease - Familial Mediterranean Fever

Turkish Journal of Pediatric Disease ◽

10.12956/tjpd.2015.186 ◽

2015 ◽

Author(s):

Gonca KESKİNDEMİRCİ ◽

Nuray AKTAY AYAZ ◽

Deniz TUĞCU ◽

Mustafa ÇAKAN ◽

Gönül AYDOĞAN ◽

...

Keyword(s):

Familial Mediterranean Fever ◽

Autoinflammatory Disease ◽

Mediterranean Fever

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Familial Mediterranean fever: the molecular pathways from stress exposure to attacks

Rheumatology ◽

10.1093/rheumatology/keaa450 ◽

2020 ◽

Vol 59 (12) ◽

pp. 3611-3621

Author(s):

Cengiz Korkmaz ◽

Döndü U Cansu ◽

Güven Barış Cansu

Keyword(s):

Familial Mediterranean Fever ◽

Autoinflammatory Disease ◽

Inflammasome Activation ◽

Molecular Pathways ◽

Stress Exposure ◽

Sympathoadrenal System ◽

Mediterranean Fever ◽

System Activation ◽

New Perspective ◽

Stress Mediators

Abstract FMF is an autoinflammatory disease characterized by recurrent attacks and increased IL-1 synthesis owing to activation of the pyrin inflammasome. Although knowledge of the mechanisms leading to the activation of pyrin inflammasome is increasing, it is still unknown why the disease is characterized by attack. The emergence of FMF attacks after emotional stress and the induction of attacks with metaraminol in previous decades suggested that stress-induced sympathoadrenal system activation might play a role in inflammasome activation and triggering attacks. In this review, we will review the possible molecular mechanism of stress mediators on the inflammation pathway and inflammasome activation. Studies on stress mediators and their impact on inflammation pathways will provide a better understanding of stress-related exacerbation mechanisms in both autoinflammatory and autoimmune diseases. This review provides a new perspective on this subject and will contribute to new studies.

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Update on the management of colchicine resistant Familial Mediterranean Fever (FMF)

Orphanet Journal of Rare Diseases ◽

10.1186/s13023-019-1201-7 ◽

2019 ◽

Vol 14 (1) ◽

Cited By ~ 4

Author(s):

Georges El Hasbani ◽

Ali Jawad ◽

Imad Uthman

Keyword(s):

Familial Mediterranean Fever ◽

Acute Phase ◽

Acute Phase Response ◽

Autoinflammatory Disease ◽

Tnf Inhibitors ◽

Phase Response ◽

Autoinflammatory Diseases ◽

Tnf Alpha ◽

Main Body ◽

Mediterranean Fever

Abstract Background Familial Mediterranean Fever (FMF), an autoinflammatory disease, is characterized by self-limited inflammatory attacks of fever and polyserositis along with high acute phase response. Although colchicine remains the mainstay in treatment, intolerance and resistance in a certain portion of patients have been posing a problem for physicians. Main body Like many autoimmune and autoinflammatory diseases, many colchicine-resistant or intolerant FMF cases have been successfully treated with biologics. In addition, many studies have tested the efficacy of biologics in treating FMF manifestations. Conclusion Since carriers of FMF show significantly elevated levels of serum TNF alpha, IL-1, and IL-6, FMF patients who failed colchicine were successfully treated with anti IL-1, anti IL-6, or TNF inhibitors drugs. It is best to use colchicine in combination with biologics.

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The Comparison of Diagnostic Criteria in Children with Familial Mediterranean Fever

10.21203/rs.3.rs-705764/v1 ◽

2021 ◽

Author(s):

Esra Nagehan Akyol Onder ◽

Kudret Ebru Özcan ◽

Feride Iffet Sahin ◽

Kaan Savas Gulleroglu ◽

Esra Baskin

Keyword(s):

Familial Mediterranean Fever ◽

Diagnostic Criteria ◽

Autoinflammatory Disease ◽

High Sensitivity ◽

Clinical Findings ◽

Classification Criteria ◽

Laboratory Findings ◽

Simple Method ◽

Group A ◽

Mediterranean Fever

Abstract Familial Mediterranean Fever (FMF) is an autoinflammatory disease characterized with recurrent attacks of fever and serositis. The diagnosis is made according to clinical findings and supported by genetic analysis. The most used adult diagnostic criteria are the Tel-Hashomer criteria. The pediatric criteria for the FMF diagnosis of children were described in 2009, but their efficacy should be supported with further reports. In this study, we planned to compare the pediatric criteria and the Tel-Hashomer criteria in our FMF patients. We also aimed to evaluate the importance of the 2019 Eurofever/PRINTO classification criteria in this patient group. A total of 113 patients diagnosed with FMF were included in our study. Demographic features and laboratory findings were retrospectively recorded from the patients’ files. The patients were evaluated with the Tel-Hashomer, pediatric and Eurofever/PRINTO classification criteria. At least two of five new pediatric criteria were as sensitive (88.6%) and specific (84.62%) as the Tel-Hashomer criteria (sensitivity 69.9%, specificity 95.7%). We also evaluated the Eurofever/PRINTO classification criteria in our patients and found its sensitivity 93.8% and specificity 90.6%. Conclusion: Using pediatric criteria in the diagnosis of FMF in children is a feasible and simple method that can diagnose the disease based on at least two criteria. Therefore, our study supports the use of pediatric criteria in the diagnosis of FMF in children. Our results also confirm that the Eurofever/PRINTO classification criteria can be successfully used in the diagnosis of FMF due to their high sensitivity (93.8%) and specificity (90.6%).

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