Abstract
Inborn errors of the "core" components of the alternative NF-κB pathway-NIK, IKK-α, RelB, and NF-κB2-underlie various T and/or B cell deficiencies, frequently associated with syndromic features, including ectodermal dysplasia and lymph node hypoplasia. Their impact on medullary thymic stromal cells (mTECs) also underlies the development of autoantibodies neutralizing type I interferons (IFNs), conferring a predisposition to severe viral diseases. Inborn errors of "upstream" ligands or surface receptors engaging this pathway affect secondary lymphoid organ organization (LTβR), B cell development and survival (BAFFR), T cell and antigen-presenting cell costimulation (CD40L/CD40), or osteoclast differentiation (RANK/RANKL). Finally, inborn errors of TRAF3, a negative "regulator" of this pathway, underlie immune dysregulation, infection, and lymphoproliferation. Various inborn errors of the human alternative NF-κB pathway have, thus, delineated the essential and redundant roles of its components in leukocytic and non-leukocytic cells.