Autoimmune Lymphoproliferative Syndrome: An Overview

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is an inherited nonmalignant lymphoproliferative disorder characterized by heterozygous mutations within the first apoptosis signal receptor (FAS) signaling pathway. Defects in FAS-mediated apoptosis cause an expansion and accumulation of autoreactive CD4^- and CD8^- (double-negative) T cells, leading to cytopenias, splenomegaly, lymphadenopathy, autoimmune disorders, and a greatly increased lifetime risk of lymphoma. The differential diagnosis of ALPS includes infection, other inherited immunodeficiency disorders, primary and secondary autoimmune syndromes, and lymphoma. The most consistent pathologic feature is a florid paracortical expansion of double-negative T cells in lymph nodes. A presumptive clinical diagnosis can be made from symptoms and a constellation of laboratory test results. However, a definitive diagnosis requires ancillary testing and enables disease subclassification. Recognition of ALPS is critical, as treatment with immunosuppressive therapies can effectively reduce or ameliorate symptoms for most patients.

Figure 1.

Simplified diagram depicting the FAS pathway involved in activation-induced cell death (AID). FAS ligand (FASL) binds FAS, causing clustering of FAS. This recruits FAS-associated protein with death domain (FADD) and Pro-Caspases 8 and 10, which together with FAS constitute the death-inducing signaling complex (DISC). The DISC then propagates a pro-apoptotic signal via the activation of terminal caspases.

Figure 2.

Lymph nodes in autoimmune lymphoproliferative syndrome (ALPS) patients often show characteristic changes. A-B) Enlarged lymph node with a florid follicular hyperplasia composed of small mature-appearing lymphocytes (hematoxylin-eosin, original magnification ×2 and ×10). C) The paracortical lymphocytes are highly proliferative (arrowheads), and may be associated with both immunoblasts (arrows) and plasma cells (circled) (hematoxylin-eosin, original magnification ×100). D) Sinus histiocytosis with emperipolesis (arrow heads) may be seen in a minority of cases (hematoxylin-eosin, original magnification ×100).

Figure 3.

Characteristic flow cytometric findings in autoimmune lymphoproliferative syndrome (ALPS). A-B) The peripheral blood of ALPS patients will show an expanded population of CD3+ T-cells that are negative for both CD4 and CD8 (double negative, highlighted in red). C) The population of double negative T-cells should be positive for alpha-beta (α/ß) T-cell receptor (TCR).

Figure 4.

Diagnostic algorithm for autoimmune lymphoproliferative syndrome (ALPS). A presumptive diagnosis of ALPS may be rendered based on clinical history and the results of laboratory testing. A definitive diagnosis requires genetic testing and potentially functional assays. Genetic testing can be performed in a stepwise fashion and may incorporate multigene panels. *** = diagnosis depends on results of multigene testing; IL = interleukin; NGS = next generation sequencing; DNT = double negative T; sFAS = somatic FAS; FASL = FAS ligand; CASP10 = Caspase 10.