Clinical, Immunologic, and Genetic Features of an Autoimmune Lymphoproliferative Syndrome Associated With Abnormal Lymphocyte Apoptosis
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- Michael C. Sneller
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Jin Wang
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Janet K. Dale
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Warren Strober
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Lindsay A. Middelton
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Youngnim Choi
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Thomas A. Fleisher
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Megan S. Lim
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Elaine S. Jaffe
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Jennifer M. Puck
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Michael J. Lenardo
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
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- Stephen E. Straus
- From the Laboratory of Immunoregulation, Laboratory of Clinical Investigation, and Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Laboratory of Gene Transfer, Medical Genetics Branch, National Center for Human Genome Research, Laboratory of Pathology, National Cancer Institute, Clinical Center, National Institutes of Health, Bethesda, MD.
説明
<jats:title>Abstract</jats:title><jats:p>Programmed cell death (apoptosis) of activated lymphocytes is critical to immune homeostasis. The cell surface protein Fas (CD95) and its ligand play a pivotal role in regulating lymphocyte apoptosis, and defective expression of either Fas or Fas ligand results in marked over accumulation of mature lymphocytes and autoimmune disease in mice. The results of recent studies suggest that defective lymphocyte apoptosis caused by mutations of the Fas gene can result in a severe autoimmune lymphoproliferative syndrome (ALPS) in humans. To define the clinical, genetic, and immunologic spectrum of ALPS, 9 patients and their families were extensively evaluated with routine clinical studies, lymphocyte phenotyping, genotyping, and in vitro assays for lymphocyte apoptosis. Individual patients were followed up for 3 months to 6 years. ALPS was identified in 9 unrelated children as manifested by moderate to massive splenomegaly and lymphadenopathy, hypergammaglobulinemia, autoimmunity, B-cell lymphocytosis, and the expansion of an unusual population of CD4−CD8− T cells that express the α/β T-cell receptor (TCR). All patients showed defective lymphocyte apoptosis in vitro. Heterozygous mutations of the Fas gene were detected in 8 patients. One ALPS patient lacked a Fas gene mutation. Healthy relatives with Fas mutations were identified in 7 of 8 ALPS kindreds. These relatives also showed in vitro abnormalities of Fas-mediated lymphocyte apoptosis, but clinical features of ALPS were not present in the vast majority of these individuals. ALPS is a unique clinical syndrome in which in vitro abnormalities of lymphocyte apoptosis are associated with abnormal lymphoproliferation and autoimmunity. These findings provide evidence that apoptosis of activated lymphocytes is an important mechanism for maintaining immunologic homeostasis and self-tolerance in humans. Fas gene mutations account for impaired lymphocyte apoptosis in only a subset of patients with ALPS.</jats:p>
収録刊行物
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- Blood
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Blood 89 (4), 1341-1348, 1997-02-15
American Society of Hematology