# Long-term outcome of bone marrow transplantation in NIK deficiency: non-redundant role of non-canonical NF-κB signaling in thymic reconstitution and secondary lymphoid organ development

## TL;DR

This study examines the long-term effects of bone marrow transplants in patients with a rare immune disorder caused by NIK deficiency, finding that while some immune recovery occurs, the treatment does not fully correct the underlying issues.

## Contribution

The study reveals that hematopoietic stem cell transplantation does not fully restore immune function in NIK deficiency due to non-hematopoietic defects in lymphoid organs.

## Key findings

- HSCT leads to early T-cell recovery but fails to correct memory T-cell differentiation and B-cell reconstitution.
- Immune dysregulation and recurrent infections persist despite donor chimerism, likely due to thymic and lymph node defects.
- Patients developed autoimmune conditions and succumbed to infection-related complications, underscoring the need for additional therapies.

## Abstract

Biallelic mutations in MAP3K14, encoding NF-κB-inducing kinase (NIK), disrupt non-canonical NF-κB signaling and lead to a rare inborn error of immunity marked by impaired lymphoid organ development, defective lymphocyte maturation, and susceptibility to recurrent infections. Hematopoietic stem cell transplantation (HSCT) has been considered a curative approach, yet its long-term efficacy remains unclear.

We report long-term outcomes of two patients with genetically confirmed NIK deficiency who underwent HSCT.

Both patients achieved full donor chimerism and early T-cell reconstitution with normalized CD3+, CD4+, and CD8+ counts and naïve T-cell subsets. However, memory T-cell differentiation remained impaired, with persistently reduced central memory T cells and circulating T follicular helper cells. Immune dysregulation emerged years after HSCT, with one patient developing seropositive arthritis and the other exhibiting autoimmune hepatitis. Thymic dysfunction was suspected as an underlying contributor to impaired central tolerance in this pathology. Similarly, B-cell reconstitution was incomplete, characterized by persistent hypogammaglobulinemia and a marked deficiency in class-switched memory B cells, despite donor-derived chimerism. Lymphoscintigraphy confirmed absence of lymph nodes. Both patients suffered from recurrent, severe infections and ultimately died of infection-related complications. Our findings indicate that HSCT alone is insufficient to fully correct the immune disorder in MAP3K14 deficiency, likely due to non-hematopoietic defects in lymph node stromal structures and thymic central tolerance.

These results highlight the importance of long-term immunologic monitoring, including assessments for immune dysregulation and anti-cytokine autoantibodies. Future therapies should consider adjunct strategies such as thymic regeneration or targeted immune modulation to address the underlying architectural defects in this disorder.