Regulation of immunological tolerance and human autoimmunity by NF-κB

Mammalian NF-κB comprises a family of five proteins that influence transcription of hundreds of genes, including many crucial for lymphoid organogenesis, immune responses, and inflammation. In resting cells, NF-κB is sequestered by a family of inhibitory proteins. Tissue-specific stimuli result in degradation of these inhibitors and nuclear translocation of transcriptionally active NF-κB complexes. NF-κB and the proteins that regulate NF-κB activation are crucial for B and T cell tolerance within primary lymphoid organs (central tolerance) and during immune responses in the periphery. Since NF-κB acts in most nonlymphoid cells, including within the specialized ectodermal structures of thymus, complex autoimmune phenotypes arise from both intrinsic and extrinsic actions of NF-κB within lymphoid cells. Characterization of accurate mouse models and recent insights from rare human Mendelian diseases arising from various gain- and loss-of-function genetic variants have refined our understanding of how NF-κB contributes to human autoimmune diseases.