Models of Autoimmune Disease in a Genetically Defined Rabbit Breeding Colony

在一个旨在开发一种或多种自身免疫性疾病模型的特殊育种项目中，我们在我们的群体中饲养了对疾病诱导敏感的兔子。我们研究的最初焦点是人系统性红斑狼疮（SLE）的兔模型。众所周知，在人类中，某些基因影响对几种不同自身免疫性疾病的易感性。因此，选择性繁殖可能导致更广泛的自身免疫性疾病的易感性。系统性红斑狼疮是一种复杂的慢性自身免疫性疾病，主要影响年轻女性。临床症状可能包括皮疹、关节炎、肾炎和神经系统破坏（包括认知能力下降、癫痫发作、精神病）。SLE的特征在于产生针对各种核抗原和双链DNA（dsDNA）的自身抗体。我们免疫组的兔子与NMDA谷氨酸受体衍生肽的多抗原肽骨架（BB）的基础上的报告，一些抗DNA抗体从小鼠和狼疮患者的交叉反应与NR 2谷氨酸受体，并扩展早期发表的报告，我们还免疫兔子与Sm B/B-总理衍生肽的BB。用这两种不同的肽免疫原免疫导致抗dsDNA抗体和人类SLE的其他相关物的产生。免疫前和免疫后血清的比较表明，抗dsDNA和抗核抗体的水平有所增加，在一些MAP肽免疫兔。观察到来自两个免疫组的具有高抗dsDNA应答的兔经历癫痫发作。我们的研究证实了使用Sm肽免疫在非纯种兔中诱导SLE样血清学的一个早期报道，并将研究扩展到新的肽免疫原（Rai等，J.Immunol 176：660-7，2006）。使用我们独特的纯种兔将加快理解遗传易感性与暴露于导致SLE样表现的确定的外部免疫原的相互作用。对前四组免疫家兔的第五组24只亲属和后代的研究已经完成，目前正在进行每组6只动物（6A、B、C和D）的研究。我们克隆并测序了Blys（BAFF）及其受体BR 3的兔同源物，并对患病兔的血清和组织进行了分析。目前正在分析血清中自身抗体的DNA微阵列和蛋白质微阵列分析的mRNA表达分析结果。

In a special breeding project with the goal of developing one or more models of autoimmune disease, we bred rabbits within our colony for susceptibility to disease induction. The initial focus of our study was a rabbit model of human Systemic Lupus Erythematosus (SLE). It is known that in man some genes affect susceptibility to several different autoimmune diseases. Thus selective breeding may result in broader susceptibility to autoimmune diseases. SLE is a complex, chronic autoimmune disorder that predominately affects young women. Clinical symptoms may include rash, arthritis, nephritis, and neurological disruption (including cognitive decline, seizures, psychosis). SLE is characterized by the production of autoantibodies to various nuclear antigens and double-stranded DNA (dsDNA). We immunized groups of rabbits with an NMDA glutamate receptor-derived peptide on a multiple antigen peptide backbone (BB) based on reports that some anti-DNA antibodies from mice and from lupus patients cross react with the NR2 glutamate receptor, and extending earlier published reports, we also immunized rabbits with an Sm B/B-prime-derived peptide on BB. Immunization with these two different peptide immunogens led to development of anti-dsDNA antibodies, and other correlates of human SLE. Comparisons of preimmune and post-immunization sera suggest that levels of anti-dsDNA and antinuclear antibodies have increased in some MAP-peptide immunized rabbits. Rabbits from both immunization groups with high anti-dsDNA responses were observed to experience seizures. Our studies confirm one earlier report that used Sm peptide immunization to induce SLE-like serology in non-pedigreed rabbits, and extend the studies to a new peptide immunogen (Rai et al J.Immunol 176:660-7, 2006,). The use of our unique pedigreed rabbits will expedite understanding the interactions of genetic susceptibility with exposure to defined external immunogens leading to SLE-like manifestations. Studies of a fifth group of 24 relatives and progeny from the first four groups of immunized rabbits have been completed and studies of groups of six animals each (6A,B ,C and D) are currently in progress. We cloned and sequenced the rabbit homologs of Blys (BAFF) and its receptor BR3 and have been analyzing sera and tissues of affected rabbits. Results of mRNA expression analyses on DNA microarrays and protein microarray analyses of autoantibodies in sera are currently being analyzed.