Bunch Donna O, Silver Jonathan S, Majure Melanie C, Sullivan Pamela, Alcorta David A, Chin Hyunsook, Hogan Susan L, Lindstrom Yoshi I, Clarke Stephen H, Falk Ronald J, Nachman Patrick H
UNC Kidney Center, Department of Medicine, Division of Nephrology and Hypertension, University of North Carolina, 5005 Burnett-Womack, Campus Box #7155, Chapel Hill, NC 27599, USA.
J Am Soc Nephrol. 2008 Sep;19(9):1763-73. doi: 10.1681/ASN.2007030382. Epub 2008 Jul 23.
Anti-neutrophil cytoplasmic autoantibodies directed toward myeloperoxidase or proteinase 3 are detected in sera of patients with small vessel vasculitis and participate in the pathogenesis of this disease. Autoantibodies develop when self-reactive B cells escape the regulation that ensures self-tolerance. In this study, regulation of anti-myeloperoxidase B cells was examined in mice that express an anti-myeloperoxidase Vkappa1C-Jkappa5 light-chain transgene, which confers anti-myeloperoxidase specificity when combined with a variety of heavy chains. Vkappa1C-Jkappa5 transgenic mice have splenic anti-myeloperoxidase B cells but do not produce circulating anti-myeloperoxidase antibodies. Two groups of transgenic mice that differed by their relative dosage of the transgene were compared; high-copy mice had a mean relative transgene dosage of 1.92 compared with 1.02 in the low-copy mice. These mice exhibited a 90 and 60% decrease in mature follicular B cells, respectively. High-copy mice were characterized by a large population of anti-myeloperoxidase B cells, a preponderance of B-1 cells, and an increased percentage of apoptotic myeloperoxidase-binding B cells. Low-copy mice had similar changes in B cell phenotype with the exception of an expanded marginal zone population. B cells from low-copy mice but not high-copy mice produced anti-myeloperoxidase antibodies after stimulation with lipopolysaccharide. These results indicate that tolerance to myeloperoxidase is maintained by central and peripheral deletion and that some myeloperoxidase-binding B cells are positively selected into the marginal zone and B-1 B cell subsets. A defect in these regulatory pathways could result in autoimmune disease.
在小血管炎患者血清中可检测到针对髓过氧化物酶或蛋白酶3的抗中性粒细胞胞浆自身抗体，这些抗体参与了该疾病的发病机制。当自身反应性B细胞逃避确保自身耐受的调节时，自身抗体就会产生。在本研究中，对表达抗髓过氧化物酶Vκ1C-Jκ5轻链转基因的小鼠的抗髓过氧化物酶B细胞调节进行了检测，当与多种重链结合时，该转基因赋予抗髓过氧化物酶特异性。Vκ1C-Jκ5转基因小鼠有脾脏抗髓过氧化物酶B细胞，但不产生循环抗髓过氧化物酶抗体。比较了两组转基因小鼠，它们的转基因相对剂量不同；高拷贝小鼠的平均转基因相对剂量为1.92，而低拷贝小鼠为1.02。这些小鼠的成熟滤泡B细胞分别减少了90%和60%。高拷贝小鼠的特征是大量抗髓过氧化物酶B细胞、B-1细胞占优势以及与髓过氧化物酶结合的凋亡B细胞百分比增加。低拷贝小鼠的B细胞表型有类似变化，但边缘区群体有所扩大。用脂多糖刺激后，低拷贝小鼠而非高拷贝小鼠的B细胞产生了抗髓过氧化物酶抗体。这些结果表明，对髓过氧化物酶的耐受是通过中枢和外周缺失来维持的，并且一些与髓过氧化物酶结合的B细胞被阳性选择进入边缘区和B-1 B细胞亚群。这些调节途径的缺陷可能导致自身免疫性疾病。
