Steinberg B J, Smathers P A, Frederiksen K, Steinberg A D
J Clin Invest. 1982 Sep;70(3):587-97. doi: 10.1172/jci110651.
F1 hybrid offspring of New Zealand Black mothers and New Zealand White fathers [(NZB X NZW)F1] female mice develop antibodies to single-stranded (ss) and native DNA, immune complex glomerulonephritis, massive proteinuria, and premature death with renal failure. By a series of matings, congenic (NZB X NZW)F1 . xid/xid mice were prepared. These mice were different from (NZB X NZW)F1 mice in having the X chromosome-linked immune deficiency gene, xid, in homozygous form. Such congenic (NZB X NZW)F1 . xid/xid females failed to develop antibodies to single-stranded or native DNA. They also failed to develop fatal renal disease as measured by proteinuria, glomerular histology, glomerular immunofluorescence, and survival. To control for unknown genetic factors, studies were performed with littermates that were derived by mating NZB . xid/+ females with NZW . xid/Y males such that the resulting offspring were either (NZB X NZW)F1 . xid/xid (and therefore "defective") or (NZB X NZW)F1 . xid/+ [phenotypically like (NZB X NZW)F1]. In these and in additional studies, mice were housed in the same cages and identified by ear tagging so as to avoid possible environmental variations from cage to cage. In these studies, xid/xid mice failed to develop the characteristic signs of autoimmunity, whereas the controls did. Similar results were also obtained with (NZW X NZB)F1 xid/xid mice compared with (NZW X NZB)F1 xid/+ mice. The effect of xid/xid upon (NZB X NZW)F1 mice was further investigated by assessing responses to immunization and polyclonal B cell activation in vivo. The xid/xid mice failed to produce anti-ssDNA following immunization with ssDNA complexed to a protein carrier in fluid form or even emulsified in adjuvant. Finally, the xid/xid mice failed to produce antiDNA in response to multiple injections of the polyclonal activator, bacterial lipopolysaccharide (LPS), or the polyclonal activator, polyribose inosinic acid . polyribose cytidylic acid. However, the xid/xid mice were neither generally hyporesponsive nor unable to recognize LPS because they made normal antibody responses following immunization with LPS to which multiple trinitrophenyl groups were chemically attached. We conclude from these studies that xid/xid, which is known to cause the deletion of a B cell subset, has a profound affect upon (NZB X NZW)F1 mice, rendering them insusceptible to the naturally occurring autoimmune disease characteristic of (NZB X NZW)F1 mice, and preventing them from producing antibodies to DNA despite purposeful immunization and polyclonal B cell activation. These results force a reevaluation of previous concepts regarding the mechanisms by which xid/xid might interfere with the development of autoimmunity, and a consideration of therapeutic implications.
新西兰黑鼠母亲与新西兰白鼠父亲的F1杂交后代[（NZB×NZW）F1]雌性小鼠会产生针对单链（ss）和天然DNA的抗体、免疫复合物性肾小球肾炎、大量蛋白尿，并因肾衰竭而过早死亡。通过一系列交配，制备了同源（NZB×NZW）F1.xid/xid小鼠。这些小鼠与（NZB×NZW）F1小鼠的不同之处在于，它们以纯合形式拥有X染色体连锁免疫缺陷基因xid。此类同源（NZB×NZW）F1.xid/xid雌性小鼠不会产生针对单链或天然DNA的抗体。通过蛋白尿、肾小球组织学、肾小球免疫荧光和存活率测量，它们也不会发展为致命性肾病。为了控制未知的遗传因素，对通过将NZB.xid/+雌性小鼠与NZW.xid/Y雄性小鼠交配而产生的同窝小鼠进行了研究，使得后代要么是（NZB×NZW）F1.xid/xid（因此“有缺陷”），要么是（NZB×NZW）F1.xid/+[表型上与（NZB×NZW）F1相似]。在这些以及其他研究中，小鼠饲养在同一笼子中，并通过耳标进行识别，以避免不同笼子之间可能存在的环境差异。在这些研究中，xid/xid小鼠未出现自身免疫的特征性迹象，而对照组则出现了。与（NZW×NZB）F1 xid/+小鼠相比，（NZW×NZB）F1 xid/xid小鼠也得到了类似结果。通过评估体内免疫反应和多克隆B细胞激活，进一步研究了xid/xid对（NZB×NZW）F1小鼠的影响。xid/xid小鼠在用与蛋白质载体复合的液体形式或甚至乳化于佐剂中的ssDNA免疫后，未能产生抗ssDNA。最后，xid/xid小鼠在多次注射多克隆激活剂细菌脂多糖（LPS）或多克隆激活剂聚肌苷酸.聚胞苷酸后，未能产生抗DNA。然而，xid/xid小鼠并非普遍反应低下，也并非无法识别LPS，因为它们在用化学连接了多个三硝基苯基基团的LPS免疫后，能产生正常的抗体反应。我们从这些研究中得出结论，已知会导致B细胞亚群缺失的xid/xid对（NZB×NZW）F1小鼠有深远影响，使其不易患（NZB×NZW）F1小鼠特有的自然发生的自身免疫性疾病，并阻止它们在有目的的免疫和多克隆B细胞激活后产生抗DNA抗体。这些结果促使重新评估关于xid/xid可能干扰自身免疫发展机制的先前概念，并考虑其治疗意义。
