Catera Rosa, Silverman Gregg J, Hatzi Katerina, Seiler Till, Didier Sebastien, Zhang Lu, Hervé Maxime, Meffre Eric, Oscier David G, Vlassara Helen, Scofield R Hal, Chen Yifang, Allen Steven L, Kolitz Jonathan, Rai Kanti R, Chu Charles C, Chiorazzi Nicholas
Feinstein Institute for Medical Research, North Shore-LIJ Health System, Manhasset, New York 11030, USA.
Mol Med. 2008 Nov-Dec;14(11-12):665-74. doi: 10.2119/2008-00102.Catera. Epub 2008 Sep 25.
Chronic lymphocytic leukemia (CLL) represents the outgrowth of a CD5(+) B cell. Its etiology is unknown. The structure of membrane Ig on CLL cells of unrelated patients can be remarkably similar. Therefore, antigen binding and stimulation could contribute to clonal selection and expansion as well as disease promotion. Initial studies suggest that CLL mAbs bind autoantigens. Since apoptosis can make autoantigens accessible for recognition by antibodies, and also create neo-epitopes by chemical modifications occurring naturally during this process, we sought to determine if CLL mAbs recognize autoantigens associated with apoptosis. In general, ~60% of CLL mAbs bound the surfaces of apoptotic cells, were polyreactive, and expressed unmutated IGHV. mAbs recognized two types of antigens: native molecules located within healthy cells, which relocated to the external cell surface during apoptosis; and/or neoantigens, generated by oxidation during the apoptotic process. Some of the latter epitopes are similar to those on bacteria and other microbes. Although most of the reactive mAbs were not mutated, the use of unmutated IGHV did not bestow autoreactivity automatically, since several such mAbs were not reactive. Particular IGHV and IGHV/D/J rearrangements contributed to autoantigen binding, although the presence and degree of reactivity varied based on specific structural elements. Thus, clonal expansion in CLL may be stimulated by autoantigens occurring naturally during apoptosis. These data suggest that CLL may derive from normal B cells whose function is to remove cellular debris, and also to provide a first line of defense against pathogens.
慢性淋巴细胞白血病（CLL）是一种CD5(+) B细胞的增殖性疾病。其病因尚不清楚。无关患者CLL细胞上膜免疫球蛋白的结构可能非常相似。因此，抗原结合和刺激可能有助于克隆选择和扩增以及疾病进展。初步研究表明，CLL单克隆抗体（mAb）可结合自身抗原。由于凋亡可使自身抗原易于被抗体识别，并且还可通过此过程中自然发生的化学修饰产生新表位，我们试图确定CLL mAb是否识别与凋亡相关的自身抗原。一般来说，约60%的CLL mAb可结合凋亡细胞表面，具有多反应性，并表达未突变的IGHV。mAb识别两种类型的抗原：位于健康细胞内、在凋亡过程中重新定位到细胞外表面的天然分子；和/或在凋亡过程中由氧化产生的新抗原。后者中的一些表位与细菌和其他微生物上的表位相似。尽管大多数反应性mAb未发生突变，但使用未突变的IGHV并不会自动赋予自身反应性，因为有几种此类mAb没有反应性。特定的IGHV和IGHV/D/J重排有助于自身抗原结合，尽管反应性的存在和程度因特定结构元件而异。因此，CLL中的克隆扩增可能受到凋亡过程中自然产生的自身抗原的刺激。这些数据表明，CLL可能起源于正常B细胞，其功能是清除细胞碎片，并提供抵御病原体的第一道防线。
