Autoinflammatory granulomatous diseases: from Blau syndrome and early-onset sarcoidosis to NOD2-mediated disease and Crohn's disease

Abstract

The recent identification of genetic mutations leading to dysfunction of inflammatory and apoptotic pathways, has allowed to characterise a group of diseases, recognised as monogenic autoinflammatory syndromes. Among those, Blau syndrome (BS) and early-onset sarcoidosis (EOS) have been identified as familial and sporadic phenotypes of the same non-caseating granulomatous form. Both the diseases are caused by mutations in the CARD15/NOD2 gene, encoding the cytosolic NOD2 protein, one of the key molecules in the regulation of innate immunity. Clinical onset is typically located in the first years of life and phenotype is characterised by simultaneous or less articular, cutaneous and ocular non-caseating granulomatous inflammation, which can be variably associated with a heterogeneous systemic spectrum. The CARD15/NOD2 gene has also been identified as one of the genes linked to susceptibility to Crohn's disease (CD), a common polygenic inflammatory granulomatous bowel disease. The heightened nuclear factor-κB activity, found in the intestinal tissue of patients affected by CD, has probably a genetic cause related to several CARD15/NOD2 polymorphisms. Other substitutions in the CARD15/NOD2 gene have also been found in a recently described disorder, called NOD2-associated autoinflammatory disease, which shares several clinical characteristics with BS and EOS. This review attempts to describe these diseases on the basis of the most recent evidences. We described genetic and clinical aspects, mainly focusing on BS and EOS, the most representative diseases of autoinflammatory granulomatous diseases, with the ultimate purpose to expand their knowledge.

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

“…Those much younger typically show the classic triad of PGA . The term “PGA” emerged after 2005 when sporadic EOS was discovered to share with heritable BS identical mutations within NOD2 . Consequently, in 2017, EOS was “transferred” to BS within OMIM…”

“…Pediatric granulomatous arthritis (PGA), sometimes called autoinflammatory granulomatosis of childhood, typically presents during the first few years of life with the clinical triad of dermatitis, uveitis, and arthritis . Beginning in 1985, autosomal dominant Blau syndrome (BS) or Jabs syndrome comprised this disorder, and later early‐onset sarcoidosis (EOS) was considered a sporadic phenocopy .…”

Immunotherapeutic Biologic Agents to Treat Autoinflammatory Diseases

“…Some autoimmune diseases, especially early-onset Crohn's disease (CrD) and sarcoidosis, are caused by innate system dysregulation occurring in concert with adaptive immune dysfunction [7]. Autoimmune diseases today are regularly treated with pharmaceutical biologic agents that target relevant inflammatory pathways.…”

“…TNF-α is present on the surface of cells as a transmembrane protein, and its cleavage leads to release of soluble TNF-α. are also pathogenic [7]. In CrD, etanercept has been found to be less effective likely due to the predominance of membrane-bound TNF in this disorder rather than soluble TNF that is inhibited by this agent [45].…”

Alterations in nucleotide-binding oligomerization domain-2 expression, pathway activation, and cytokine production in Yao syndrome

“…YAOS was initially reported in 2011 and originally designated as NOD2 -associated autoinflammatory disease (NAID) (5, 10, 11). YAOS patients are predominantly white adults with a female to male ratio of 2:1 at an estimated disease prevalence of 1–10/100,000(6).…”