Autoimmunity versus Apoptosis in some cases of Chronic Lymphocytic Leukemia

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Introduce: Apoptosis, with roll in the scheduling of cell life, is a normal process different from cell necrosis, which occurs due to physical or chemical aggression. The decision to activate a suicide process is made based on intrinsic or extrinsic apoptotic messages. The extrinsic ways which inducer apoptosis are ligands and cytokines for death receptors, (DR-Death receptors), being on each cell surface. The intrinsic ways which inducer apoptosis come from the mitochondria or nucleus. Proapoptotic signals, which promote or cause apoptosis, participate in a cascade that leads to the culmination cleavage of a set of proteins, resulting in the disassembly of the cells for apoptosis. Aim: The scope of this review is to emphasise that massive apoptosis overloading the phagocytic capacity can trigger an autoimmune reaction through the presentation of nucleosomes to the immune system. Methods: A large cohort study of cases with the primary Chronic Lymphocytic Leukemia, (CLL), examined samples from more than 100 patients for response to MDM2 protein inhibition and found a direct correlation between wild-type P53 status and MDM2 inhibitor, Nutlin-3, which induced a cytotoxicity across various CLL subtypes. In experimental models, disrupting the MDM2–p53 protein interaction restored p53 function and sensitized tumours to chemotherapy or radiotherapy. This response was not presented in malignant B cells lymphocytes having the expression of ZAP-70 receptor membrane, the expression of CD38 receptor with un-mutated immunoglobulin variable genes and with IGHV and mono-allelic ATM gene loss. Results: Pro-apoptotic signals apoptosis receptors, such as TNF-related apoptosis-inducing ligand, (TRAIL), Tumour Necrosis Factor, (TNF) and Fas receptor, also known as APO-1 or CD95 receptors are the key adaptor proteins transmitting apoptotic signals mediated by the main death receptors, (DRs), known to induce and autophagy process. Apoptosis is characterized by the apoptotic pathways, starting from the activation of the death receptor, (DRs), which is followed by a downstream signalling cascade including the involvement of mitochondria, subsequent caspase activation and DNA cleavage. However, pro-apoptotic signals apoptosis receptors, such as TNF-related apoptosis-inducing ligand, (TRAIL), Tumour Necrosis Factor, (TNF) and Fas receptor, also known as APO-1 or CD95 receptors are the key adaptor proteins transmitting apoptotic signals mediated by the main death receptors, (DRs). Pro-apoptotic signals, which promote or cause apoptosis, participate in a cascade and leads to the culmination cleavage ogene, which by its product, the p53 protein, inhibits the Nk-beta nuclear factor. Mutations of the P53 gene will lead to insufficient action of the p53 protein and trigger autoimmunity. Auto-reactive B and T cells, which escaped from natural apoptosis, might represent an additional necessary condition.

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The study was published in the February 2, 2016, online edition of the Journal Nature Communication, (www.cnio.es ). By the Warburg effect, glucose maintains the stability mutant P53 gene and promotes cancer cells. Most researches seem to indicate that, in line with its role as a tumour suppressor p53 is able to fall glycolysis16. The mTORc2/Akt complex controls mitochondrial metabolism and physiology, through the phosphorylation of the glycolytic enzyme hexokinase 2, thus promoting cancer cell’s aerobic glycolysis (Warburg effect) and preventing mitochondrial apoptosis. In the studies conducted from years 2025, highly effective treatments of CLL, combining fludarabine with other agents (ie, cyclophosphamide, [FC], FC + rituximab, [FCR]), were associated with a low proportion of AIHA then another previous standard chemotherapy along years. Taken together, these results convincingly suggest that rather than treatment it is the lack of response to it that conveys a higher risk of AIC. Also, two retrospective studies addressed the prevalence of AIC in subjects with CLL-treated ibrutinib and/or idelalisib, as well as their efficacy in AIC, if present. Autoimmune phenomena are frequently observed in patients with CLL and are mainly attributable to underlying dysfunctions of the immune system. Also, autoimmune cytopenia, (AIC), affect 4-7% of patients with CLL and mainly consist of autoimmune hemolytic anaemia and immune thrombocytopenia. Whereas the association of CLL with autoimmune cytopenia, particularly autoimmune haemolytic anaemia and immune thrombocytopenia, is well established, there is no proof of an increased risk of non-hemic autoimmune disorders in CLL. The mechanisms leading to autoimmune cytopenia in CLL are complex and involve interactions between the malignant B-CLL, abnormally functioning T cells, the microenvironment, and the immune system. Patients showing anaemia, associated with the presence of anti-erythrocyte autoantibody (Ae-Ab), were considered as CLL with AHA. The Ae-Ab complex and the Complement bound to the red cell membrane are detected by the direct antiglobulin test, (DAT), using a broad-spectrum antiserum. Conclusion Presented researches are impact on the clinical management of patients and require an attitude adjustment therapeutic adequate in a personalized medicine. Personalized treatments will be applied by combining diagnostic tools, knowledge databases and therapeutic drugs.

Institutions

• Titu Maiorescu University

  București, Bucharest

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Funders

• Unitatea Executiva Pentru Finantarea Invatamantului Superior a Cercetarii Dezvoltarii si Inovarii

  National Research Council

  București, Bucharest

  Grant ID: U-1900-063Y4656

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