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Blood, 15 October 2001, Vol. 98, No. 8, pp. 2466-2473
IMMUNOBIOLOGY
Immunophenotypic profiles in families with autoimmune
lymphoproliferative syndrome
Jack J. H. Bleesing,
Margaret R. Brown,
Stephen E. Straus,
Janet K. Dale,
Richard M. Siegel,
Michele Johnson,
Michael J. Lenardo,
Jennifer M. Puck, and
Thomas A. Fleisher
From the Immunology Service, Department of Laboratory
Medicine, Clinical Center, Laboratory of Clinical Investigation and
Laboratory of Immunology, National Institute of Allergy and Infectious
Diseases, and the Genetics and Molecular Biology Branch, National Human
Genome Research Institute, National Institutes of Health, Bethesda, MD.
Autoimmune lymphoproliferative syndrome (ALPS) type Ia
is caused by inherited defects in apoptosis and is characterized by nonmalignant lymphoaccumulation, autoimmunity, and increased
 / + double-negative T cells (/+-DNT
cells). This study reports immunophenotypic findings in 166 members of
31 families with ALPS type Ia, associated with genetic mutations in the
TNFRSF6 gene encoding Fas. The ALPS type Ia probands (n = 31) and relatives having both a Fas mutation and clinically proven ALPS (n = 28) showed significant expansion of CD8+
T cells, /+-DNT cells,
 / +-DNT cells,
CD3+/ HLA-DR+ T cells,
CD8+/CD57+ T cells, and CD5+ B
cells. Relatives with Fas mutations, but without all the required criteria for ALPS (n = 42), had expansions of CD8+ T
cells, /+-DNT cells, and /+-DNT
cells. Interestingly, relatives without a Fas mutation and with no
features of ALPS (n = 65) demonstrated a small but significant expansion of CD8+ T cells, both DNT cell subsets, and
CD5+ B cells. As compared to unrelated healthy controls,
lymphocyte subset alterations were greatest in the probands, followed
by the relatives with mutations and ALPS. Probands and relatives with
mutations and ALPS also showed a lower number of
CD4+/CD25+ T cells that, in combination with an
independent increase in HLA-DR+ T cells, provided a profile
predictive of the presence of clinical ALPS. Because quantitative
defects in apoptosis were similar in mutation-positive relatives
regardless of the presence of clinical ALPS, factors, other than
modifiers of the Fas apoptosis pathway, leading to these distinctive
immunophenotypic profiles most likely contribute to disease penetrance
in ALPS.
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