Non-Canonical NF-kB Signaling in Immune-Mediated Inflammatory Diseases and Malignancies

In thirty years since its discovery as a regulator of transcription in B cells, the NF-kB family of transcription factors has been demonstrated to mediate activation and differentiation of many components of immunity, and has also been shown to have actions in other tissues and cell types. Genetic approaches to discover and characterize the components of the NF-kB family, including the receptors and proximal signaling events that liberate NF-kB for nuclear translocation, as well as the transcriptional events downstream of NF-kB activation, have been elucidated through cloning, deletion studies, and most recently through characterization of human genetic variants. The last approach has provided new insights into human disease because the phenotypes conferred by missense mutations are often distinct from those conferred by gene deletion. NF-kB proteins are important regulators of immunity via their collective coordination of the transcription or repression of >500 genes (encoding cytokines, chemokines, apoptosis factors), involved in proliferation, inflammation, cell development, survival, and immune cell function. Compared with the canonical pathway, expression of components of the non-canonical NF-kB pathway is much more restricted, and therefore defects often result in immune pathology, including autoimmunity, immune deficiency, and lymphoid malignancy.

We aim to provide the context of recent progress in understanding non-canonical NF-kB contributions to pathology by summarising activation, regulation, signaling, and outcomes of the non-canonical pathway. We will review the diverse molecular mechanisms of rare germline variants in immune dysregulation. For example, pathogenic germline NFKB2 variants can result in haploinsufficiency, dominant negativity, or gain-of-function. We will consider the spectrum of somatic variants that arise in lymphoid malignancy, and compare those with germline variants in patients with inborn errors of immunity. We will also cover the spectrum of phenotypes implicated in patients with non-canonical NF-kB variants in complex disease/ inborn errors of non-canonical NF-kB in complex disease, and how this helps us to understand susceptibility to infection, autoimmune and inflammatory disease, and B cell malignancies. In addition, we will provide space for recent advances on the importance of non-canonical NF-kB in pathological processes involved in immune-mediated inflammatory diseases, including the role of this pathway in stromal cells and immune cells. Finally, we will discuss how these advances might result in new approaches to treatment.

In this Research Topic we welcome the submission of Original Research, Review, Mini Review, Case Report, Perspective, and Opinion articles covering, but not limited to, the following subtopics:

• Biology of NF-kB signaling

• Actions of the non-canonical pathway in immunity

• Human pathology arising from rare genetic variants

• Pathology resulting from common variants

• Non-canonical NF-kB in immune-mediated inflammatory diseases

• Non-canonical NF-kB in B cell malignancies

• Therapeutic approaches to modification of NF-kB