Brenda Reid

Mutations in STAT3 and IL12RB1 impair the development of human IL-17–producing T cells

The cytokines controlling the development of human interleukin (IL) 17–producing T helper cells in vitro have been difficult to identify. We addressed the question of the development of human IL-17–producing T helper cells in vivo by quantifying the production and secretion of IL-17 by fresh T cells ex vivo, and by T cell blasts expanded in vitro from patients with particular genetic traits affecting transforming growth factor (TGF) β, IL-1, IL-6, or IL-23 responses. Activating mutations in TGFB1, TGFBR1, and TGFBR2 (Camurati-Engelmann disease and Marfan-like syndromes) and loss-of-function mutations in IRAK4 and MYD88 (Mendelian predisposition to pyogenic bacterial infections) had no detectable impact. In contrast, dominant-negative mutations in STAT3 (autosomal-dominant hyperimmunoglobulin E syndrome) and, to a lesser extent, null mutations in IL12B and IL12RB1 (Mendelian susceptibility to mycobacterial diseases) impaired the development of IL-17–producing T cells. These data suggest that IL-12Rβ1– and STAT-3–dependent signals play a key role in the differentiation and/or expansion of human IL-17–producing T cell populations in vivo.

The outcome of patients with hypogammaglobulinemia in infancy and early childhood

A 10-year prospective cohort study followed the evolution of antibodies in children less than 4 years of age with hypogammaglobulinemia. Three patterns were identified: in group 1, immunoglobulins and antibody production normalized;iin group 2, patients continued to have low IgG levels; and in group 3, IgG levels normalized but antibody levels were transient. Statistical analysis showed that invasive infection or low tetanus antibodies at presentation were associated with the development of significant humoral immunodeficiency.

Clinical utility of high-resolution pulmonary computed tomography in children with antibody deficiency disorders.

Objective. To assess the value of high-resolution computed tomography (HRCT) in determining the extent and significance of lung disease in children with antibody deficiency states. Materials and methods. Seventy HRCT scans performed on 37 children with various antibody deficiency disorders over a 5-year period were retrospectively scored using a previously described demerit scoring system (0–25 with 0 = worst, 25 = best). Points are subtracted from 25 with increasing severity of disease. The potential correlations between CT scores and clinical factors, including age at diagnosis, age at CT, type of immunoglobulin deficiency, length of respiratory symptoms before diagnosis, number of pneumonias before diagnosis, type, length and success of therapy, patient compliance and pulmonary function tests (PFTs), were assessed. Results. Of the 37 children, a demonstrated 22 abnormal scans (CT score ≤ 22). All nine demonstrated bronchiectasis with a lower lobe and right middle lobe predominance. Statistically significant correlations were seen between severity of lung disease (CT score) and length of respiratory symptoms before diagnosis (p = 0.01), success of therapy (P = 0.001) and PFTs (P = 0.0008). Of seven children who were followed with repeated scans, 4 of the 7 demonstrated CT scores which improved on high-dose intravenous immunoglobulin replacement therapy. Conclusion. HRCT is a useful adjunct to demonstrate the extent and severity of lung disease at diagnosis and during therapy. Correlation with clinical factors suggests a higher risk group needing more aggressive management.

Compound heterozygous mutations in the noncoding RNU4ATAC cause Roifman Syndrome by disrupting minor intron splicing

Roifman Syndrome is a rare congenital disorder characterized by growth retardation, cognitive delay, spondyloepiphyseal dysplasia and antibody deficiency. Here we utilize whole-genome sequencing of Roifman Syndrome patients to reveal compound heterozygous rare variants that disrupt highly conserved positions of the RNU4ATAC small nuclear RNA gene, a minor spliceosome component that is essential for minor intron splicing. Targeted sequencing confirms allele segregation in six cases from four unrelated families. RNU4ATAC rare variants have been recently reported to cause microcephalic osteodysplastic primordial dwarfism, type I (MOPD1), whose phenotype is distinct from Roifman Syndrome. Strikingly, all six of the Roifman Syndrome cases have one variant that overlaps MOPD1-implicated structural elements, while the other variant overlaps a highly conserved structural element not previously implicated in disease. RNA-seq analysis confirms extensive and specific defects of minor intron splicing. Available allele frequency data suggest that recessive genetic disorders caused by RNU4ATAC rare variants may be more prevalent than previously reported.

Combined immunodeficiency and atopy caused by a dominant negative mutation in caspase activation and recruitment domain family member 11 (CARD11)

Background Combined immunodeficiency (CID) is a T‐cell defect frequently presenting with recurrent infections, as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. Objective We sought to identify the genetic aberration in 4 related patients with CID, early‐onset asthma, eczema, and food allergies, as well as autoimmunity. Methods We performed whole‐exome sequencing, followed by Sanger confirmation, assessment of the genetic variant effect on cell signaling, and evaluation of the resultant immune function. Results A heterozygous novel c.C88T 1‐bp substitution resulting in amino acid change R30W in caspase activation and recruitment domain family member 11 (CARD11) was identified by using whole‐exome sequencing and segregated perfectly to family members with severe atopy only but was not found in healthy subjects. We demonstrate that the R30W mutation results in loss of function while also exerting a dominant negative effect on wild‐type CARD11. The CARD11 defect altered the classical nuclear factor &kgr;B pathway, resulting in poor in vitro T‐cell responses to mitogens and antigens caused by reduced secretion of IFN‐&ggr; and IL‐2. Conclusion Unlike patients with biallelic mutations in CARD11 causing severe CID, the R30W defect results in a less profound yet prominent susceptibility to infections, as well as multiorgan atopy and autoimmunity.

Gastrointestinal Abnormalities among Patients with Chronic Granulomatous Disease

Objective: Chronic granulomatous disease (CGD) is characterized by increased susceptibility to infections and inflammation that may lead to various gastrointestinal (GI) abnormalities. Our objective was to better characterize the GI manifestations among patients suffering from CGD as well as the effects of different treatments.Methods: We analyzed 11 patients with CGD managed by the immunology service at the Hospital for Sick Children, Toronto, Ontario between 2000 and 2012.Results: All patients had one or more GI abnormality including colitis (72.7%), peri-anal fissure/abscess (36.3%) or oral aphthous ulcers (36.3%). Failure to thrive occurred in 5 patients (45.4%), all with associated colitis. Bone marrow transplantations (BMT) using HLA-identical sibling donors were performed in 4 patients, with 3 patients surviving. In these 3 patients, the inflammation-mediated GI manifestations present before BMT resolved during the follow-up period of 3.2-4.6 years. In contrast, 6 of 7 patients who did not receive BMT (p=0.033) continued to suffer from GI disease resulting in failure to thrive, GI bleeding and life threatening small bowel perforation and often required immune suppressive medications.Conclusions: Inflammatory GI manifestations, particularly colitis, are very common in CGD and are often associated with significant morbidity. Allogeneic BMT, particularly if an HLA-matched sibling donor is available should be considered in patients with CGD who suffer from significant GI involvement.

Long-term Remission for Disseminated Mycobacterium avium-intracellulare Complex Associated With Antibody Deficiency

Mycobacterium avium-intracellulare (MAI) is a ubiquitous organism with limited virulence in the immunocompetent host. Disseminated disease is associated with a high mortality rate. Except for localized cervical adenitis, MAI disease is rare in immunocompetent children. We report a child with antibody deficiency (dysgammaglobulinemia) and disseminated MAI infection, in whom complete, long-term remission was attained with multiple antimycobacterial therapy. The patient presented with progressive cervical lymphadenopathy and hepatomegaly at 7 years of age. A lymph node biopsy showed acid-fast bacilli and granulomas. Despite a transient response to conventional antituberculous therapy, including isoniazid and rifampin, his symptoms progressed. Cultures from blood, bone marrow, spleen, and cervical lymph node tissues revealed an MAI organism. Subsequent treatment using a combination of clarithromycin, amikacin, and ethambutol for 16 months resolved clinical symptoms, and subsequent blood culture results became negative. By the time of this report, the patient has been disease-free for 4 years. Multiple-drug therapy is promising for the treatment of MAI in children with antibody deficiency; however, the selection of antiinfective drugs should include a member of the newer macrolide family. acquired immunodeficiency syndrome, clarithromycin, dysgammaglobulinemia, Mycobacterium avium-intracellulare, treatment.

Matched Unrelated Bone Marrow Transplant for Omenn Syndrome

Little information is currently available on the outcome and the long-term restoration of immune function in infants with Omenn syndrome (OS) treated with bone marrow transplantation (BMT). We prospectively followed patients with OS who received matched unrelated donor (MUD) BMT at our center. Engraftment, immune reconstitution, and transplant-related complications were recorded. Humoral and cellular immunity were evaluated. Six patients with OS were diagnosed at a mean age of 4.6 months and received a matched unrelated donor BMT as the first BMT at the mean age of 9.4 months. All six patients are alive and well at a mean 95 months after transplant. All patients have evidence of full hemopoetic engraftment and robust immune function. We have shown here that matched unrelated donor BMT is highly effective in curing patients with OS regardless of their genotype. This mode of treatment should be preferred for patients with OS when a related identical donor is not available.