A Severe Form of Human Combined Immunodeficiency Due to Mutations in DNA Ligase IV
Autor: | Charlotte M. Niemeyer, Barbara Selle, M Orlowska-Volk, Anke M.J. Peters, Ulrich Pannicke, Anselm Enders, W. Friedrich, Detlev Schindler, Ulrich Duffner, Elisabeth Nikolopoulos, Stephan Ehl, Klaus Schwarz, Paul Fisch |
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Rok vydání: | 2006 |
Předmět: |
Heterozygote
DNA Ligases T-Lymphocytes Immunology LIG4 syndrome Biology LIG4 medicine.disease_cause Radiation Tolerance DNA Ligase ATP Immune system medicine Humans Immunology and Allergy Gene Rearrangement B-Lymphocyte Immunodeficiency B-Lymphocytes Mutation Base Sequence Infant Newborn DNA Gene rearrangement Immune dysregulation medicine.disease Molecular biology Phenotype Immunoglobulin class switching Child Preschool Antibody Formation Microcephaly Female Severe Combined Immunodeficiency |
Zdroj: | The Journal of Immunology. 176:5060-5068 |
ISSN: | 1550-6606 0022-1767 |
Popis: | DNA ligase IV (LigIV) deficiency was identified as the molecular basis for a severe form of combined immunodeficiency in two microcephalic siblings with cellular radiosensitivity. In one patient the diagnosis was made directly after birth, allowing analysis of the role of LigIV in the development of specific immune cells. Absolute numbers of B cells were reduced 100-fold and αβ T cells 10-fold, whereas γδ T cells were normal. Spectratyping of all three cell populations showed a diverse repertoire, but sequencing of IgH V(D)J junctions revealed shorter CDR3 regions due to more extensive nucleotide deletions among D and J elements and fewer N nucleotide insertions. Clonal restriction of IgG-expressing, but not IgM-expressing, B cells and the lack of primary and secondary lymph node follicles indicated impaired class switch recombination. Observations in the older sibling showed that this rudimentary immune system was able to mount specific responses to infection. However, partial Ab responses and extensive amplification of γδ T cells could not prevent a life-threatening course of viral and bacterial infections, the development of an EBV-induced lymphoma, and immune dysregulation reflected by severe autoimmune cytopenia. Impaired generation of immune diversity under conditions of limited LigIV activity can cause a human SCID variant with a characteristic immunological phenotype. |
Databáze: | OpenAIRE |
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