An inherited disorder of lymphocyte apoptosis: the autoimmune lymphoproliferative syndrome

SE Straus, M Sneller, MJ Lenardo, JM Puck… - Annals of internal …, 1999 - acpjournals.org
SE Straus, M Sneller, MJ Lenardo, JM Puck, W Strober
Annals of internal medicine, 1999acpjournals.org
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 …
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.
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