López-Hoyos Marcos, Marquina Regina, Tamayo Esther, González-Rojas Jovanna, Izui Shozo, Merino Ramón, Merino Jesús
Laboratorio de Immunologia del Trasplante, Unidad de Investigación, Hospital Universitario Marqués de Valdecilla, Departamento de Medicina y Psiquiatría, Av. Valdecilla s/n, 39008 Santander, Spain.
Arthritis Rheum. 2003 Aug;48(8):2353-61. doi: 10.1002/art.11107.
Protein deimination, a process to modify arginine residues to citrulline by the addition of a neutral oxygen group, is associated with apoptosis. The presence of autoantibodies recognizing citrullinated peptides is highly specific to rheumatoid arthritis (RA) and is therefore a useful marker for the early diagnosis of RA. In this study, we explored whether anti-cyclic citrullinated peptide (anti-CCP) autoantibodies are produced in several experimental models of autoimmune diseases in mice.
The levels of anti-CCP autoantibodies were analyzed by enzyme-linked immunosorbent assay in several lupus-prone strains of mice, in animals with type II collagen (CII)-induced arthritis, and after induction of neonatal tolerance to alloantigens.
We observed the production of these autoantibodies in 2 different lupus-prone mice, MRL-lpr/lpr and (NZW x B6)F(1)-hbcl-2 transgenic mice, characterized by the presence of abnormalities in the regulation of B cell apoptosis. Other genetic defects, determining autoimmune susceptibility, present in MRL and NZW mice were additionally required for anti-CCP autoantibody production. The induction of autoantibodies in normal BALB/c mice injected at birth with semiallogeneic spleen cells from (BALB/c x B6)F(1)-hbcl-2 transgenic mice suggested that these additional autoimmune defects may be related, at least in part, to the establishment of abnormal interactions between T cells and B cells. In addition, anti-CCP autoantibodies were not produced in the course of CII-induced arthritis, an experimental model of RA in mice.
Our study provides evidence for the association between defects in the regulatory cell death machinery of B lymphocytes and the production of certain autoantibody specificities.
蛋白质脱亚氨基作用是一种通过添加中性氧基团将精氨酸残基修饰为瓜氨酸的过程，与细胞凋亡相关。识别瓜氨酸化肽的自身抗体的存在对类风湿关节炎（RA）具有高度特异性，因此是RA早期诊断的有用标志物。在本研究中，我们探讨了在小鼠自身免疫性疾病的几种实验模型中是否产生抗环瓜氨酸肽（抗CCP）自身抗体。
通过酶联免疫吸附测定法分析了几种狼疮易感小鼠品系、II型胶原（CII）诱导性关节炎动物以及诱导新生鼠对同种异体抗原产生耐受性后的抗CCP自身抗体水平。
我们在两种不同的狼疮易感小鼠，即MRL-lpr/lpr和（NZW×B6）F1-hbcl-2转基因小鼠中观察到了这些自身抗体的产生，其特征是B细胞凋亡调节存在异常。抗CCP自身抗体的产生还需要MRL和NZW小鼠中存在的其他决定自身免疫易感性的遗传缺陷。给正常BALB/c小鼠出生时注射来自（BALB/c×B6）F1-hbcl-2转基因小鼠的半同种异体脾细胞后诱导出自身抗体，这表明这些额外的自身免疫缺陷可能至少部分与T细胞和B细胞之间异常相互作用的建立有关。此外，在CII诱导性关节炎（一种小鼠RA实验模型）过程中未产生抗CCP自身抗体。
我们的研究为B淋巴细胞调节性细胞死亡机制缺陷与某些自身抗体特异性产生之间的关联提供了证据。
