Potential Benefits of TNF Targeting Therapy in Blau Syndrome, a NOD2-Associated Systemic Autoinflammatory Granulomatosis

Abstract

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.

Implications of combined NOD2 and other gene mutations in autoinflammatory diseases

“…Germline and somatic variants of NLRs are linked to polygenic and monogenic diseases, such as NOD2-associated diseases ( 2 ), and periodic fever syndromes ( 3 ). Blau syndrome or early-onset sarcoidosis (at age 4 and younger) is an autosomal dominant granulomatous disease and is caused by NOD2 mutations of high penetrance ( 4 , 5 ). Another NOD2-associated disease is Yao syndrome (YAOS, OMIM #617321), formerly designated NOD2-associated autoinflammatory disease.…”

Clinical Disease States Related to Mutations of the NOD2 Gene: A Case Report and Literature Review

“…An ex vivo study was performed using peripheral blood and induced pluripotent stem cells from 10 patients with NOD2 mutations. The study demonstrated that long-term administration of anti-TNF antibodies may correct the abnormalities that occur in the early progenitor stage by blocking the autoinflammatory loop and restoring the threshold for which IFNγ stimulation triggers an inflammatory response in macrophages [ 19 ].…”

“…Additional studies have investigated the role of methotrexate, Janus kinase (JAK) inhibitors, anti-IL-6, and anti-IL-1 therapies in patients with NOD2 mutations, with a controversial response [ 18 , 19 ]. Unfortunately, further clinical trials are required to establish better treatment modalities for different disease states associated with NOD2 mutations.…”

Elevated G-CSF, IL8, and HGF in patients with definite Meniere’s disease may indicate the role of NET formation in triggering autoimmunity and autoinflammation

“…It is well known that both IL1α and IL1β activate the same receptor and induce similar biological effects, but IL1α is present in healthy cells in a wide variety of cells and it is expressed in hematopoietic and nonhematopoietic cells 63 . TNF receptor activation was also indicated in the development of autoinflammatory disease 64,65 .…”