New advances in the diagnosis and treatment of autoimmune lymphoproliferative syndrome

Abstract

Purpose of review: Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of disrupted lymphocyte homeostasis, resulting from mutations in the Fas apoptotic pathway. Clinical manifestations include lymphadenopathy, splenomegaly, and autoimmune cytopenias. A number of new insights have improved the understanding of the genetics and biology of ALPS. These will be discussed in this review.

Recent findings: A number of key observations have been made recently that better define the pathophysiology of ALPS, including the characterization of somatic FAS variant ALPS, the identification of haploinsufficiency as a mechanism of decreased Fas expression, and the description of multiple genetic hits in FAS in some families that may explain the variable penetrance of the disease. In addition, ALPS has been shown to be a more common condition, as patients diagnosed with other disorders, including Evans syndrome and common variable immune deficiency, have been found to have ALPS. Finally, the treatment of the disease has changed as splenectomy and rituximab have been shown to have unexpected ALPS-specific toxicities, and mycophenolate mofetil and sirolimus have been demonstrated to have marked activity against the disease.

Summary: On the basis of novel advances, the diagnostic algorithm and recommended treatment for ALPS have changed significantly, improving quality of life for many patients.

Figure 1. Fas apoptotic pathway

ALPS is caused by defective Fas-mediated apoptosis. Normally, as part of the down-regulation of the immune response, activated B and T lymphocytes increase Fas expression, and activated T lymphocytes increase expression of Fas ligand. Fas and Fas ligand interact which activates the Fas-associated death domain (FADD) and triggers the caspase cascade, culminating in cellular apoptosis. Fas-mediated signaling is part of the extrinsic apoptotic pathway, because it is activated through the interactiong of cell surface death receptors. In contrast, the intrinsic apoptotic pathway is activated by cellular stressors that lead to decreased mitochondrial membrane permeability with release of apoptosis-inducing substances. © Sue Seif, MA (used with permission).

Figure 2. Hypothetical Model of Dysregulation of PI3K/Akt/mTOR Signaling in ALPS

ALPS is a defined by defects in the Fas apoptotic pathway; however, individuals with causative mutations do not always manifest disease symptoms. Fas must be recruited into lipid rafts in order to stimulate apoptosis. We hypothesize that in ALPS the defects in the Fas pathway lead to decreased distribution of Fas receptor into lipid rafts, thereby activating the serine threonine kinase Akt. In support, Akt activity and distribution of Fas into lipid rafts are inversely correlated in some lymphocyte subsets.[54] Constitutive activation of Akt stimulates the mTOR pathway, causing uncontrolled proliferation of the double negative T cells (DNTs) with consequent lymphadenopathy and splenomegaly. These DNTs also secrete IL-10, causing autoimmunity.High levels of IL-10 down-regulate TGF-β producing T_regs, a subset of T lymphocytes that can regulate immune tolerance.[55,56] We observe abnormally low T_reg numbers in ALPS (unpublished). Moreover, low levels of TGF-β producing T-cells can cause an “ALPS-like” disease in mice.[57] Thus, the T_reg dysregulation may exacerbate the systemic autoimmunity. Accordingly, mTOR inhibitors, including sirolimus may alleviate ALPS through combined mechanisms indicated by stars. First, mTOR inhibitors can directly target the dysregulated PI3K/Akt/mTOR signaling axis and reduce accumulation of abnormal DNTs. Second, mTOR inhibitors may block signaling through IL-10.[58,59] Finally, in contrast to most immunosuppressants, mTOR inhibitors can spare T_regs, and thereby help to reset the immune imbalance.