Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients

Compound heterozygous mutations in the kinase domain of IKKα lead to immunodeficiency and immune dysregulation

“…The T cell compartment was characterized by a relative excess of naïve CD4+ and CD8+ T cells as previously observed in patients with a defective canonical NF-κB pathway ( Figure 2B, Supplementary Figure 2B ). This patient had an excess of highly activated HLA-DR+ CD38 high CD127 low effector memory CD8+ T cells, a cluster that we and others have already described to be associated to chronic viral infections ( Supplementary Figure 2B ) (Riller et al, 2023; Klocperk et al, 2022; Paiardini et al, 2005) . In contrast, we observed a decrease of Th2 and Th17 polarized memory CD4+ T cells, in accordance with the involvement of IKKα in the generation of Th17 in the recently reported bi-allelic loss-of-function CHUK variant p.Y580C ( Supplementary Figure 3B ) (Bainter et al, 2021) .…”

“…A diagnosis of celiac disease was made based on villous atrophy, following the exploration of growth failure without growth hormone deficiency. This villous atrophy did not respond well to gluten-free regimen and it was hypothesized to be a consequence of a chronic enteric viral infection or immune dysregulation and T-cell infiltration rather than a bona fide celiac disease (Riller et al, 2023; Strohmeier et al, 2022; Klocperk et al, 2022) . Peripheral blood immunophenotyping showed a lack of memory B-cells and an excess of naïve T cells as well as an excess of effector memory CD8+ T cells and a CD4+ lymphocytosis ( Supplementary Table 1 ).…”

“…Accordingly, the studied patient displayed neutralizing autoantibodies against type I IFNs as recently shown in human with other germline deleterious mutations of the non-canonical NF-κB pathway (Le Voyer et al, 2023; Bodansky et al, 2023) . Another possibility could be that the patient herein studied suffered from a recently described entity called EVAH for enteric viral-associated hepatitis where chronic infections with enteric viruses in immunodeficient patients were associated to chronic hepatitis (Riller et al, 2023; Fourgeaud et al, 2023; Bucciol et al, 2018)…”

Inborn Errors of Immunity

“…Although HLA-genoidentical sibling donor BM may be infused into SCID recipients without any conditioning or GvHD prophylaxis, usually only T-cells of donor origin will engraft, and myeloid and often B-cells will remain of recipient origin. Patients with insufficient myeloid engraftment and/or poor or declining naïve T-cell compartments may experience severe complications that require a second, conditioned HCT (Riller et al 2023). Therefore, and if tolerable for the patient, conditioning is recommended for all SCID patients in order to achieve optimal clinical and immunological outcomes (Lankester et al 2022).…”