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Blau Syndrome

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C D Rose – One of the best experts on this subject based on the ideXlab platform.

  • Autoinflammatory Granulomatous Disease: Blau Syndrome
    Textbook of Autoinflammation, 2019
    Co-Authors: C D Rose, Carine Wouters

    Abstract:

    Blau Syndrome (BS) is a monogenic granulomatous polyarthritis associated with rather severe uveitis resulting from mutations at or near the nucleotide-binding oligomerization domain (NOD) domain of NOD2. It encompasses early-onset sarcoidosis (EOS), a form of granulomatous arthritis affecting children before the age of 5 years and known since the mid-1970s, and a familial form described separately by Blau and Jabs in 1985. Once the mutation was identified it was clear that BS and EOS were the same disease and both are now covered under the eponym Blau Syndrome. This chapter covers the spectrum of clinical manifestations of and diagnostic strategies for the investigation of patients with Blau Syndrome, provides an update on pathogenesis and highlights several management recommendations. These developed as knowledge of the natural history improved with the creation of multicenter cross-sectional studies and an ongoing multicenter cohort study.

  • Blau Syndrome associated nod2 mutation alters expression of full length nod2 and limits responses to muramyl dipeptide in knock in mice
    Journal of Immunology, 2015
    Co-Authors: Jae Dugan, C D Rose, James T. Rosenbaum, Eric Griffiths, Paige Snow, Holly L Rosenzweig, Brieanna Brown, Daniel W Carr, Michael P. Davey

    Abstract:

    The biochemical mechanism by which mutations in nucleotide-binding oligomerization domain containing 2 ( NOD2 ) cause Blau Syndrome is unknown. Several studies have examined the effect of mutations associated with Blau Syndrome in vitro, but none has looked at the implication of the mutations in vivo. To test the hypothesis that mutated NOD2 causes alterations in signaling pathways downstream of NOD2, we created a Nod2 knock-in mouse carrying the most common mutation seen in Blau Syndrome, R314Q (corresponding to R334Q in humans). The endogenous regulatory elements of mouse Nod2 were unaltered. R314Q mice showed reduced cytokine production in response to i.p. and intravitreal muramyl dipeptide (MDP). Macrophages from R314Q mice showed reduced NF-κB and IL-6 responses, blunted phosphorylation of MAPKs, and deficient ubiquitination of receptor-interacting protein 2 in response to MDP. R314Q mice expressed a truncated 80-kDa form of NOD2 that was most likely generated by a posttranslational event because there was no evidence for a stop codon or alternative splicing event. Human macrophages from two patients with Blau Syndrome also showed a reduction of both cytokine production and phosphorylation of p38 in response to MDP, indicating that both R314Q mice and cells from patients with Blau Syndrome show reduced responses to MDP. These data indicate that the R314Q mutation when studied with the Nod2 endogenous regulatory elements left intact is associated with marked structural and biochemical changes that are significantly different from those observed from studies of the mutation using overexpression, transient transfection systems.

  • Blau Syndrome–Associated Nod2 Mutation Alters Expression of Full-Length NOD2 and Limits Responses to Muramyl Dipeptide in Knock-in Mice
    Journal of Immunology, 2014
    Co-Authors: Jae Dugan, C D Rose, James T. Rosenbaum, Eric Griffiths, Paige Snow, Holly L Rosenzweig, Brieanna Brown, Daniel W Carr, Ellen Lee, Michael P. Davey

    Abstract:

    The biochemical mechanism by which mutations in nucleotide-binding oligomerization domain containing 2 (NOD2) cause Blau Syndrome is unknown. Several studies have examined the effect of mutations associated with Blau Syndrome in vitro, but none has looked at the implication of the mutations in vivo. To test the hypothesis that mutated NOD2 causes alterations in signaling pathways downstream of NOD2, we created a Nod2 knock-in mouse carrying the most common mutation seen in Blau Syndrome, R314Q (corresponding to R334Q in humans). The endogenous regulatory elements of mouse Nod2 were unaltered. R314Q mice showed reduced cytokine production in response to i.p. and intravitreal muramyl dipeptide (MDP). Macrophages from R314Q mice showed reduced NF-κB and IL-6 responses, blunted phosphorylation of MAPKs, and deficient ubiquitination of receptor-interacting protein 2 in response to MDP. R314Q mice expressed a truncated 80-kDa form of NOD2 that was most likely generated by a posttranslational event because there was no evidence for a stop codon or alternative splicing event. Human macrophages from two patients with Blau Syndrome also showed a reduction of both cytokine production and phosphorylation of p38 in response to MDP, indicating that both R314Q mice and cells from patients with Blau Syndrome show reduced responses to MDP. These data indicate that the R314Q mutation when studied with the Nod2 endogenous regulatory elements left intact is associated with marked structural and biochemical changes that are significantly different from those observed from studies of the mutation using overexpression, transient transfection systems.

Tammy M. Martin – One of the best experts on this subject based on the ideXlab platform.

  • Sporadic Blau Syndrome with onset of widespread granulomatous dermatitis in the newborn period
    Pediatric Dermatology, 2010
    Co-Authors: Johanna Stoevesandt, Tammy M. Martin, Henner Morbach, Manfred Zierhut, Hermann Girschick, Henning Hamm

    Abstract:

    :  Blau Syndrome is a dominantly inherited, chronic autoinflammatory disorder characterized by the clinical triad of granulomatous dermatitis, symmetric arthritis, and recurrent uveitis with onset below 4 years of age. It is caused by activating mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene, previously referred to as CARD15 gene. Noncaseating granulomas in affected tissues are the pathologic hallmark of the condition. We report the lifelong severe disease course in a 14-year-old Caucasian boy with sporadic Blau Syndrome. Unusually, granulomatous dermatitis started in the first week of life. Whereas skin involvement faded away spontaneously in subsequent years, polyarthritis and anterior uveitis appeared in the second and third year of life respectively. Mutational analysis of the NOD2 gene revealed a missense mutation (R334W) previously detected in other Blau Syndrome pedigrees. With this report, we would like to stress the rare possibility of Blau Syndrome in generalized papular rashes of infancy and the importance of histopathologic study for clarification. The finding of early-onset widespread granulomatous dermatitis should prompt eye and joint examination in regular intervals and entail mutational analysis of the NOD2 gene.

  • The NOD2 defect in Blau Syndrome does not result in excess interleukin 1 activity
    Arthritis & Rheumatism, 2009
    Co-Authors: Tammy M. Martin, C D Rose, Michael P. Davey, Zili Zhang, Paul A. Kurz, Hong Chen, Stephen R. Planck, James T. Rosenbaum

    Abstract:

    Objective
    Blau Syndrome is a rare, autosomal dominant, autoinflammatory disorder characterized by granulomatous arthritis, uveitis, and dermatitis. Genetic studies have shown that the disease is caused by single, nonsynonymous substitutions in NOD2, a member of the NOD-like receptor, or NACHT-LRR, (NLR) family of intracellular proteins. Several NLR function in the innate immune system as sensors of pathogen components and participate in immune-mediated cellular responses via the caspase 1 inflammasome. Mutations in a gene related to NOD2, NLRP3, are responsible for excess caspase 1-dependent IL-1β in cryopyrinopathies like Muckle-Wells Syndrome. Furthermore, functional studies demonstrate that caspase 1-mediated release of IL-1β also involves NOD2. Here we test the hypothesis that IL-1β may mediate the inflammation seen in Blau Syndrome patients.

  • Interstitial pneumonitis in Blau Syndrome with documented mutation in CARD15
    Arthritis & Rheumatism, 2007
    Co-Authors: Mara L. Becker, T. M. Doyle, Tammy M. Martin, C D Rose

    Abstract:

    This is the first report of a CARD15 mutation-positive patient with Blau Syndrome who exhibited interstitial lung disease, a feature historically considered absent from Blau Syndrome, while typical of the adult form of sarcoidosis. This case illustrates the continued evolution of the phenotype of a disease initially conceived as a familial inflammatory granulomatous disease limited to the triad of synovitis, dermatitis, and uveitis.

Naotomo Kambe – One of the best experts on this subject based on the ideXlab platform.

  • Clinical characteristics and treatment of 50 cases of Blau Syndrome in Japan confirmed by genetic analysis of the NOD2 mutation.
    Annals of the Rheumatic Diseases, 2020
    Co-Authors: Tomoko Matsuda, Naotomo Kambe, Syuji Takei, Nobuo Kanazawa, Yoko Ueki, Kazushi Izawa, Yoshitaka Honda, Atsushi Kawakami, Kyoko Tonomura, Masami Inoue

    Abstract:

    Objectives To collect clinical information and NOD2 mutation data on patients with Blau Syndrome and to evaluate their prognosis. Methods Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. Results The study population comprised 26 males and 24 females aged 0–61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau Syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. Conclusions In patients with Blau Syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

  • Blau Syndrome: NOD2-related systemic autoinflammatory granulomatosis.
    Giornale italiano di dermatologia e venereologia : organo ufficiale Società italiana di dermatologia e sifilografia, 2020
    Co-Authors: Sanami Takada, Megumu K. Saito, Naotomo Kambe

    Abstract:

    Blau Syndrome, or early-onset sarcoidosis, is hereditary juvenile-onset systemic granulomatosis. Clinical symptoms appear before the age of 4 years and mainly affect the skin, joints, and eyes. The symptoms are progressive and cause severe complications, such as joint destruction and blindness. Although tumor necrosis factor alpha (TNFα) antagonists are effective for controlling some of the symptoms of Blau Syndrome, there is no specific curative treatment. Heterozygous mutations in nucleotide-binding oligomerization domain 2 (NOD2) were identified as the cause of Blau Syndrome onset. NOD2 is an intracellular pathogen recognition receptor, the ligand of which is muramyl dipeptide (MDP) found in bacterial cell walls. Upon binding to MDP, NOD2 activates the NF-κB pathway, which leads to upregulation of proinflammatory cytokines. However, the detailed molecular mechanisms by which disease associated NOD2 mutations lead to autoinflammation and granuloma formation are still unclear. To clarify the relationship between disease associated NOD2 mutations and the inflammatory response, we established induced pluripotent stem (iPS) cells from Blau Syndrome patients. Functional analyses using these iPS cells suggested that IFNγ is a critical mediator of the inflammatory manifestations in this disease. This experimental finding is supported by the clinical observation that bacillus Calmette-Guesrin (BCG) vaccination is sometimes associated with disease onset, since IFNγ is a major cytokine associated with BCG-mediated immune responses. Further investigation of NOD2 signaling and accumulation of clinical cases are essential to elucidate the mechanisms of Blau Syndrome and develop an effective treatment for patients.

  • pluripotent stem cell models of Blau Syndrome reveal an ifn γ dependent inflammatory response in macrophages
    The Journal of Allergy and Clinical Immunology, 2018
    Co-Authors: Naotomo Kambe, Sanami Takada, Yuri Kawasaki, Akira Niwa, Kazuki Kobayashi, Mitsujiro Osawa, Ayako Nagahashi, Fumiko Hondaozaki, Katsunori Semi

    Abstract:

    Background Blau Syndrome, or early-onset sarcoidosis, is a juvenile-onset systemic granulomatosis associated with a mutation in nucleotide-binding oligomerization domain 2 (NOD2) . The underlying mechanisms of Blau Syndrome leading to autoinflammation are still unclear, and there is currently no effective specific treatment for Blau Syndrome. Objectives To elucidate the mechanisms of autoinflammation in patients with Blau Syndrome, we sought to clarify the relation between disease-associated mutant NOD2 and the inflammatory response in human samples. Methods Blau Syndrome–specific induced pluripotent stem cell (iPSC) lines were established. The disease-associated NOD2 mutation of iPSCs was corrected by using a CRISPR-Cas9 system to precisely evaluate the in vitro phenotype of iPSC-derived cells. We also introduced the same NOD2 mutation into a control iPSC line. These isogenic iPSCs were then differentiated into monocytic cell lineages, and the statuses of nuclear factor κB pathway and proinflammatory cytokine secretion were investigated. Results IFN-γ acted as a priming signal through upregulation of NOD2. In iPSC-derived macrophages with mutant NOD2, IFN-γ treatment induced ligand-independent nuclear factor κB activation and proinflammatory cytokine production. RNA sequencing analysis revealed distinct transcriptional profiles of mutant macrophages both before and after IFN-γ treatment. Patient-derived macrophages demonstrated a similar IFN-γ–dependent inflammatory response. Conclusions Our data support the significance of ligand-independent autoinflammation in the pathophysiology of Blau Syndrome. Our comprehensive isogenic disease-specific iPSC panel provides a useful platform for probing therapeutic and diagnostic clues for the treatment of patients with Blau Syndrome.