Dataset Information

IL-7 receptor deficient SCID with a unique intronic mutation and post-transplant autoimmunity due to chronic GVHD.

ABSTRACT: Severe combined immunodeficiency (SCID) may result from a variety of genetic defects that impair the development of T cells. Signaling mediated by the cytokine interleukin-7 is essential for the differentiation of T cells from lymphoid progenitors, and mutations of either the interleukin-7 receptor alpha chain (IL-7Ralpha) or its associated cytokine receptor chain, the common gamma chain (gammac), result in SCID. Here we report a case of SCID due to heterozygous mutations of the IL7R gene encoding IL-7Ralpha. A previously unrecognized mutation found within intron 3 created a new exon between exons 3 and 4 in the mRNA transcribed from this allele, producing a truncated, unstable mRNA. This mutation illustrates the necessity of evaluating both coding and non-coding regions of genes when searching for pathogenic mutations. Following hematopoietic stem cell transplantation of our patient, immune reconstitution was accompanied by two unusual complications, immune-mediated myositis and myasthenia gravis.

SUBMITTER: Butte MJ

PROVIDER: S-EPMC2100404 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

IL-7 receptor deficient SCID with a unique intronic mutation and post-transplant autoimmunity due to chronic GVHD.

Butte Manish J MJ Haines Charles C Bonilla Francisco A FA Puck Jennifer J

Clinical immunology (Orlando, Fla.) 20070912 2

Severe combined immunodeficiency (SCID) may result from a variety of genetic defects that impair the development of T cells. Signaling mediated by the cytokine interleukin-7 is essential for the differentiation of T cells from lymphoid progenitors, and mutations of either the interleukin-7 receptor alpha chain (IL-7Ralpha) or its associated cytokine receptor chain, the common gamma chain (gammac), result in SCID. Here we report a case of SCID due to heterozygous mutations of the IL7R gene encodi ...[more]

PMID: 17827065

Similar Datasets

Project description:BackgroundThe DNA-repair enzyme Artemis is essential for rearrangement of T- and B-cell receptors. Mutations in DCLRE1C, which encodes Artemis, cause Artemis-deficient severe combined immunodeficiency (ART-SCID), which is poorly responsive to allogeneic hematopoietic-cell transplantation.MethodsWe carried out a phase 1-2 clinical study of the transfusion of autologous CD34+ cells, transfected with a lentiviral vector containing DCLRE1C, in 10 infants with newly diagnosed ART-SCID. We followed them for a median of 31.2 months.ResultsMarrow harvest, busulfan conditioning, and lentiviral-transduced CD34+ cell infusion produced the expected grade 3 or 4 adverse events. All the procedures met prespecified criteria for feasibility at 42 days after infusion. Gene-marked T cells were detected at 6 to 16 weeks after infusion in all the patients. Five of 6 patients who were followed for at least 24 months had T-cell immune reconstitution at a median of 12 months. The diversity of T-cell receptor β chains normalized by 6 to 12 months. Four patients who were followed for at least 24 months had sufficient B-cell numbers, IgM concentration, or IgM isohemagglutinin titers to permit discontinuation of IgG infusions. Three of these 4 patients had normal immunization responses, and the fourth has started immunizations. Vector insertion sites showed no evidence of clonal expansion. One patient who presented with cytomegalovirus infection received a second infusion of gene-corrected cells to achieve T-cell immunity sufficient for viral clearance. Autoimmune hemolytic anemia developed in 4 patients 4 to 11 months after infusion; this condition resolved after reconstitution of T-cell immunity. All 10 patients were healthy at the time of this report.ConclusionsInfusion of lentiviral gene-corrected autologous CD34+ cells, preceded by pharmacologically targeted low-exposure busulfan, in infants with newly diagnosed ART-SCID resulted in genetically corrected and functional T and B cells. (Funded by the California Institute for Regenerative Medicine and the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT03538899.).

Project description:BACKGROUND:Low-dose post-transplant cyclophosphamide (PTCy) in conjunction with anti-thymocyte globulin (ATG) appears as a potentially effective graft-versus-host disease (GVHD) prevention strategy in haploidentical hematopoietic cell transplant (haplo-HCT). Our study aims to assess the efficacy of this regimen. METHODS:We extended our prospective study in patients treated with low-dose PTCy (14.5 mg/kg on days 3 and 4) in ATG/granulocyte colony-stimulating factor (G-CSF)-based regimen and compared the results to the contemporary cohort of patients without low-dose PTCy (ATG cohort). Both study cohort and control are transplanted from maternal donor or collateral relatives. RESULTS:We identified 239 consecutive patients (ATG-PTCy cohort = 114; ATG cohort = 125). All patients but one in ATG cohort achieved myeloid engraftment by day 30 post-HCT. We found that both the cumulative incidence of 100-day grade III-IV aGvHD and non-relapse-mortality (NRM) in the ATG-PTCy cohort was significantly reduced than that in the ATG group (5% vs 18%; P = 0.003; and 6% vs 15%; P= 0.045); the 2-year cumulative incidences of relapse and overall survival were comparable between the two cohorts (13% vs 14%; P = 0.62; and 83% vs 77%; P = 0.18, respectively). Furthermore, GVHD-free, relapse-free survival (GRFS) was significantly improved in the ATG-PTCy arm (63% vs 48%; P = 0.039). In multivariate analysis, the joint treatment resulted in lower grade II-IV acute GVHD (HR 0.58; P = 0.036), grade III-IV aGvHD (HR 0.28; P = 0.006), chronic GVHD (HR 0.60; P = 0.047), NRM (HR 0.26; P = 0.014), and higher GRFS (HR 0.59; P = 0.021) but slower myeloid and platelet recovery (HR 0.29 and 0.30; both P < 0.001). CONCLUSIONS:These results suggested that ATG/PTCy (low-dose) can reduce both acute and chronic GVHD as compared with standard ATG-based prophylaxis using maternal donor or collateral relatives at particular high GVHD risk.

Dataset Information

IL-7 receptor deficient SCID with a unique intronic mutation and post-transplant autoimmunity due to chronic GVHD.

Publications

IL-7 receptor deficient SCID with a unique intronic mutation and post-transplant autoimmunity due to chronic GVHD.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets