NFKB1-Associated Autoinflammatory Diseases

The NFKB1-associated autoinflammatory diseases (NFKB1-AD) comprise a group of three different autosomal dominant diseases that are caused by mutations in the NFKB1 gene. The NFKB1 gene (NFKB1 stands for "Nuclear Factor Kappa B Subunit 1") is a protein-coding gene located on chromosome 4q24. Alternative splicing results in several transcript variants that code for different isoforms, at least one of which is proteolytically processed. The mutations in NFKB1-AD affect the NK-κB subunitsp50 and p105, which in some cases leads to increased expression of IL-1β and TNF and corresponding clinical symptoms (Kaustio M et al. 2019).

Initial descriptions of patients with NFKB1 gene mutations were associated with a phenotype of immunodeficiency (Common variable immunodeficiency-12 with autoimmunity/CVID12) consisting of recurrent respiratory tract infections, chronic lung disease with bronchiectasis, diarrhea, lymphadenopathy, splomegaly, recurrent autoimmune phenomena (hemolytic anemia, thrombocytopenia and leukopenia), and hypogammopathy, lymphadenopathy, splenomegaly, recurrent autoimmune phenomena (hemolytic anemia, thrombocytopenia and leukopenia), hypogammaglobulinemia, deficient production of specific antibodies and a reduced number of class-specific and memory B cells (Kaustio M et al. 2019; Schipp C et al. 2016; Lorenzini T et al. 2020, see case report)

Two other autoinflammatory phenotypes associated with mutations in the NFKB1 gene have been described in two families (Kaustio M et al. 2017):

• NFKB1-associated Behçet-like disease, which is associated with the non-truncating mutation H67R in the NFKB1 gene. It has been described in six individuals in the same family with clinical manifestations similar to those of Behçet's disease (aphthae, arthritis and abdominal pain) (Kaustio M et al. 2017). It is noteworthy that the mutations in NFKB1 affect the same signaling pathway as in HA20 (ubiquinopathy - Behcet's-like familial autoinflammatory syndrome). However, HA20 is associated with IgG hypogammaglobulinemia. The Behcet-like phenotype does not appear to cause any overactivation of the canonical inflammasome in vitro, so that drug suppression of IL-1β and TNF may not appear useful. (Kaustio M et al. 2017).
• NFKB1-associated sterile familial autoinflammatory necrotizing fasciitis (FANF), which is caused by a truncating mutation R157X in the NFKB1 gene. This disease was described in two brothers who suffered from localized, recurrent, sterile, necrotizing inflammation after banal tissue trauma (e.g. after minor surgery) that spread to the muscle fascia (clinical picture of necrotizing fasciitis). The patients had no other organ or systemic involvement nor any obvious manifestations of immunodeficiency (Kaustio M et al. 2017). This mutation causes increased inflammasome activation in vitro. In this respect, it can be assumed that agents that inhibit IL-1β or TNF could be useful.

Dermatologic manifestations: The most common skin lesions in patients with NFKB1-associated Behçet-like disease are mucosal aphthae affecting the oral mucosa, esophagus and genitalia (Figueras-Nart I et al. 2019).

Biopsies of the genital aphthae showed vasculitis of the small vessels, analogous to those of Behçet's disease.

Lorenzini et al. (2020) identified 157 individuals from 68 unrelated families, mostly of European descent, with CVID12. The phenotype was highly variable. Most patients had hypogammaglobulinemia (88.9% of patients), reduced switched memory B cells (60.3%) and infections of the sinus (83%) and gastrointestinal tract (28.6%), which is consistent with a primary immunodeficiency. There was an increased tendency to infection with bacteria, viruses and fungi, and in rare cases also mycobacteria and cytomegaloviruses (CMV). The immunological examination revealed hypogammaglobulinemia, poor antibody responses, low concentrations of switched memory B cells and sometimes low NK levels in most patients. Autoimmunity (57.4 %), lymphoproliferation (52.4 %), non-infectious enteropathy (23.1 %), opportunistic infections (15.7 %), auto-inflammation (29.6 %) and malignancy (16.8 %) were also very common.

Less common autoimmune features included macular exanthema, arthritis, thyroiditis, hepatitis, pernicious anemia, type I diabetes, vasculitis and Addison's disease. Autoantibodies against red blood cells or granulocytes were detected in 18% of patients. One patient presented at the age of 11 years with severe pancytopenia, hypogammaglobulinemia, decreased vaccination response, reduced memory B cells and slightly decreased NK cells. She had hepatosplenomegaly, lymphadenopathy, recurrent genital and oral ulcerations, arthralgias and enthesopathy associated with elevated inflammatory markers. Her mother and brother had hypogammaglobulinemia. There were also 5 asymptomatic mutation carriers in the family. An uncle with autoimmunity died of lymphoma at the age of 40.

A patient from another family presented at the age of 38 years with recurrent severe respiratory infections and was diagnosed with hypogammaglobulinemia at the age of 43 years. He also developed autoimmune features such as vitiligo, arthritis and keratoconjunctivitis and had lymphadenopathy, hepatosplenomegaly and a lack of plasma cells on bone marrow biopsy. His adult sister suffered from recurrent bacterial and viral infections and lymph gland hyperplasia. The most common causes of death were infections on the background of a chronic illness and complications of malignant diseases.

1. Figueras-Nart I et al. (2019) Dermatologic and Dermatopathologic Features of Monogenic Autoinflammatory Diseases. Front Immunol 10:2448.
2. Kaustio M et al. (2019) Primary immunodeficiency, a possible cause of neutrophilic necrotizing dermatosis. JAMA Dermatol. 155:863-864.
3. Kaustio M et al. (2017) Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes. J Allergy Clin Immunol140:782-786
4. Lorenzini T et al. (2020) Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations. J Allergy Clin Immun 146: 901-911.
5. Poladian N et al. (2023) Role of NF-κB during Mycobacterium tuberculosis infection. Int J Mol Sci 24:1772.
6. Schipp C et al. (2016) Specific antibody deficiency and autoinflammatory disease extend the clinical and immunological spectrum of heterozygous NFKB1 loss-of-function mutations in humans. Haematologica 101:e392-396.