A novel nucleotide oligomerisation domain 2 mutation in a family with Blau syndrome: Phenotype and function

Ong, Lawrence; Nachbur, Ueli; Rowczenio, Dorota; Ziegler, John B.; Fischer, Eddy; Lin, Ming

doi:10.1177/1753425917727063

Cited by 9 publications

(8 citation statements)

References 18 publications

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“…Indeed, early studies in HEK cell lines transfected with NOD2 or Blau-variant NOD2 showed excessive NF-κB activity 50 , 51 at baseline levels and in response to MDP; thereby implicating over-activation of the canonical Nod2-signaling axis in Blau syndrome. However, more recent in vitro studies using PBMCs or monocytes 52 – 55 derived from patients with Blau syndrome showed reduced NF-κB activation and cytokines such as IL-1β in response to MDP, suggestive of a loss-of-function or “exhausted phenotype” in myeloid cells. We have also observed impaired MDP-signaling and NF-κB activation in macrophages derived from Blau patients, a cellular mechanism which was further dissected in Blau-mutant mice 56 .…”

Section: Discussionmentioning

confidence: 99%

T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

et al. 2020

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Mutations in nucleotide-binding oligomerization domain-containing protein 2 (NOD2) cause Blau syndrome, an inflammatory disorder characterized by uveitis. The antimicrobial functions of Nod2 are well-established, yet the cellular mechanisms by which dysregulated Nod2 causes uveitis remain unknown. Here, we report a non-conventional, T cell-intrinsic function for Nod2 in suppression of Th17 immunity and experimental uveitis. Reconstitution of lymphopenic hosts with Nod2−/− CD4+ T cells or retina-specific autoreactive CD4+ T cells lacking Nod2 reveals a T cell-autonomous, Rip2-independent mechanism for Nod2 in uveitis. In naive animals, Nod2 operates downstream of TCR ligation to suppress activation of memory CD4+ T cells that associate with an autoreactive-like profile involving IL-17 and Ccr7. Interestingly, CD4+ T cells from two Blau syndrome patients show elevated IL-17 and increased CCR7. Our data define Nod2 as a T cell-intrinsic rheostat of Th17 immunity, and open new avenues for T cell-based therapies for Nod2-associated disorders such as Blau syndrome.

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Section: Discussionmentioning

confidence: 99%

T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

et al. 2020

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“…The 38 patients with digestive system involvement comprised 15 men, 18 women, and five with unknown gender, with a median age at baseline evaluation of 20.3 years (range: 1.4–57). Of the 38 patients with digestive system involvement, 14 had hepatic granulomas proven by liver biopsy ( 5 , 7 , 11 , 16 , 20 – 27 ); five patients with hepatic granulomas had liver cirrhosis ( 21 , 23 , 24 , 26 , 27 ); 24 had enlarged liver and/or spleen ( 5 , 11 , 12 , 15 , 16 , 18 , 22 , 26 , 27 , 29 – 35 ); six had elevated liver enzymes including transaminase and cholestatic liver enzyme ( 21 – 24 , 26 , 27 ); five had gastrointestinal diseases including gastric ulcer, diverticulitis, Barrett's esophagus and small and large intestine granulomas ( 6 , 13 , 36 ); one had multiple splenic and hepatic lesions ( 28 ); and one had fatty liver ( 13 ) ( Supplementary Table S2 ).…”

Section: Resultsmentioning

confidence: 99%

Blau syndrome with hypertension and hepatic granulomas: a case report and literature review

Yao

Tan

et al. 2023

Front. Pediatr.

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BackgroundBlau syndrome (BS) is a monogenic disorder caused by NOD2 gene variants characterized by the triad of granulomatous polyarthritis, rash, and uveitis. Atypical symptoms were recognized in one-third to one-half of individuals with BS. This study aims to describe the clinical features of BS patients with hypertension and digestive system involvement.MethodsThe complete clinical data of a BS patient complicated with hypertension and hepatic granulomas were collected and documented. We also performed a literature search to find all reported cases of BS with hypertension and digestive system involvement.ResultsWe reported the case of a 19-year-old man who presented with early onset symmetric polyarthritis and hypertension at age 5 and hepatic granulomas and cirrhosis at age 19. He was diagnosed with BS by the finding of a variant of the NOD2 gene (R334W). Through the literature review, 24 patients with BS were found who were reported to have hypertension, and 38 patients were found who had different digestive system manifestations such as hepatic granulomas, hepatosplenomegaly, diverticulitis, and intestinal granuloma. Among the 38 BS patients with digestive system involvement, 14 had hepatic granulomas proven by liver biopsy.ConclusionsHypertension and digestive system involvement are rare manifestations of BS. Clinicians, especially rheumatologists, must be aware of atypical symptoms of BS.

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“…Defects within the nucleotide binding domain of NOD2 would act through receptor‐interacting protein kinase 2 and then the MAP kinase and NF‐κB pathways. However, gain‐of‐function of NOD2 in PGA was challenged in 2017 by Ong and colleagues, who found in peripheral blood monocytic cells obtained from affected family members with BS impaired production of IL‐6, TNFα, NF‐κB, IL‐1β, and INF‐γ. We note that INF‐γ1b (Actimmune) is used to treat malignant OPT before hematopoietic marrow cell transplantation .…”

Section: Discussionmentioning

confidence: 99%

“…In PGA, granulomas are commonly identified in the associated dermatitis, but our patient's skin did not show this complication and therefore was not biopsied. Granulomas in PGA have been found in liver, kidney, a lymph node and tonsil, esophagus, synovial cyst, tendon, and elsewhere. In classic sarcoidosis, skeletal granulomas typically involve the marrow or cortex, and aberrant vitamin D and Ca metabolism occurs in up to 50% of patients .…”

Section: Discussionmentioning

confidence: 99%

“…(11,12,49,50) Defects within the nucleotide binding domain of NOD2 would act through receptor-interacting protein kinase 2 and then the MAP kinase and NF-kB pathways. However, gain-of-function of NOD2 in PGA was challenged in 2017 by Ong and colleagues, (37) who found in peripheral blood monocytic cells obtained from affected family members with BS impaired production of IL-6, TNFa, NF-kB, IL-1b, and INF-g. We note that INF-g1b (Actimmune) is used to treat malignant OPT before hematopoietic marrow cell transplantation. (51,52) In fact, the etiology and pathogenesis of pediatric granulomatous disease seems especially complicated (13) because it can apparently occur despite wild-type NOD2, and mutations in NOD2 can be clinically silent.…”

Section: Nod2 Pathophysiologymentioning

confidence: 99%

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Unique Variant of NOD2 Pediatric Granulomatous Arthritis With Severe 1,25-Dihydroxyvitamin D-Mediated Hypercalcemia and Generalized Osteosclerosis

Whyte

Lim

McAlister

et al. 2018

Journal of Bone and Mineral Research

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Pediatric granulomatous arthritis (PGA) refers to two formerly separate entities: autosomal dominant Blau syndrome (BS) and its sporadic phenocopy early-onset sarcoidosis (EOS). In 2001 BS and in 2005 EOS became explained by heterozygous mutations within the gene that encodes nucleotide-binding oligomerization domain-containing protein 2 (NOD2), also called caspase recruitment domain-containing protein 15 (CARD15). NOD2 is a microbe sensor in leukocyte cytosol that activates and regulates inflammation. PGA is characterized by a triad of autoinflammatory problems (dermatitis, uveitis, and arthritis) in early childhood, which suggests the causal NOD2/CARD15 mutations are activating defects. Additional complications of PGA were recognized especially when NOD2 mutation analysis became generally available. However, in PGA, hypercalcemia is only briefly mentioned, and generalized osteosclerosis is not reported, although NOD2 regulates NF-κB signaling essential for osteoclastogenesis and osteoclast function. Herein, we report a 4-year-old girl with PGA uniquely complicated by severe 1,25(OH) D-mediated hypercalcemia, nephrocalcinosis, and compromised renal function together with radiological and histopathological features of osteopetrosis (OPT). The classic triad of PGA complications was absent, although joint pain and an antalgic gait accompanied wrist, knee, and ankle swelling and soft non-tender masses over her hands, knees, and feet. MRI revealed tenosynovitis in her hands and suprapatellar effusions. Synovial biopsy demonstrated reactive synovitis without granulomas. Spontaneous resolution of metaphyseal osteosclerosis occurred while biochemical markers indicated active bone turnover. Anti-inflammatory medications suppressed circulating 1,25(OH) D, corrected the hypercalcemia, and improved her renal function, joint pain and swelling, and gait. Mutation analysis excluded idiopathic infantile hypercalcemia, type 1, and known forms of OPT, and identified a heterozygous germline missense mutation in NOD2 common in PGA (c.1001G>A, p.Arg334Gln). Thus, radiological and histological findings of OPT and severe hypercalcemia from apparent extrarenal production of 1,25(OH) D can complicate NOD2-associated PGA. Although the skeletal findings seem inconsequential, treatment of the hypercalcemia is crucial to protect the kidneys. © 2018 American Society for Bone and Mineral Research.

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A novel nucleotide oligomerisation domain 2 mutation in a family with Blau syndrome: Phenotype and function

Cited by 9 publications

References 18 publications

T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

T cell-intrinsic role for Nod2 in protection against Th17-mediated uveitis

Blau syndrome with hypertension and hepatic granulomas: a case report and literature review

Unique Variant of NOD2 Pediatric Granulomatous Arthritis With Severe 1,25-Dihydroxyvitamin D-Mediated Hypercalcemia and Generalized Osteosclerosis

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