The Institute for Medical Research, Galilee Medical Center, Nahariya, Israel.
Azrieli Faculty of Medicine, Bar Ilan University, Safed, Israel.
Front Immunol. 2022 Sep 2;13:953644. doi: 10.3389/fimmu.2022.953644. eCollection 2022.
Chronic lymphocytic leukemia (CLL), the most common adult's leukemia in the western world, is caused in 95% of the cases by uncontrolled proliferation of monoclonal B-lymphocytes. The complement system in CLL is chronically activated at a low level the classical pathway (CP). This chronic activation is induced by IgG-hexamers, which are formed after binding to alpha-2-macroglobulin (A2M). The study investigated for the first time the serum levels of A2M in CLL patients, their association with the disease severity, and A2M production by the malignant B-lymphocytes. Blood samples were collected from 65 CLL patients and 30 normal controls (NC) subjects, and used for quantifications of the A2M levels, the complement activation marker (sC5b-9), the complement components C2, C3 and C4, and clinical biochemistry and hematology parameters. The production of A2M was studied in B-lymphocytes isolated from blood samples as well as in CLL and non-CLL cell lines.The serum A2M levels were significantly higher in CLL patients vs NCs, showing values of 3.62 ± 0.22 and 1.97 ± 0.10 mg/ml, respectively. Within the CLL group, A2M levels correlated significantly with the disease stage, with sC5b-9, and with clinical indicators of the disease severity. Increased A2M production was showed in three out of four CLL B-lymphocytic lines that were studied, as compared to non-CLL lines, to a non-lymphocytic line, and to blood-derived primary B-lymphocytes. A2M production was further increased both in primary cells and in the CLL cell-line after incubation with CLL sera, compared to NC sera. This study shows for the first time that serum A2M levels in CLL are significantly increased, likely due to A2M production by the malignant B-lymphocytes, and are correlated with the disease severity and with chronic complement activation. The moderate change in A2M production after incubation with NC sera supports the hypothesis that inhibition of excess A2M production can be achieved, and that this may potentially down-regulate the IgG-hexamerization and the resulting chronic CP activation. This may also help restore complement system activity, and eventually improve complement activity and immunotherapy outcomes in CLL.
慢性淋巴细胞白血病（CLL）是西方世界最常见的成人白血病，95%的病例是由单克隆 B 淋巴细胞不受控制的增殖引起的。补体系统在 CLL 中处于慢性低度激活状态，主要是经典途径（CP）。这种慢性激活是由与α-2-巨球蛋白（A2M）结合后形成的 IgG-六聚体诱导的。该研究首次调查了 CLL 患者的血清 A2M 水平、它们与疾病严重程度的相关性以及恶性 B 淋巴细胞产生 A2M 的情况。采集了 65 例 CLL 患者和 30 例正常对照组（NC）的血液样本，用于定量检测 A2M 水平、补体激活标志物（sC5b-9）、补体成分 C2、C3 和 C4 以及临床生化和血液学参数。还研究了从血液样本中分离的 B 淋巴细胞以及 CLL 和非 CLL 细胞系中 A2M 的产生情况。CLL 患者的血清 A2M 水平明显高于 NCs，分别为 3.62±0.22 和 1.97±0.10mg/ml。在 CLL 组中，A2M 水平与疾病分期、sC5b-9 以及疾病严重程度的临床指标显著相关。在所研究的四个 CLL B 淋巴细胞系中，有三个系与非 CLL 系、非淋巴细胞系和血液来源的原代 B 淋巴细胞相比，A2M 的产生增加。与 NC 血清相比，原代细胞和 CLL 细胞系在孵育 CLL 血清后 A2M 的产生进一步增加。这项研究首次表明，CLL 患者的血清 A2M 水平显著升高，可能是由于恶性 B 淋巴细胞产生 A2M，并且与疾病严重程度和慢性补体激活相关。与 NC 血清孵育后 A2M 产生的适度变化支持了这样的假设，即可以抑制过量的 A2M 产生，并且可能下调 IgG-六聚体化和由此产生的慢性 CP 激活。这也可能有助于恢复补体系统的活性，并最终改善 CLL 中的补体活性和免疫治疗效果。
