Autoimmune Lymphoproliferative Syndrome (ALPS) Caused by Fas (CD95) Mutation Mimicking Sarcoidosis

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited disorder associated with defects in apoptosis, characterized by childhood onset of lymphadenopathy, splenomegaly, hyperimmunoglobulinemia, and autoimmune disease. ALPS is most frequently associated with a mutation in the cell death receptor Fas (CD95). Very rarely a mutation in caspase 10 is present. An increase of CD4/CD8 double negative T cells in the peripheral blood and lymph nodes is a feature characteristic of ALPS. Additionally, histiocytic proliferations resembling sinus histiocytosis with massive lymphadenopathy (Rosai-Dorfman disease) were reported recently in patients with ALPS. In the rare cases with a caspase 10 mutation an accumulation of dendritic cells in lymphoid organs was noted. We describe a different, sarcoidosislike, histiocytic infiltration of lymph nodes that persisted for years in a girl, that was initially supposed to suffer from sarcoidosis, but was eventually diagnosed as ALPS, associated with a missense mutation in the intracellular death domain of Fas. This sarcoidosislike histologic picture extends the spectrum of histiocytic lymph node alterations observed in ALPS and alerts of a potential diagnostic pitfall.

CD3+CD4−CD8− (double negative) T cells: Saviours or villains of the immune response?

“…These results together with other evidence [26][27][28][29] suggest that the increased number of DN T cells may represent a sensitive test or biomarker to screen patients who should undergo testing for ALPS. In this regard it is interesting to mention that the analysis of DN T cell levels has been used to distinguish ALPS from other autoimmune disease such as Evans syndrome [27] or sarcoidosis [47]. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 10 amount of IL-17A during the early stages of infection (7 days) while CD4+ T cells start to produce this cytokine later (14 days) [48].…”

Renal double negative T cells: unconventional cells in search of a function

“…For example, in Systemic Lupus Erythematosus (SLE) patients, DN T cell numbers were found to be significantly increased and were a major producer of IL-17, the key inflammatory cytokine in SLE (2). Similarly, in Autoimmune Lymphoproliferative Syndrome (ALPS) patients, peripheral DN T cell numbers have been reported to increase from 1% in controls to 40% of T cells, making DN T cell number a potential disease biomarker (3). Peripheral DN T cell numbers have also been shown to increase in HIV patients.…”

Development of Disseminated Histiocytic Sarcoma in a Patient With Autoimmune Lymphoproliferative Syndrome and Associated Rosai-Dorfman Disease

“…Benign histiocytic proliferations have been described previously by our group,13 as well others,15 in the context of ALPS, although these generally do not attain clinical significance. We previously characterized the occurrence of SHML-type S-100 positive histiocytes reminiscent of Rosai-Dorfman disease (RDD) in a cohort of 44 patients with ALPS Type Ia 13.…”