Severe Toxoplasma gondii infection in a member of a NFKB2-deficient family with T and B cell dysfunction.

We report the case of a 9 years old girl (III.1), first referred at the age of 2 years for alopecia totalis, trachonychia and recurrent respiratory infections. Few months later, she was admitted for pneumonia and adrenal insufficiency secondary to ACTH hormone deficiency. The family history identified grandmother (I.2) and mother (II.2) with common variable immunodeficiency (CVID) (Fig. 1A). Her mother (II.2), also affected by ACTH deficiency, had alopecia areata during childhood. The grandmother (I.2) had developed later in life chronic intestinal CMV infection and died at the age of 68. The immune evaluation of the child showed mild decrease of IgG, low IgM and IgA, absence of isohemagglutinins, low specific response against Tetanus, H. influenzae and S. pneumoniae, but normal against measles and rubella. Immunoglobulin replacement therapy (IgRT) led to improvement of recurrent infections. She had persistent lymphocytosis, with normal T, B and NK distribution. Increased naïve T cell frequency with decreased T cell memory subsetswere reported includingmarked reduction of regulatory T cells (Treg), T follicular helper (Tfh) and Th17. Low Treg was confirmed molecularly by measuring demethylation of the Treg-specificdemethylated region (TSDR) of FOXP3. However, Treg suppressive activity in vitro resulted normal. Decreasedmemory B cells were detected (Table 1) with impaired response to TLR9-ligand CpG. Similar perturbations in T and B cells differentiation were detected in her 36 years old mother (II.2) (Table 1, Supplementary Fig. E1, E2). The trend to increased naive versus memory cells becomes more evident with age, as shown by the mother's percentage of naive T cells (Table 1). Unfortunately data on grandmother (I.2) are not available. Despite CMV and EBV persistent viremia the girl had undergone a complete CMVbut incomplete EBV-seroconversion. The endocrinopathy was not associated with autoantibodies (Abs). However, we found high levels of Abs against multiple type I interferons (IFN-αB2, IFN-α2A, and IFN-ω), type III IFNs (IFN-λ1, IFN-λ2), and IL-12 using protein microarrays. Anti-IFN-ω Abs were confirmed in the patient's serum but were absent in themother's (II.2) and grandmother's sera (I.2). At the age of 6 years, the child experienced severe bilateral visual impairment. Neurophysiology studies showed retinal and bilateral optical nerve damage. The MRI