Hematopoietic stem cell transplantation (HSCT) is a curative treatment for an expanding spectrum of inborn errors of immunity (IEI). Whilst the utility and success of this treatment is well established for common, or historically described IEI (severe combined immunodeficiency, Wiskott-Aldrich syndrome, CD40L deficiency, the role of HSCT for emerging, newly described IEI is less clear. This review examines HSCT results for recently described IEI or those in which HSCT has only recently and rarely been employed. The literature search included HSCT in IEI from 2020 to 2025. We report the HSCT experience and outcome in newly described diseases including RIPK1, ARPC1B, CD27/CD70 deficiency. More established diseases for which HSCT has only recently been reported are described, including female carriers of X-linked chronic granulomatous disease, and X-linked agammaglobulinemia. We report on recently described diseases with limited HSCT experience including CTLA-4/LRBA deficiency, STAT1 gain-of-function. Finally, we consider diseases where HSCT has previously been considered inappropriate, like STAT3 loss-of-function. Previous experience implies that younger age and fewer co-morbidities at time of HSCT improve outcomes, but limited natural history data combined with increased use of targeted therapies make HSCT decisions difficult in new diseases. Adoption of disease-appropriate scoring tools may aid decision making.

Common variable immunodeficiency (CVID) includes a heterogeneous group of disorders of predominantly antibody deficiencies featuring infectious and noninfectious complications that might lead to severe organ damage and shortened survival. Appropriate clinical management of CVID has been hampered by the lack of robust biomarkers to predict the development of clinical complications and patient outcome. We investigated the association of individual serologic, cellular, and molecular biomarkers with disease behavior and outcome in CVID. A multicenter cohort of 209 CVID patients was studied using age-matched reference values from 334 healthy donors to better define TCD4+-naive cell defects (late-onset combined immunodeficiency [LOCID]) and classify CVID-associated B-cell/plasma cell (PC) and natural killer (NK) cell defects. Globally, susceptibility to respiratory infections was strongly associated with low serum immunoglobulin (sIg), particularly sIgA, whereas noninfectious complications and disease severity mostly depended on TCD4+-naive cell, NK cell, and B-cell/PC defects. LOCID was independently associated with splenomegaly, lymphadenopathy, interstitial lung disease, cytopenia, and lymphoma. Milder B-cell/PC defects (MBC+/PC+/Ab-) protected from noninfectious complications, whereas a marked defect of classical CD27+ memory B cells (27MBC-) (with decreased NK cell and sIgM) was associated with enteropathy and (with LOCID and sIgA) liver disease. Together, lower sIgG, LOCID, and particularly 27MBC-, were strongly associated with shorter survival and early death in CVID. Conversely, CVID-associated pathogenic/risk alleles did not emerge as independent factors associated with disease behavior and outcome. Our results provide a new set of biomarkers closely associated with infectious and noninfectious complications of CVID, which together predict survival and might contribute to guide patient monitoring and clinical management.

Autoantibodies against IFN-α (anti-IFN-α) have been reported in recombinase activating gene (RAG) deficiency, attributed to impaired central and peripheral T-cell/B-cell tolerance. However, the clinical features, especially viral infections, associated with these autoantibodies at baseline, their kinetics over time, and their response to hematopoietic cell transplantation are not well defined. We described the clinical and immunologic findings linked to anti-IFN-α IgG in RAG deficiency and tracked its kinetics longitudinally, including in those who underwent hematopoietic cell transplantation. We measured anti-IFN-α IgG by enzyme-linked immunosorbent assay in 80 RAG-deficient patients with curated clinical and immunologic data from a multinational collaboration. Forty-eight patients (60.0%) had positive anti-IFN-α at baseline; these patients were typically older at time of testing, fulfilled the phenotype of delayed-onset combined immunodeficiency with granuloma and/or autoimmunity (70.8% vs 31.3%, P = .001), and had a history of more frequent viral infections, mainly from the Herpesviridae family (62.5% vs 21.9%, P < .001). These patients also showed higher levels of serum immunoglobulins and expanded populations of peripheral blood autoreactive-prone (CD19hiCD21lo) (14.3 vs 5.2%, P = .016) and double-negative (IgD-CD27-) B cells (12.8 vs 5.8%, P = .001). In cases with longitudinal evaluation, anti-IFN-α titers were largely stable, although an increase was observed with concurrent active cytomegalovirus infections. Despite some decline after transplantation, these autoantibodies persisted during follow-up. Anti-IFN-α autoantibodies reflect immune dysregulation in partial RAG deficiency. Their production is likely aggravated by environmental factors, especially frequent viral infections. Further studies are needed to define their pathogenic role in RAG deficiency.

Reduced function or hypomorphic variants in recombination-activating genes (RAG) 1 or 2 result in a broad clinical phenotype including common variable immunodeficiency (CVID) and even adult-onset disease. Milder RAG variants are less characterized. Here we describe the longitudinal course of a milder combined RAG deficiency in 3 of 7 siblings sharing the same RAG2 mutations over a 50-year study. Whole-genome and repertoire sequencing, bacteriophage immunizations, and deep immunophenotyping were used to compare affected and unaffected family members. The clinical phenotype of three affected siblings with hypomorphic RAG deficiency ranged from combined immunodeficiency and early mortality to a late-onset CID with hyper-IgM phenotype. T cells were remarkably similar across affected siblings, yet CDR3 skewing and regulatory T cell defects were not observed. B cell analysis showed elevated unswitched CD27+ and CD21low cells as well as features of an autoreactive antibody repertoire and presence of secreted autoantibodies, yet no clinical autoimmunity was present. Most striking was an expanded polyclonal marginal zone-like B cell population (IgM+IgD+CD27+) utilizing the self-reactive unmutated VH4-34 receptor demonstrating that hypomorphic RAG deficiency can promote expansion of self-reactive B cells. This process, however, was not sufficient to trigger clinical autoimmunity. Utilizing multiple approaches, we functionally measured the specific RAG2 variant effects and assessed how selection and secondary triggers altered the BCR repertoire and immunophenotype overtime. Overall, we demonstrate a broad disease spectrum in siblings with identical hypomorphic RAG deficiency, highlighting that phenotypic divergence can result from expansion of IgM + memory B cells.

Combined immunodeficiency due to CD70 deficiency is characterized by increased susceptibility to infections, hypogammaglobulinemia, and malignancy. These patients typically present with chronic Epstein Barr virus (EBV) viremia, severe EBV-related hemophagocytic lymphohistiocytosis, lymphoproliferation, and Hodgkin and non-Hodgkin lymphomas. Plasmablastic lymphoma (PBL) is an extremely rare malignancy in all ages and is predominantly seen in male adults with human immunodeficiency virus infection. EBV infection, immunosuppression, solid organ transplantation, and age-related immune deterioration are also suspected causes of PBL. Nevertheless, there is scarce data about its association with primary immunodeficiencies in the literature. Here, we present the first case of a CD70 -deficient pediatric patient with PBL.