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，我们在我们的群体内饲养了对疾病易感性的兔子。我们最初的研究重点是人类系统性红斑狼疮(SLE)的兔模型。众所周知，在人类中，一些基因影响着对几种不同的自身免疫性疾病的易感性。因此，选择性繁殖可能导致对自身免疫性疾病的更广泛的易感性。SLE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、肾炎和神经紊乱(包括认知能力下降、癫痫发作、精神病)。系统性红斑狼疮的特征是产生针对各种核抗原的自身抗体和双链DNA(DsDNA)。根据来自小鼠和狼疮患者的一些抗DNA抗体与NR2谷氨酸受体发生交叉反应的报道，我们用多抗原肽骨架(BB)上的NMDA谷氨酸受体衍生肽免疫兔组，并扩展了先前发表的报道，我们还用BB上的Sm B/B素衍生肽免疫兔子。用这两种不同的多肽免疫原免疫导致了抗双链DNA抗体的产生，以及与人类系统性红斑狼疮相关的其他疾病。免疫前和免疫后血清的比较表明，在一些MAP多肽免疫的兔体内，抗dsDNA抗体和抗核抗体水平有所增加。两个免疫组的抗dsDNA高反应性兔均出现癫痫发作。我们的研究证实了早先的一份报告，即使用Sm肽免疫在非纯种兔中诱导类SLE血清学，并将研究扩展到一种新的多肽免疫原(Rai等人，免疫学杂志176：660-7,2006)。我们独一无二的纯种兔的使用将加速了解遗传易感性与暴露于特定的外部免疫原导致SLE样表现的相互作用。对前四组免疫兔子的第五组24只亲属和后代的研究已经完成，目前正在进行每组六只动物(6A、B、C和D)的研究。我们克隆并测序了兔BLyS(BAFF)及其受体BR3的同源物，并对发病兔的血清和组织进行了分析。DNA微阵列的mRNA表达分析结果和血清中自身抗体的蛋白质微阵列分析结果目前正在分析中。

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.