Autoimmune lymphoproliferative syndrome pathophysiology
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Editor-In-Chief: David Teachey, MD [1]
Overview
Autoimmune lymphoproliferative syndrome(ALPS) is the first disease in human beings which are caused by apoptosis defect. Defect in FAS signaling cause benign chronic lymphoproliferation followed by accumulation of TCRαβ(+) CD4(-) CD8(-) double-negative T (DNT) cells. FAS also prevent the mailgnant proliferation of lymphocytes , so ALPS patients are at higher risk of developing lymphoma.There is an identified genetic defect in 2/3 rd of the total cases of ALPS. Germline mutation is the most common type. Somatic mutation, mutations in the proteins of FAS ligand(FASL) and caspase are also responsible in some cases.The pathogenesis of ALPS is still not very clear and research is ongoing.
Pathophysiology
Normally, after infectious insult, the immune system down-regulates by increasing Fas expression on activated B and T lymphocytes and Fas-ligand on activated T lymphocytes. Fas and Fas-ligand interact to trigger the caspase cascade, leading to cell apoptosis. Patients with ALPS have a defect in this apoptotic pathway, leading to chronic non-malignant lymphoproliferation, autoimmune disease, and secondary cancers.[1] T cell activation induce FASL expression leading to binding with the FAS receptor on nearby cells. This pathway activates the FAS associated protein with death domain (FADD). FADD then create the death inducing signal complex(DISC) in association with pro-caspase 8 and pro-caspase 10. DISC activates terminal caspases and induce apoptosis which is known as activation induced cell death(AICD). In ALPS , T cells become defective due to the mutation in FASL pathway. Though most of these mutations are autosomal dominant, some are autosomal recessive type or sporadic mutations. Self reactive T cells are accumulated in ALPS which are negative for both CD4 and CD8 cells(double negative,DNT) and positive for α/β T cell receptor. DNT cells are responsible for hyperavtive mTOR oathway. Hyperactive mTOR pathway induce abnormal lymphoproliferation in ALPS.[2][3]
Associated Conditions
- Autoimmune cytopenias: Most common. Can be mild to very severe. Can be intermittent or chronic.[4]
- Autoimmune Hemolytic Anemia
- Autoimmune Neutropenia
- Autoimmune Thrombocytopenia
- Other: Can affect any organ system similar to systemic lupus erythematosis (most rare affecting <5% of patients)
- Nervous: Autoimmune cerebellar ataxia; Guillain-Barre; Transverse myelitis
- GI: Autoimmune esophagitis, gastritis, colitis, hepatitis, pancreatitis
- Derm: Urticaria
- Pulmonary: Bronchiolitis obliterans
- Renal: Autoimmune glomerulonephritis, nephrotic syndrome
- Cancer: Secondary neoplasms affect approximately 10% of patients. True prevalence unknown as <20 reported cases of cancer. Most common EBER+ Non-Hodgkin's and Hodgkin's lymphoma
References
- ↑ Teachey DT, Seif AE, Grupp SA (2010). "Advances in the management and understanding of autoimmune lymphoproliferative syndrome (ALPS)". Br J Haematol. 148 (2): 205–16. doi:10.1111/j.1365-2141.2009.07991.x. PMC 2929682. PMID 19930184.
- ↑ 2.0 2.1 Matson, Daniel R.; Yang, David T. (2019). "Autoimmune Lymphoproliferative Syndrome: An Overview". Archives of Pathology & Laboratory Medicine. 144 (2): 245–251. doi:10.5858/arpa.2018-0190-RS. ISSN 0003-9985.
- ↑ Völkl, Simon; Rensing-Ehl, Anne; Allgäuer, Andrea; Schreiner, Elisabeth; Lorenz, Myriam Ricarda; Rohr, Jan; Klemann, Christian; Fuchs, Ilka; Schuster, Volker; von Bueren, André O.; Naumann-Bartsch, Nora; Gambineri, Eleonora; Siepermann, Kathrin; Kobbe, Robin; Nathrath, Michaela; Arkwright, Peter D.; Miano, Maurizio; Stachel, Klaus-Daniel; Metzler, Markus; Schwarz, Klaus; Kremer, Anita N.; Speckmann, Carsten; Ehl, Stephan; Mackensen, Andreas (2016). "Hyperactive mTOR pathway promotes lymphoproliferation and abnormal differentiation in autoimmune lymphoproliferative syndrome". Blood. 128 (2): 227–238. doi:10.1182/blood-2015-11-685024. ISSN 0006-4971.
- ↑ Teachey DT, Manno CS, Axsom KM, Andrews T, Choi JK, Greenbaum BH; et al. (2005). "Unmasking Evans syndrome: T-cell phenotype and apoptotic response reveal autoimmune lymphoproliferative syndrome (ALPS)". Blood. 105 (6): 2443–8. doi:10.1182/blood-2004-09-3542. PMID 15542578.