NOD2-Related Multisystem Inflammatory Disorders and Recent Advances

Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is an intracellular innate immune sensor. Its functions have been extensively studied. Variants in the NOD2 gene are associated with several human diseases. This report provides a comprehensive review of these diseases and biomedical and immunological roles of NOD2.

Blau syndrome is an autosomal dominant disease primarily occurring in children and is caused by highly penetrant NOD2 variants. Approximately 40% of Caucasian patients with Crohn's disease (CD) are associated with three main NOD2 variants of low penetrance. Yao syndrome (YAOS), a recently reported novel disease, possesses characteristic clinical pattern or constellation of recurrent fever, dermatitis, arthralgia, distal leg swelling, gastrointestinal, sicca-like symptoms, and eyelid swelling among others. This disease is associated with specific NOD2 variants including the CD-associated three main variants. Our recent large case-control study of population genetics and haplotype analyses confirms the association between certain NOD2 variants and YAOS and the coinheritance in cis of the commonly encountered variants. Molecular testing is required for the diagnosis of YAOS. The prevalence of the disease is estimated to approach that of CD. There are identified effective drugs to manage this condition. Functional studies of NOD2 have revealed its contribution to both innate and adaptive immune responses, and there are interplays between these cellular components and cytokines. NOD2 has been extensively studied for innate immune response. Specific NOD2 variants are associated with different diseases, highlighting the fact that the same genotype can contribute to different phenotypes. Further studies are warranted to focus on adaptive immunity and bridge the gap between innate and adaptive immune responses in individual diseases.