Remmers Elaine F, Joe Bina, Griffiths Marie M, Dobbins David E, Dracheva Svetlana V, Hashiramoto Akira, Furuya Takefumi, Salstrom Jennifer L, Wang JianPing, Gulko Pércio S, Cannon Grant W, Wilder Ronald L
National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland20892, USA.
Arthritis Rheum. 2002 Aug;46(8):2225-34. doi: 10.1002/art.10439.
Collagen-induced arthritis (CIA) is a model of inflammatory arthritis with many similarities to rheumatoid arthritis (RA). We previously mapped in F(2) offspring of CIA-susceptible DA and CIA-resistant F344 rats, 5 quantitative trait loci (QTLs) for which F344 alleles were associated with reduced CIA severity. In the present study, we sought to characterize the independent arthritis-modulating effects of these 5 QTLs.
CIA-regulatory regions were transferred from the F344 genome to the DA background or vice versa by repeated backcrossing. The arthritis-modulating effects of the transferred alleles were determined by comparing the severity of experimentally induced arthritis in congenic rats with that in DA rats.
Congenic lines with either the F344 major histocompatibility complex (MHC) on the DA background or the DA MHC on the F344 background were resistant to CIA, confirming both MHC and non-MHC contributions to the genetic regulation of CIA. F344 alleles at the Cia3 and Cia5 regions of chromosomes 4 and 10 reduced CIA severity relative to that observed in DA rats. F344 Cia4 and Cia6 regions of chromosomes 7 and 8 failed to significantly alter CIA severity. Arthritis-modifying effects of Cia4 and Cia6 were, however, detected in pristane-induced and/or Freund's incomplete adjuvant oil-induced arthritis. The arthritis-modifying effects of the non-MHC CIA-regulatory loci differed in males and females.
These congenic lines confirmed the existence and location of genes that regulate the severity of experimental arthritis in rats. Mechanisms responsible for the sex-specificity of individual arthritis-regulatory loci may explain some of the sex differences observed in RA and other autoimmune diseases in humans.
胶原诱导性关节炎（CIA）是一种炎症性关节炎模型，与类风湿关节炎（RA）有许多相似之处。我们之前在CIA易感的DA大鼠和CIA抗性的F344大鼠的F(2)后代中定位了5个数量性状基因座（QTL），其中F344等位基因与CIA严重程度降低相关。在本研究中，我们试图表征这5个QTL独立的关节炎调节作用。
通过反复回交，将CIA调节区域从F344基因组转移到DA背景，反之亦然。通过比较同源基因大鼠和DA大鼠实验性诱导关节炎的严重程度，确定转移等位基因的关节炎调节作用。
在DA背景上带有F344主要组织相容性复合体（MHC）或在F344背景上带有DA MHC的同源品系对CIA具有抗性，证实了MHC和非MHC对CIA遗传调节的作用。相对于DA大鼠，位于4号和10号染色体的Cia3和Cia5区域的F344等位基因降低了CIA的严重程度。位于7号和8号染色体的F344 Cia4和Cia6区域未能显著改变CIA的严重程度。然而，在 pristane诱导和/或弗氏不完全佐剂油诱导的关节炎中检测到了Cia4和Cia6的关节炎改善作用。非MHC CIA调节基因座的关节炎改善作用在雄性和雌性中有所不同。
这些同源品系证实了调节大鼠实验性关节炎严重程度的基因的存在和位置。个体关节炎调节基因座性别特异性的机制可能解释了在人类RA和其他自身免疫性疾病中观察到的一些性别差异。
