Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans

Abstract

The nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (NF-κB1) is a master regulator of immune and inflammatory responses.1,2 NF-κB1 belongs to the NF-κB/Rel family of transcription factors that consists of five members in humans: NF-κB1 (p105/p50), NF-κB2 (p100/p52), RelA, c-Rel, and RelB. The p105 and p100 precursors are proteolytically processed by the proteasome to generate the shorter p50 and p52 isoforms. Homo-and heterodimers are formed by p50, p52 and the Rel proteins. Unstimulated, these dimeric complexes are sequestered in the cytoplasm by inhibitory IκB proteins in an inactive state. Upon stimulation, the phosphorylation and subsequent degradation of IκB proteins is rapidly triggered, releasing the NF-κB/Rel complexes to enter the nucleus where they bind to DNA at κB sites and activate or repress the expression of their target genes. 3 Recently, heterozygous mutations affecting the NFKB1 gene were identified in three human families. Haploinsufficiency of NF-κB1 was causative for combined variable immunodeficiency (CVID) characterized by recurrent infections due to immunoglobulin deficiency (pan-IgG, IgA and/or IgM). 4 We report here on two pediatric patients from unrelated families with two novel NFKB1 gene mutations identified by whole-exome sequencing ( Figure 1A,B). Both patients had early onset of disease during their teenage years and presented in addition to hypogammaglobulinemia or selective IgA deficiency with a striking lack of specific antibodies (clinical characteristics are summarized in Table 1 and Online Supplementary Table S1).Patient 1 is a now 26-year old female who first presented with recurrent autoimmune hemolytic anemia at the age of 14. Hypogammaglobulinemia (IgG2 subclass deficiency), deficient production of specific antibodies, decreased class-switched and memory B cells, naïve CD4-positive and regulatory T cells, increased activated and double-negative T cells (DNT cells, CD4 -CD8 -TCRα/β + ), autoimmune phenomena (hemolytic anemia, thrombocytopenia and leukopenia), lymphadenopathy, and hepatosplenomegaly were observed. She developed chronic lung disease with bronchiectasis, frequent respiratory tract infections and pneumonia. Infections with viral, bacterial and fungal pathogens were frequent. She suffered from intractable abdominal pain and bloody diarrhea without evidence of infection. After a liver biopsy she developed pancolitis with subsequent sepsis and multi-organ failure and was successfully resuscitated. The patient is being treated with intravenous immunoglobulin. Steroids were intermittently given to reduce pulmonary infiltrates with partial response. Mycophenolate mofetil stabilized blood counts, but pulmonary symptoms and infections remained.To identify the genetic cause of disease whole exome sequencing was performed for the patient and her family (Online Supplementary Methods, Online Supplementary Table S2). A heterozygous de novo NFKB1 frameshift mutation was detected ( Figure 1A). The NFKB1 gene encodes two proteins: p50 and its precursor ...

Autoimmunity/inflammation in a monogenic primary immunodeficiency cohort

“…P9.1 and P9.2 ( NFKB1 p.S302Ffs∗7) both suffered autoimmunehaemolytic anaemia, which is reported in NFKB1 haploinsufficient patients 24 , 25 . Differing AI/I is observed in patients with NKFB1 mutations, ranging from antibody deficiency, Behcet‐like disease, to an autoinflammatory phenotype 26 …”

“…23 NFKB1 haploinsufficiency (OMIM 616576) P9.1 and P9.2 (NFKB1 p.S302Ffs*7) both suffered autoimmune haemolytic anaemia, which is reported in NFKB1 haploinsufficient patients. 24,25 Differing AI/I is observed in patients with NKFB1 mutations, ranging from antibody deficiency, Behcet-like disease, to an autoinflammatory phenotype. 26 Autoimmunity in a PID cohort W Rae et al NFKB2 dominant negative immunodeficiency (OMIM 615577) P10 (NFKB2 p.R853*) suffered autoimmune alopecia, which is widely reported in patients with dominant negative NFKB2 variants but the renal disease that was present in P10 has not been reported in NKFB2 variants to date.…”

Novel heterozygous NFKB1 mutation in a pediatric patient with cytopenias, splenomegaly, and lymphadenopathy

“…We report a novel mutation of NFKB1 in a pediatric patient with cytopenias, lymphadenopathy, and splenomegaly. To the best of our knowledge, this variant has not been reported in previously described NFKB1 cases (Boztug et al 2016;Maffucci et al 2016;Schipp et al 2016;Kaustio et al 2017;Lougaris et al 2017;Dieli-Crimi et al 2018;Fliegauf and Grimbacher 2018;Tuijnenburg et al 2018).…”

“…Multiple recent studies have identified variants in NFKB1 as a monogenic cause of immunodeficiency/ immune dysregulation (Table 2) (Maffucci et al 2016;Schipp et al 2016;Kaustio et al 2017;Lougaris et al 2017;Dieli-Crimi et al 2018;Fliegauf and Grimbacher 2018;Tuijnenburg et al 2018). Patients display a wide range of phenotypic heterogeneity including recurrent sinopulmonary infections, viral and fungal infections, autoimmunity, lymphoproliferation, and malignancy.…”

“…Although haploinsufficiency of NFKB1 has been predominantly described as a defect of B cells, there are reported cases of diminished T cell function, EBVassociated lymphoproliferation, and viral and fungal infections, suggesting that it may also affect T cell function (Boztug et al 2016;Schipp et al 2016). One patient first presented with autoimmune hemolytic anemia at 14 years of age, then developed lymphadenopathy, hepatosplenomegaly, and frequent viral, bacterial, and fungal infections (Schipp et al 2016). She had hypogammaglobulinemia, decreased class-switched B cells, naïve CD4 and regulator T cells, and increased double negative T cells.…”