Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis
Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upr...
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| Format: | Article |
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Frontiers Media S.A.
2022-05-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2022.895765/full |
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| author | Tomoko Matsuda Naotomo Kambe Naotomo Kambe Riko Takimoto-Ito Yoko Ueki Satoshi Nakamizo Megumu K. Saito Syuji Takei Nobuo Kanazawa |
| author_facet | Tomoko Matsuda Naotomo Kambe Naotomo Kambe Riko Takimoto-Ito Yoko Ueki Satoshi Nakamizo Megumu K. Saito Syuji Takei Nobuo Kanazawa |
| author_sort | Tomoko Matsuda |
| collection | DOAJ |
| description | Blau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome. |
| first_indexed | 2024-04-12T11:15:33Z |
| format | Article |
| id | doaj.art-2533f05b4c0b415c9e65a5d3e36ccc1b |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-04-12T11:15:33Z |
| publishDate | 2022-05-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2533f05b4c0b415c9e65a5d3e36ccc1b2022-12-22T03:35:30ZengFrontiers Media S.A.Frontiers in Immunology1664-32242022-05-011310.3389/fimmu.2022.895765895765Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory GranulomatosisTomoko Matsuda0Naotomo Kambe1Naotomo Kambe2Riko Takimoto-Ito3Yoko Ueki4Satoshi Nakamizo5Megumu K. Saito6Syuji Takei7Nobuo Kanazawa8Department of Dermatology, Kansai Medical University, Hirakata, JapanDepartment of Dermatology, Kansai Medical University, Hirakata, JapanDepartment of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Dermatology, Kansai Medical University, Hirakata, JapanDepartment of Dermatology, Kyoto University Graduate School of Medicine, Kyoto, JapanDepartment of Clinical Application, Center for iPS Cell Research and Application, Kyoto University, Kyoto, JapanDepartment of Pediatrics, Kagoshima University, Kagoshima, JapanDepartment of Dermatology, Hyogo Medical University, Nishinomiya, JapanBlau syndrome is a systemic autoinflammatory granulomatous disease caused by mutations in the nucleotide-binding oligomerization domain 2 (NOD2) gene. NOD2 is an intracellular pathogen recognition receptor. Upon binding to muramyl dipeptide (MDP), NOD2 activates the NF-κB pathway, leading to the upregulation of proinflammatory cytokines. Clinical manifestations of Blau syndrome appear in patients before the age of four. Skin manifestations resolve spontaneously in some cases; however, joint and eye manifestations are progressive, and lead to serious complications, such as joint contracture and blindness. Currently, there is no specific curative treatment for the disease. Administration of high-dose oral steroids can improve clinical manifestations; however, treatments is difficult to maintain due to the severity of the side effects, especially in children. While several new therapies have been reported, including JAK inhibitors, anti-IL-6 and anti-IL-1 therapies, anti-TNF therapy plays a central role in the treatment of Blau syndrome. We recently performed an ex vivo study, using peripheral blood and induced pluripotent stem cells from patients. This study demonstrated that abnormal cytokine expression in macrophages from untreated patients requires IFNγ stimulation, and that anti-TNF treatment corrects the abnormalities associated with Blau syndrome, even in the presence of IFNγ. Therefore, although the molecular mechanisms by which the genetic mutations in NOD2 lead to granuloma formation remain unclear, it is possible that prior exposure to TNFα combined with IFNγ stimulation may provide the impetus for the clinical manifestations of Blau syndrome.https://www.frontiersin.org/articles/10.3389/fimmu.2022.895765/fullBlau syndromeNOD2granulomaIFNγTNF |
| spellingShingle | Tomoko Matsuda Naotomo Kambe Naotomo Kambe Riko Takimoto-Ito Yoko Ueki Satoshi Nakamizo Megumu K. Saito Syuji Takei Nobuo Kanazawa Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis Frontiers in Immunology Blau syndrome NOD2 granuloma IFNγ TNF |
| title | Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis |
| title_full | Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis |
| title_fullStr | Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis |
| title_full_unstemmed | Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis |
| title_short | Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis |
| title_sort | potential benefits of tnf targeting therapy in blau syndrome a nod2 associated systemic autoinflammatory granulomatosis |
| topic | Blau syndrome NOD2 granuloma IFNγ TNF |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2022.895765/full |
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