Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis.
Disease-promoting and -protective genomic loci on mouse chromosomes 3 and 19 control the incidence and severity of autoimmune arthritis.
复制标题
小鼠 3 号和 19 号染色体上的疾病促进和保护性基因组位点控制自身免疫性关节炎的发病率和严重程度。
DOI：
10.1038/gene.2012.2
复制
发表时间：
2012
影响因子：
5
通讯作者：
Rauch,TA
中科院分区：
文献类型：
--
作者：
Glant,TT;Adarichev,VA;Boldizsar,F;Besenyei,T;Laszlo,A;Mikecz,K;Rauch,TA
蛋白聚糖（PG）诱导的关节炎（PGIA）是类风湿性关节炎的鼠模型。易患关节炎的BALB/c小鼠100%易感，而主要组织相容性复合物匹配的DBA/2品系对PGIA完全耐药。为了减少用于测序的疾病抑制基因座的大小并找到关节炎的致病基因，我们创建了一组BALB/c。DBA/2-在关节炎易感的BALB/c背景中，DBA/2基因组间隔与3号染色体（chr 3）上的整个Pgia 26基因座和chr 19上的Pgia 23/Pgia 12基因座重叠的同源/亚同源菌株。在免疫这些亚同源菌株和它们的野生型（BALB/c）同窝仔，我们确定了一个主要的Pgia 26 a亚位点的chr 3抑制疾病的发作，发病率和严重程度，通过控制T细胞反应的复杂性状。该区域的大小减少到3 Mbp（11.8 Mbp，侧翼区），并含有影响许多促炎细胞因子产生的基因。此外，两个独立的基因座（Pgia 26 b和Pgia 26 c）抑制关节炎的临床评分。chr 19上的Pgia 23位点（大小为1.3Mbp）降低了关节炎的易感性和发病率，而Pgia 12位点（6 Mbp）与关节炎的严重程度低相关。因此，我们已经在小鼠chr 3和chr 19上达到了关节炎相关基因组位点的临界大小，这为基因组DNA的高通量测序做了准备。
Proteoglycan (PG)-induced arthritis (PGIA) is a murine model of rheumatoid arthritis. Arthritis-prone BALB/c mice are 100% susceptible, whereas the major histocompatibility complex-matched DBA/2 strain is completely resistant to PGIA. To reduce the size of the disease-suppressive loci for sequencing and to find causative genes of arthritis, we created a set of BALB/c. DBA/2-congenic/subcongenic strains carrying DBA/2 genomic intervals overlapping the entire Pgia26 locus on chromosome 3 (chr3) and Pgia23/Pgia12 loci on chr19 in the arthritis-susceptible BALB/c background. Upon immunization of these subcongenic strains and their wild-type (BALB/c) littermates, we identified a major Pgia26a sublocus on chr3 that suppressed disease onset, incidence and severity via controlling the complex trait of T-cell responses. The region was reduced to 3 Mbp (11.8 Mbp with flanking regions) in size and contained gene (s) influencing the production of a number of proinflammatory cytokines. Additionally, two independent loci (Pgia26b and Pgia26c) suppressed the clinical scores of arthritis. The Pgia23 locus (∼ 3 Mbp in size) on chr19 reduced arthritis susceptibility and onset, and the Pgia12 locus (6 Mbp) associated with low arthritis severity. Thus, we have reached the critical sizes of arthritis-associated genomic loci on mouse chr3 and chr19, which are ready for high-throughput sequencing of genomic DNA.