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Autoimmune Lymphoproliferative Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder of apoptosis characterized by accumulation of autoreactive lymphocytes and childhood-onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, along with predisposition to Hodgkin and non-Hodgkin lymphomas.
Death Receptor-Mediated Apoptosis and Lymphocyte Homeostasis
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Lixin Zheng, Richard M. Siegel, Jagan R. Muppidi, Felicita Hornung, Michael J. Lenardo
Sneller et al, in 1992 first described two patients with a progressive lymphoproliferative disorder associated with autoimmunity. Their clinical and immunological features resembled the lymphoproliferative/autoimmune disease seen in Ipr and gld mice.124 In 1995, CD95 mutations were identified in two series of patients. The pathogenic role of these mutations was confirmed by experiments showing that the mutant protein could dominantly interfere with wild type CD95 signaling.125,126 Given the association between lymphoproliferation and autoimmunity as a prominent feature of this disease, it has since been designated as the Autoimmune Lymphoproliferative Syndrome (ALPS). Subsequently, other groups also identified CD95 mutations from patients with symptoms of ALPS.127,128 Typical ALPS patients usually present with progressive lymphadenopathy, splenomegaly, and autoimmune disorders that often accompany increased levels of autoantibodies. Activated T cells from ALPS patients are resistant to both TCR-induced apoptosis as well as CD95-induced apoptosis. Another unique feature of ALPS patients, which has been also observed in Ipr mice, is the accumulation of polyclonal CD4-, CD8-, CD3+ lymphocytes in their peripheral blood.129
Primary immunodeficiency diseases
Published in Gabriel Virella, Medical Immunology, 2019
John W. Sleasman, Gabriel Virella
Autoimmune lymphoproliferative syndrome (ALPS) is a representative example of immune dysregulation due to defective T-cell apoptosis resulting in the accumulation of senescent T cells and autoimmunity. The condition is the result of mutation within the genes encoding the FAS/FAS ligand signaling pathways and of the caspase system including CD95, CD95L, caspases 10 and 8. Patients develop hepatosplenomegaly, generalized lymphadenopathy, and severe autoimmune hemolytic anemia and thrombocytopenia (Evan's syndrome). There is an accumulation of CD4−/CD8−αβ CD3T cells in the blood and lymphoid tissues.
Cellular mechanisms and clinical applications for phenocopies of inborn errors of immunity: infectious susceptibility due to cytokine autoantibodies
Published in Expert Review of Clinical Immunology, 2023
Rui Sun, Yating Wang, Hassan Abolhassani
Autoimmune lymphoproliferative syndrome (ALPS) is an inborn immune regulatory disorder due to mutations in FAS (tumor necrosis factor receptor superfamily member 6) and other genes characterized by lymphoproliferation and autoimmunity [56]. B cell differentiation is frequently altered in ALPS-FAS. The mice model study showed an absence of apoptosis in non-selected clones and subsequently impaired germinal center reaction allowed survival of dysregulated autoreactive B cells [56,57]. Also, dysregulation between Bcl-2 or FAS apoptotic pathways is found in SLE because of the significantly high expression of BCL-2 in peripheral blood B and T lymphocytes which can change the function of antigen-presenting cells (APCs) [58]. Germline genetic defects on FAS cause dysregulation in extrinsic apoptosis and have been verified as the reason for the autoimmune lymphoproliferative syndrome (ALPS or Canale-Smith syndrome), which is associated with CD4-T cells autoAbs over production lead to the accumulation of double negative T cells (DNTCs) [59].
Protein Kinase C-Delta Defect in Autoimmune Lymphoproliferative Syndrome-Like Disease: First Case from the National Iranian Registry and Review of the Literature
Published in Immunological Investigations, 2022
Niusha Sharifinejad, Gholamreza Azizi, Nasrin Behniafard, Majid Zaki-Dizaji, Mahnaz Jamee, Reza Yazdani, Hassan Abolhassani, Asghar Aghamohammadi
Autoimmune lymphoproliferative syndrome (ALPS) is an inherited lymphoproliferative disorder caused by mutations in genes within the apoptotic signaling pathway mediated by the first apoptosis signal (FAS), which plays central role in lymphocyte homeostasis (Puck and Sneller 1997). Although most of ALPS patients harbor mutations in FAS gene, mutations in other genes associated with the FAS signaling pathway including FAS ligand, Caspase 8, Caspase 10, and FADD are classified as typical ALPS. Moreover, pathogenic variants in genes outside the FAS pathway have been reported in association with clinical findings similar to ALPS. However, they either do not fulfill the current diagnostic criteria of ALPS or have other distinct phenotypes, therefore are listed as ALPS-like disorders. These disorders include defect in the lipopolysaccharide responsive beige-like anchor protein (LRBA), cytotoxic T-lymphocyte associated protein 4 (CTLA4), KRAS proto-oncogene, Magnesium transporter 1 (MAGT1), NRAS proto-oncogene, Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and signal transducer and activator of transcription 3 (STAT3) (Bousfiha et al. 2020).
Efficacy of sirolimus for treatment of autoimmune lymphoproliferative syndrome: a systematic review of open label clinical studies
Published in Expert Opinion on Orphan Drugs, 2021
Shweta Sharma, Md Sarfaraj Hussain, Nidhi.B. Agarwal, Dinesh Bhurani, Mohd Ashif Khan, Md Aejaz Ahmad Ansari
Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder most prevalent in pediatrics and whose manifestations could be managed using targeted therapies. Sirolimus is a Federal Drug Administration-approved immunosuppressant targeting mTOR which has been in clinical use for prophylaxis of organ rejection for over 20 years, although it’s absolute efficacy for managing ALPS remains unsubstantiated [15]. A primary evidence of using sirolimus was drawn from various animal studies depicting poorly regulated mTOR signaling in cases of ALPS [16,17]. In a 2014 literature review on ALPS, patients with symptoms of ALPS and refractory cytopenias who had previously failed initial corticosteroids and intravenous immunoglobulin had successfully been treated with sirolimus thereby, suggesting mTOR inhibitors to be a good option [5]. Moreover, a suggestion of using sirolimus as a first-line single agent has been recommended on the basis of findings from other published studies [4,7,8].