Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)

Abstract

Autoimmune lymphoproliferative syndrome (ALPS) is a disorder of T cell dysregulation caused by defective Fas-mediated apoptosis. Patients with ALPS can develop a myriad of clinical manifestations including lymphadenopathy, hepatosplenomegaly, autoimmunity and increased rates of malignancy. ALPS may be more common that originally thought, and testing for ALPS should be considered in patients with unexplained lymphadenopathy, hepatosplenomegaly, and/or autoimmunity. As the pathophysiology of ALPS is better characterized, a number of targeted therapies are in preclinical development and clinical trials with promising early results. This review describes the clinical and laboratory manifestations found in ALPS patients, as well as the molecular basis for the disease and new advances in treatment.

Fig 1

Fas apoptotic pathway. Patients with ALPS have defective Fas-mediated apoptosis. During downregulation of the immune response, activated B and T lymphocytes upregulate expression of Fas ligand, and activated T lymphocytes up-regulate expression of Fas. Fas ligand and Fas interact, activating the intracellular Fas-associated death domain (FADD) and triggering the caspase cascade with subsequent proteolysis, DNA degradation, and apoptosis. Apoptotic signalling mediated by Fas is part of the extrinsic pathway as it is activated through engangement of cell surface death receptors. The intrinsic apoptotic pathway is activated by cellular stressors, leading to alterations in mitochondrial membrane permeability and release of apoptosis-inducing substances. © Sue Seif, MA (used with permission).

Fig 2

ALPS apoptosis assay. Peripheral blood mononuclear cells are isolated from a patient, and T cells are activated with mitogen (phytohae-magglutinin, PHA) and expanded with IL-2 in culture for approximately 28 d (Fisher et al, 1995). In normal individuals, mitogen activation and expansion results in upregulation and priming of the Fas apoptotic pathway. When normal T cells are exposed to anti-Fas IgM monoclonal antibody in vitro, they undergo rapid cell death and apoptosis (Teachey et al, 2005). Because patients with ALPS have a defect in this pathway, the cells do not die after exposure to anti-Fas IgM monoclonal antibody (Sneller et al, 2003). Dexamethasone and ceramide (C2) are used as positive controls. (A) Red wells depict cell death after treatment with anti-fas IgM, C2, or dexamethasone. Yellow wells depict lack of cell death with similar treatment. (B) Normal control demonstrating cell death with anti-Fas IgM, ceramide, and dexamethasone as depicted by histogram for 7-Aminoactinomycin D. (C) Prototypical patient with ALPS demonstrating cell death with exposure to ceramide and dexamethasone, but no increased death over baseline with exposure to anti-Fas monoclonal antibody. Data collected under Institutional Review Board approved protocol. © Sue Seif, MA (used with permission).

Fig 3

Treatment of autoimmune cytopenias in ALPS patients. Front-line therapy for autoimmune cytopenias in patients with ALPS is corticosteroids. For patients with disease refractory to steroids, for patients who cannot tolerate steroids, or for patients who need long-term immunosuppression, alternative immunosuppressive agents are required. Mycophenolate mofetil (MMF) and sirolimus are the most studied and most effective agents in patients with ALPS and autoimmune disease (Rao et al, 2005; Janić et al, 2009; Teachey et al, 2009). For patients with moderate disease, MMF is a well-tolerated medication that should be considered as second-line therapy after steroids. For patients with severe disease, sirolimus may be indicated, as it has established efficacy in MMF-refractory patients (Teachey et al, 2009). Sirolimus should also be considered for patients with moderate disease who fail MMF. Sirolimus requires therapeutic drug monitoring. For patients who are intolerant of or refractory to MMF and/or sirolimus, other agents include vincristine, methotrexate, mercaptopurine and rituximab. Combination therapy with sirolimus and methotrexate or mercaptopurine and methotrexate may be required in the most severe cases.