Reduced thymic output, cell cycle abnormalities, and increased apoptosis of T lymphocytes in patients with cartilage-hair hypoplasia

• Published in: Journal of allergy and clinical immunology 2011-07, Vol.128 (1), p.139-146
• Main Authors: de la Fuente, Miguel A., MD, PhD, Recher, Mike, MD, Rider, Nicholas L., DO, Strauss, Kevin A., MD, Morton, D. Holmes, MD, Adair, Margaret, MD, Bonilla, Francisco A., MD, PhD, Ochs, Hans D., MD, Gelfand, Erwin W., MD, Pessach, Itai M., MD, PhD, Walter, Jolan E., MD, PhD, King, Alejandra, MD, Giliani, Silvia, PhD, Pai, Sung-Yun, MD, Notarangelo, Luigi D., MD
• Format: Article
• Language: English
• Subjects: Adolescent; Allergy and Immunology; Apoptosis; Apoptosis - immunology; Biological and medical sciences; Cartilage-hair hypoplasia; Cell activation; Cell cycle; Cell Cycle - immunology; Cell migration; Cell proliferation; Cell Separation; Child; Child, Preschool; Data processing; Diseases of the osteoarticular system; Female; Flow Cytometry; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Genotype; Hair - abnormalities; Hair - immunology; Hair - pathology; Hirschsprung Disease - genetics; Hirschsprung Disease - immunology; Hirschsprung Disease - pathology; Humans; Immune response; Immunity (cell-mediated); Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunodeficiency; Immunologic Deficiency Syndromes - genetics; Immunologic Deficiency Syndromes - immunology; Immunologic Deficiency Syndromes - pathology; Immunopathology; Infant; Lymphocytes; Lymphocytes B; Lymphocytes T; Male; Malformations and congenital and or hereditary diseases involving bones. Joint deformations; Medical sciences; Mutation; Osteochondrodysplasias - congenital; Osteochondrodysplasias - genetics; Osteochondrodysplasias - immunology; Osteochondrodysplasias - pathology; Phenotype; Polymerase Chain Reaction; RMRP; RNA, Long Noncoding; RNA, Untranslated - genetics; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; T-Lymphocytes - immunology; Thymus; Thymus Gland - immunology; T lymphocytes; Young Adult
• ISSN: 0091-6749; 1097-6825
• DOI: 10.1016/j.jaci.2011.03.042

Background Cartilage-hair hypoplasia (CHH) is characterized by metaphyseal dysplasia, bone marrow failure, increased risk of malignancies, and a variable degree of immunodeficiency. CHH is caused by mutations in the RNA component of the mitochondrial RNA processing (RMRP) endoribonuclease gene, which is involved in ribosomal assembly, telomere function, and cell cycle control. Objectives We aimed to define thymic output and characterize immune function in a cohort of patients with molecularly defined CHH with and without associated clinical immunodeficiency. Methods We studied the distribution of B and T lymphocytes (including recent thymic emigrants), in vitro lymphocyte proliferation, cell cycle, and apoptosis in 18 patients with CHH compared with controls. Results Patients with CHH have a markedly reduced number of recent thymic emigrants, and their peripheral T cells show defects in cell cycle control and display increased apoptosis, resulting in poor proliferation on activation. Conclusion These data confirm that RMRP mutations result in significant defects of cell-mediated immunity and provide a link between the cellular phenotype and the immunodeficiency in CHH.