Deficiency of Innate and Acquired Immunity Caused by an IKBKB Mutation

Abstract

A form of human SCID is characterized by normal lymphocyte development despite a loss of IKK2 function. IKK2 deficiency results in an impaired response to activation stimuli in a variety of immune cells, leading to clinically relevant impairment of adaptive and innate immunity. Although Ikk2 deficiency is lethal in mouse embryos, our observations suggest a more restricted, unique role of IKK2-NF-κB signaling in humans. (Funded by the German Federal Ministry of Education and Research and others.).

Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

“…IKK complex, hindering the phosphorylation of IκB. Mutations affect the innate and adaptive immunity, without clear EDA features (Pannicke et al 2013;Mousallem et al 2014). …”

Integrity of IKK/NF‐κB Shields Thymic Stroma That Suppresses Susceptibility to Autoimmunity, Fungal Infection, and Carcinogenesis

“…[54,67,68] IKK/NF-kB regulate expression of these cytokines. [69,70] APECED patients have high titers of neutralizing autoantibodies against these cytokines, [71,72] suggesting that loss of IL-17, IL-22, and IFN-γ may contribute to increased fungal infection. On the other hand, occasional or weak autoantibodies against IL-6, IL-9, IL-12, IL-21, IL-23, IL-26, and IL-29 were found, while no autoantibodies against IL-1α/β, IL-2, IL-4, IL-8, IL-10, IL-18, TGF-β1, and TNF were found in APECED patients, [72] suggesting that the cytokines that are not neutralized may promote inflammation and tumorigenesis.…”

“…[69,85] Affected infants are usually identified in the first months of life with Pneumocystis jiroveci pneumonia, bacterial sepsis, cytomegalovirus, oral candida infection, persistent respiratory, or gastrointestinal viral infection that is often associated with protracted diarrhea and failure to thrive. SCID involves a defective antibody response due to either direct involvement with B cells or improper B-cell activation caused by nonfunctional T helper cells.…”

“…Inborn errors in the IKBKB locus, which encodes IKKβ, were found in SCID [69,[86][87][88] (Table 2). Pannicke et al [69] reported four SCID cases that carried a homozygous duplication of the frameshift mutation in IKBKB that leads to a premature stop codon, resulting in a complete loss of the IKKβ protein.…”

“…[89][90][91] Tnfr deletion-rescued p65 À/À mice develop severe infections, leading to failure to thrive. [92,93] Furthermore, Hassall's corpuscles, which are differentiated from mTECs due to a lack of AIRE expression, [94] were observed in the medulla of human SCID patients, and a scant lymphoid population was seen in the thymus but was largely located in the medulla, [69] indicating that IKKβ mutations impair AIRE expression and mTEC development in SCID patients. A germline mutation delivers the inborn error to most cell populations in humans.…”