An Inherited Disorder of Lymphocyte Apoptosis: The Autoimmune Lymphoproliferative Syndrome

An Inherited Disorder of Lymphocyte Apoptosis: The Autoimmune Lymphoproliferative Syndrome

For definitions of terms used in the text, see Glossary.

Abstract

The autoimmune lymphoproliferative syndrome (ALPS) affords novel insights into the mechanisms that regulate lymphocyte homeostasis and underlie the development of autoimmunity. This syndrome arises early in childhood in persons who inherit mutations in genes that mediate apoptosis, or programmed cell death. The timely deletion of lymphocytes is a way to prevent their accumulation and the persistence of cells that can react against the body's own antigens. In ALPS, defective lymphocyte apoptosis permits chronic, nonmalignant adenopathy and splenomegaly; the survival of normally uncommon “double-negative” CD3⁺ CD4 ⁻CD8 ⁻T cells; and the development of autoimmune disease. Most cases of ALPS involve heterozygous mutations in the lymphocyte surface protein Fas that impair a major apoptotic pathway. Detailed immunologic investigations of the cellular and cytokine profiles in ALPS show a prominent skewing toward a T-helper 2 phenotype; this provides a rational explanation for the humoral autoimmunity typical of patients with ALPS. Prospective evaluations of 26 patients and their families show an ever-expanding spectrum of ALPS and its major complications: hypersplenism, autoimmune hemolytic anemia, thrombocytopenia, and neutropenia. Defective apoptosis may also contribute to a heightened risk for lymphoma.

Article and Author Information

An edited summary of a Clinical Staff Conference held on 25 February 1998 at the National Institutes of Health, Bethesda, Maryland.
Authors who wish to cite a section of the conference and specifically indicate its author may use this example for the form of the reference: Lenardo MJ. Molecular regulation of lymphocyte apoptosis, pp 595-596. In: Straus SE, moderator. An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome. Ann Intern Med. 1999; 130:591-601.
Requests for Reprints: Stephen E. Straus, MD, Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N228, 10 Center Drive, National Institutes of Health, Bethesda, MD 20892-1888; e-mail, sstraus{at}nih.gov.
Current Author Addresses: Drs. Straus and Strober: Laboratory of Clinical Investigation, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N228, 10 Center Drive, National Institutes of Health, Bethesda, MD 20892-1888.
Dr. Lenardo: Laboratory of Immunology, National Institute of Allergy and Infectious Diseases, Building 10, Room 11N331, 10 Center Drive, National Institutes of Health, Bethesda, MD 20892.
Dr. Puck: Immunologic Genetics Branch, National Human Genome Research Institute, Building 49, Room 3W14, 9000 Rockville Pike, National Institutes of Health, Bethesda, MD 20892.
Dr. Sneller: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, Building 10, Room 11C410, 10 Center Drive, National Institutes of Health, Bethesda, MD 20892.