Immunophenotypic profiles in families with autoimmune lymphoproliferative syndrome

Autoimmune lymphoproliferative syndrome (ALPS) type Ia is caused by inherit ed defects in apoptosis and is characterized by nonmalignant lymphoaccumula tion, autoimmunity, and increased alpha/beta (+) double-negative T cells (a lpha/beta (+)-DNT cells). This study reports immunophenotypic findings in 1 66 members of 31 families with ALPS type Ia, associated with genetic mutati ons in the TNFRSF6 gene encoding Fas. The ALPS type Ia probands (n = 31) an d relatives having both a Fas mutation and clinically proven ALPS (n = 28) showed significant expansion of CD8(+) T cells, alpha/beta (+)-DNT cells, g amma/delta (+)-DNT cells, CD3(+)/HLA-DR+ T cells, CD8(+)/CD57(+) T cells, a nd CD5(+) B cells. Relatives with Fas mutations, but without all the requir ed criteria for ALPS (n = 42), had expansions of CD8(+) T cells, alpha/beta (+)-DNT cells, and gamma/delta (+)-DNT cells. Interestingly, relatives wit hout a Fas mutation and with no features of ALPS (n = 65) demonstrated a sm all but significant expansion of CD8(+) T cells, both DNT cell subsets, and CD5(+) B cells. As compared to unrelated healthy controls, lymphocyte subs et alterations were greatest in the probands, followed by the relatives wit h mutations and ALPS. Probands and relatives with mutations and ALPS also s howed 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 we re similar in mutation-positive relatives regardless of the presence of cli nical ALPS, factors, other than modifiers of the Fas apoptosis pathway, lea ding to these distinctive immunophenotypic profiles most likely contribute to disease penetrance in ALPS. (Blood. 2001;98:2466-2473) (C) 2001 by The A merican Society of Hematology.