NOD2-Related Multisystem Inflammatory Disorders and Recent Advances

Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem. 2001;276(7):4812–8.

Article  CAS  PubMed  Google Scholar 

Hedl M, Li J, Cho JH, Abraham C. Chronic stimulation of Nod2 mediates tolerance to bacterial products. Proc Natl Acad Sci U S A. 2007;104(49):19440–5.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Lala S, Ogura Y, Osborne C, Hor SY, Bromfield A, Davies S, Ogunbiyi O, Nunez G, Keshav S. Crohn’s disease and the NOD2 gene: a role for Paneth cells. Gastroenterology. 2003;125(1):47–57.

Article  CAS  PubMed  Google Scholar 

Yao Q. Nucleotide-binding oligomerization domain containing 2: Structure, function, and diseases. Semin Arthritis Rheum; 2013.

Abraham C, Cho JH. Functional consequences of NOD2 (CARD15) mutations. Inflamm Bowel Dis. 2006;12(7):641–50.

Article  PubMed  Google Scholar 

Hugot JP, Chamaillard M, Zouali H, Lesage S, Cezard JP, Belaiche J, Almer S, Tysk C, O’Morain CA, Gassull M, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to crohn’s disease. Nature. 2001;411(6837):599–603.

Article  CAS  PubMed  Google Scholar 

McGovern DP, van Heel DA, Ahmad T, Jewell DP. NOD2 (CARD15), the first susceptibility gene for crohn’s disease. Gut. 2001;49(6):752–4.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cho JH. The Nod2 gene in crohn’s disease: implications for future research into the genetics and immunology of crohn’s disease. Inflamm Bowel Dis. 2001;7(3):271–5.

Article  CAS  PubMed  Google Scholar 

Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S, Hafner R, Chamaillard M, Zouali H, Thomas G, Hugot JP. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29(1):19–20.

Article  CAS  PubMed  Google Scholar 

Wang X, Kuivaniemi H, Bonavita G, Mutkus L, Mau U, Blau E, Inohara N, Nunez G, Tromp G, Williams CJ. CARD15 mutations in Familial granulomatosis syndromes: a study of the original Blau syndrome kindred and other families with large-vessel arteritis and cranial neuropathy. Arthritis Rheum. 2002;46(11):3041–5.

Article  CAS  PubMed  Google Scholar 

Yao Q, Su LC, Tomecki KJ, Zhou L, Jayakar B, Shen B. Dermatitis as a characteristic phenotype of a new autoinflammatory disease associated with NOD2 mutations. J Am Acad Dermatol. 2013;68(4):624–31.

Article  CAS  PubMed  Google Scholar 

Wu S, Deng Z, Uddin A, Xin B, Gorevic P, Yao Q. Utilization of the All of Us Research Program in a study of genetics of Yao syndrome. J Allergy Clin Immunol 2025 Nov 7:S0091–6749(25)01118–2 https://doi.org/10.1016/j.jaci.2025.10.028. Online ahead of print.

Google Scholar 

Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr. 1985;107(5):689–93.

Article  CAS  PubMed  Google Scholar 

Kanazawa N, Okafuji I, Kambe N, Nishikomori R, Nakata-Hizume M, Nagai S, Fuji A, Yuasa T, Manki A, Sakurai Y, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-kappaB activation: common genetic etiology with Blau syndrome. Blood. 2005;105(3):1195–7.

Article  CAS  PubMed  Google Scholar 

Matsuda T, Kambe N, Ueki Y, Kanazawa N, Izawa K, Honda Y, Kawakami A, Takei S, Tonomura K, Inoue M, et al. Clinical characteristics and treatment of 50 cases of Blau syndrome in Japan confirmed by genetic analysis of the NOD2 mutation. Ann Rheum Dis. 2020;79(11):1492–9.

Article  CAS  PubMed  Google Scholar 

Rose CD, Pans S, Casteels I, Anton J, Bader-Meunier B, Brissaud P, Cimaz R, Espada G, Fernandez-Martin J, Hachulla E, et al. Blau syndrome: cross-sectional data from a multicentre study of clinical, radiological and functional outcomes. Rheumatology (Oxford). 2015;54(6):1008–16.

Article  CAS  PubMed  Google Scholar 

Ikeda K, Kambe N, Takei S, Nakano T, Inoue Y, Tomiita M, Oyake N, Satoh T, Yamatou T, Kubota T, et al. Ultrasonographic assessment reveals detailed distribution of synovial inflammation in Blau syndrome. Arthritis Res Ther. 2014;16(2):R89.

Article  PubMed  PubMed Central  Google Scholar 

Sarens IL, Casteels I, Anton J, Bader-Meunier B, Brissaud P, Chedeville G, Cimaz R, Dick AD, Espada G, Fernandez-Martin J, et al. Blau Syndrome-Associated uveitis: preliminary results from an international prospective interventional case series. Am J Ophthalmol. 2018;187:158–66.

Article  PubMed  Google Scholar 

Matsuda T, Kambe N, Takimoto-Ito R, Ueki Y, Nakamizo S, Saito MK, Takei S, Kanazawa N. Potential benefits of TNF targeting therapy in Blau Syndrome, a NOD2-Associated systemic autoinflammatory granulomatosis. Front Immunol. 2022;13:895765.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Kitagawa Y, Kawasaki Y, Yamasaki Y, Kambe N, Takei S, Saito MK. Anti-TNF treatment corrects IFN-gamma-dependent Proinflammatory signatures in Blau syndrome patient-derived macrophages. J Allergy Clin Immunol. 2022;149(1):176–e188177.

Article  CAS  PubMed  Google Scholar 

Ueki Y, Takimoto-Ito R, Saito MK, Tanizaki H, Kambe N. Tofacitinib, a suppressor of NOD2 expression, is a potential treatment for Blau syndrome. Front Immunol. 2023;14:1211240.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang S, Cai Z, Mo X, Zeng H. Tofacitinib effectiveness in Blau syndrome: a case series of Chinese paediatric patients. Pediatr Rheumatol Online J. 2021;19(1):160.

Article  PubMed  PubMed Central  Google Scholar 

Yao Q, Shen B. A Systematic Analysis of Treatment and Outcomes of NOD2-Associated Autoinflammatory Disease. Am J Med. 2017;130(3):365. e313–365 e318.

Article  CAS  Google Scholar 

Nomani H, Wu S, Saif A, Hwang F, Metzger J, Navetta-Modrov B, Gorevic PD, Aksentijevich I, Yao Q. Comprehensive clinical phenotype, genotype and therapy in Yao syndrome. Front Immunol. 2024;15:1458118.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Williamson KA, Samec MJ, Patel JA, Orandi AB, Wang B, Crowson CS, Loftus EV Jr., Alavi A, Moyer AM, Davis JM. 3rd: clinical phenotype, NOD2 genotypes, and treatment observations in Yao syndrome: a retrospective case series. Front Immunol. 2024;15:1304792.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Davis JM 3rd, McDonald C, Yao Q. Editorial: Basic, clinical, and translational studies of Yao syndrome and other NOD2 related diseases. Front Immunol. 2024;15:1521815.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Karamanakos A, Vougiouka O, Sapountzi E, Venetsanopoulou AI, Tektonidou MG, Germenis AE, Sfikakis PP, Laskari K. The expanding clinical spectrum of autoinflammatory diseases with NOD2 variants: a case series and literature review. Front Immunol. 2024;15:1342668.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Zhang J, Huang X, Shen M. Expanding clinical characteristics and genotypic profiling of Yao syndrome in Chinese patients. Front Immunol. 2024;15:1444542.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Cresoe-Ortiz S, Hall G, Randell RL, Lawrence MG, Patel A, Peroutka C, Yao Q, Mousallem T. Yao syndrome in a child with C2 deficiency. J Allergy Clin Immunol Pract. 2024;12(11):3159–62.

Article  CAS  PubMed  PubMed Central  Google Scholar 

Yao Q, Schils J. Distal lower extremity swelling as a prominent phenotype of NOD2-associated autoinflammatory disease. Rheumatology (Oxford). 2013;52(11):2095–7.

Article  PubMed 

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