The non-major histocompatibility complex quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation, and joint damage
The non-major histocompatibility complex quantitative trait locus Cia10 contains a major arthritis gene and regulates disease severity, pannus formation, and joint damage
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DOI：
10.1002/art.20782
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发表时间：
2005-01-01
影响因子：
--
通讯作者：
Gulko, NS
中科院分区：
文献类型：
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作者：
Brenner, M;Meng, HC;Gulko, NS
Objective.构建与2号染色体关节炎调控数量性状位点Cia 10同源的大鼠，并确定该同源间隔对降植烷诱导的关节炎（PIA）大鼠关节炎严重程度、关节组织学结构和细胞因子转录的影响。来自ACI（CIA和PIA抗性）菌株并含有Cia 10间隔的52.6-MB间隔通过基因型指导的同源育种渗入DA（关节炎易感）背景。本实验研究了DA、ACI（Cia 10）同型大鼠对PIA的易感性和严重程度，并与同性别DA大鼠进行了比较。对在降植烷注射后第32天收集的后爪进行组织学分析。用实时荧光定量聚合酶链反应检测第32天踝关节滑膜组织中白细胞介素-1 β（IL-1 β）和肿瘤坏死因子α（TNF α）mRNA的水平。雄性和雌性DA.ACI（Cia 10）同类大鼠均发生了显著较轻形式的关节炎，与DA雄性和雌性对照组相比，关节炎严重程度指数分别降低了95%和92%（雄性P小于或等于0.001，雌性P = 0.003）。与DA滑膜组织相比，ACI（Cia 10）同源大鼠滑膜组织更有可能保持其正常的组织学结构，包括最小至无软骨和骨侵蚀、滑膜增生和血管翳形成，以及血管数量减少（血管生成）。与DA大鼠相比，DA.ACI（Cia 10）同源大鼠滑膜组织中IL-1 β和TNF α mRNA的量分别减少2.7倍和2.4倍。Cia 10预测的候选基因Ptpn 8（类风湿性关节炎（RA）易感基因PTPN 22的大鼠同源物）的互补DNA测序分析显示DA和ACI株之间没有多态性。这项研究确定Cia 10携带一个主要的自身免疫性关节炎调控基因。该基因调节临床疾病的严重程度、组织学损伤和至少两种中枢促炎细胞因子的水平。我们正在缩小Cia 10基因定位克隆的关键区域。该基因的鉴定将为RA的候选基因研究提供新的靶点或途径。
Objective. To construct rats congenic for the chromosome 2 arthritis-regulatory quantitative trait locus Cia10, originally identified in a (DA x ACI)F-2 intercross rat strain that had been assessed for collagen-induced arthritis (CIA), and to determine the effect of this congenic interval on arthritis severity, joint histologic structure, and cytokine transcription in rats with pristane-induced arthritis (PIA).Methods. A 52.6-MB interval derived from the ACI (CIA- and PIA-resistant) strain and containing the Cia10 interval was introgressed into the DA (arthritis-susceptible) background through genotype-guided congenic breeding. Homozygous male and female DA.ACI(Cia10) congenic rats were studied for their susceptibility to and severity of PIA, and were compared with same-sex DA rats. Histologic analyses were done on hind paws collected on day 32 following the pristane injection. Levels of interleukin-1beta (IL-1beta) and tumor necrosis factor alpha (TNFalpha) messenger RNA (mRNA) were measured with real-time polymerase chain reaction on synovial tissues from day-32 ankles.Results. Both male and female DA.ACI(Cia10) congenic rats developed a significantly milder form of arthritis, with a 95% and 92% reduction in the arthritis severity index compared with DA male and female controls, respectively (males P less than or equal to 0.001 and females P = 0.003). DA.ACI(Cia10) congenic rat synovial tissue was more likely to preserve its normal histologic architecture, including minimal to no cartilage and bone erosions, synovial hyperplasia, and pannus formation, and reduced numbers of vessels (angiogenesis), when compared with DA synovial tissue. There was a 2.7- and 2.4-fold reduction in the amount of IL-1beta and TNFalpha mRNA, respectively, in the synovial tissue of DA.ACI(Cia10) congenic rats compared with DA rats. Sequencing analyses of complementary DNA for the Cia10-predicted candidate gene Ptpn8, the rat homolog of the rheumatoid arthritis (RA)-susceptibility gene PTPN22, revealed no polymorphisms between the DA and ACI strains.Conclusion. This study determined that Cia10 harbors a major autoimmune arthritis-regulatory gene. This gene regulates clinical disease severity, histologic damage, and the levels of at least two central proinflammatory cytokines. We are in the process of narrowing down the critical region for positional cloning of the Cia10 gene. The identification of this gene will provide novel targets or pathways for focused candidate-gene studies in RA.