Anticytokine autoantibodies in a patient with a heterozygous NFKB2 mutation

[...]she developed recurrent deep-seated pyogenic bacterial infections throughout childhood and early teenage years, which included a deep abscess in the left proximal tibia complicated by septic arthritis of the hip, septic arthritis of the right knee, and osteomyelitis of the left pubic ramus, and prepatellar bursitis and bacterial cellulitis of the right thigh with associated bacteremia. Because of the autosomal-dominant pattern of inheritance of CVID within the family, genetic investigation was performed. Whole-exome sequencing and Sanger sequencing confirmation identified a heterozygous NFKB2 NM_001077494.2 c.2557C>T:p.Arg853Ter variant that resulted in a truncated NF-κB2 p100 subunit to be present in the I.1 and II.2 (Fig 1; see Figs E2 and E3 in this article's Online Repository at www.jacionline.org). Because of disease severity discordance between I.1 and II.2, further immunological investigations were performed. The development and pattern of ACAAs, as well as clinical feature of alopecia and trachyonychia, observed in II.2 is reminiscent of that of autoimmune polyendocrinopathy-candidasis-ectodermal dysplasia (APECED) and thymoma patients in whom there is impairment of thymic medullary function, resulting in autoimmunity (Fig 2, B).2 Correct function of the NF-κB2 pathway is required to establish the thymic medullary compartment and correctly regulate AIRE expression.3 NFKB2Lym1−/− knockout mice also show significant impairment of medullary thymic epithelial cell maturation and AIRE expression, leading to the development of autoantibodies.4 Therefore, we hypothesize that errant thymic function in patients with heterozygous NFKB2 mutations may led to ACAAs and the broad organ-specific autoimmunity, including the cutaneous manifestations, which are present in this patient group.1 ACAAs have been reported in other primary immunodeficiencies, including patients with biallelic hypofunctional RAG variants in whom neutralizing anti–IFN-α, IFN-ω, and IL-12 autoantibodies were associated with increased susceptibility to viral infections.5 IFN-α, IFN-ω, and IL-12p40 ACAAs were present in II.2, and we may postulate that it is similarly also underlying medullary thymic epithelial cell impairment in patients with hypofunctional RAG genes, AIRE deficiency, and thymoma that leads to the development of this specific ACAA pattern.6 However, the precise role of neutralizing ACAAs in health and disease remains elusive with the presence of neutralizing type 1 IFN AC