Abstract
Therapy regimens for Chronic lymphocytic leukemia (CLL) commonly include chemotherapy and immunotherapy, which act through complement-mediated-cytotoxicity (CDC) and other mechanisms. CDC depends on several factors, including the availability and activity of the complement classical pathway (CP). Recently, a significant decrease in CP activity was shown to be associated with an immunoglobulin-C5a complex (Ig-C5a) and other markers of chronic CP activation in 40% of the patients. The study focused on the involvement of IgG-hexamers, an established CP activator, in the mechanism of chronic CP activation in CLL. Sera from 51 naïve CLL patients and 20 normal controls were collected. CP and alternative pathway (AP) activities were followed by the complement activity marker sC5b-9. Serum high molecular weight (HMW) proteins were collected by gel-filtration chromatography and their complement activation capacity was assessed. The levels of IgM, another established CP activator, were measured. Data were associated with the presence of Ig-C5a. Baseline levels of activation markers negatively correlated with CP and the AP activities, supporting chronic complement activation. In patients with Ig-C5a, HMW proteins that are not IgM, activated the complement. HMW proteins were identified as IgG-aggregates by affinity binding assays and Western blot analysis. The data indicate chronic CP activation, mediated by cell-free IgG-hexamers as a cause of decreased CP activity in part of the CLL population. This mechanism may affect immunotherapy outcomes due to compromised CP activity and CDC.
Highlights
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, accounts for 30% of all leukemia cases
This study describes the presence of a cell-free C activator in plasma of some CLL patients
The presence of a classical pathway (CP) activator in plasma of CLL patients can provide an explanation to the chronic CP activation and the CP exhaustion observed in some CLL patients
Summary
Chronic lymphocytic leukemia (CLL), the most common adult leukemia in the Western world, accounts for 30% of all leukemia cases. CLL is characterized by 5000 monoclonal B lymphocytes/μl in peripheral blood, which co-express the antigens CD5, CD19, CD20 and CD23 [1], and exhibit mature phenotype. CLL is associated with an inherent immune dysfunction that is related to morbidity and mortality as well as to infections, which account for 50 to 60% of all deaths [1,2]. The infections in CLL are related both to the disease and to the immuno-suppressive effects of the therapy. The therapeutic approach in fit CLL patients includes therapeutic monoclonal antibodies (mAbs), commonly used in combination with chemotherapy [1,2,3], so that the mAb drugs trigger immune responses against the leukemic B-cells that synergize with cytotoxic chemotherapeutic agents. The efficacy of the therapeutic mAbs depends on various factors, including the availability and activity of the complement (C) system [7,8,9]
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