A multimorphic mutation in IRF4 causes human autosomal dominant combined immunodeficiency.

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii, and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced TH17 and TFH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4T95R variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4WT. Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4T95R. Simultaneously, IRF4T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4T95R but not by IRF4WT. This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

First-line haploidentical stem cell transplantation in children and adolescents with severe aplastic anemia using mobilized peripheral blood as source of CD34+: Single-institutional experience in a transplant center from northeast Mexico.

INTRODUCTION: The only curative treatment for severe aplastic anemia in children is an allogeneic stem cell transplant; however, few patients have a matched related or unrelated donor. Haploidentical stem cell transplantation (haplo-SCT) using bone marrow (BM) and peripheral blood stem cells (PBSC) has been recently described as effective and safe. In this study, we retrospectively report the outcome of twelve pediatric patients who underwent haplo-SCT using only PBSC. METHODS: The conditioning regimen consisted on rabbit anti-thymocyte globulin (r-ATG) 2.5 mg/kg/d on days -7, -6,-5, and -4, and cyclophosphamide (Cy) 50 mg/kg/d on days -3 and -2. We used Cy 50 mg/kg/d on days +3 and +4, tacrolimus and mycophenolic acid as graft versus host disease (GVHD) prophylaxis. RESULTS: The median follow-up was 1,099 days (45-1258 days). The overall survival rate up-to-date is 83.3%. In 10 of the 12 patients, a sustained graft was achieved. None of the patients had acute or chronic GVHD. CONCLUSIONS: Haplo-SCT could be established as a first-line treatment when there is no matched related or unrelated donor. According to this short sample and previous reports, PBSC are a feasible option effectively used as the sole source of stem cells. Additionally, post-transplant cyclophosphamide remains a good strategy for GVHD prevention.