Hematopoietic stem cell transplantations for primary immune deficiencies associated with NFκB mutations: A review of the literature

Abstract

The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) family of transcription factors plays an instrumental role in human immunity and lymphoid organ development. Inherited defects affecting these factors or their regulation are associated with increased susceptibility to infections, as well as non-immune abnormalities. Hematopoietic stem cell transplantations (HSCT) have been shown to correct the immune abnormalities in a few patients with NFκB pathway defects. Here we review the pre-HSCT characteristics, as well as the HSCT and outcome of 35 patients who received HSCT for NFκB defects. Twenty-three patients (65.7%) were reported to have survived HSCT. Survival was higher among patients with X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID), and those with CARD11-BCL10-MALT1 (CBM) complex defects, in comparison to patients with autosomal dominant ectodermal dysplasia and immunodeficiency (AD-EDA-ID) and IKBKB defects. Survival following myeloablative conditioning was similar to that after reduced intensity conditioning, although donor cells engraftment and immune reconstitution after HSCT was not complete in some patients. The effects of HSCT on organ dysfunction associated with NFκB defects, such as liver toxicity or bowel inflammation, are still not clear. Earlier identification and transplantation of affected patients, as well as better understanding of the pathogenesis and complications of the different NFκB mutations, might improve outcome of HSCT for specific patient populations. Statement of novelty:This review highlights the current indications, regimens, and outcome of HSCT for inherited defects involving various components of the canonical and non-canonical NFκB pathways.

NF-κB pathway and the Goldilocks principle: Lessons from human disorders of immunity and inflammation

“…In addition, 2 previously unaffected children had de novo inflammatory bowel disease after HSCT. 83 These findings mirror those reported elsewhere in human subjects, 82 as well as in mice, which is suggestive of a robust immune response to intestinal bacteria after acquisition of a competent immune system. 84 With respect to conditioning, a recent review demonstrated that in 5 children with XL-EDA-ID who received reduced-intensity conditioning, 3 did not engraft after first HSCT, and 1 more did not show T-cell engraftment.…”

“…In this regard outcome studies show considerable variability depending on the underlying disease process, as well as transplant factors, such as choice of conditioning. 82,83 To date, the majority of experience has been described in patients with NEMO defects. A recent HSCT study in 29 patients with XL-EDA-ID showed 74% survival within a median followup period of 57 months.…”

Progressive B cell depletion in human MALT1 deficiency

“…Nevertheless, post-HCT IBD symptoms were found in some patients with IPEX syndrome, suggesting the complex etiology underlying intestinal inflammation that could not be completely managed by the rescue of T regs after HCT [7,31]. Among PIDs due to defects in the CBM signaling complex and NF-κB pathway, early-onset IBD (EO-IBD) has been uncontrollable in patients with NEMO deficiency after HCT [32,33]. IBD in MALT1-deficient patients has been shown to be well controlled after HCT; however, IBD in MALT1 deficiency needs careful pre-transplant assessment.…”