Griffiths M M, Wang J, Joe B, Dracheva S, Kawahito Y, Shepard J S, Reese V R, McCall-Vining S, Hashiramoto A, Cannon G W, Remmers E F, Wilder R L
Department of Veterans Affairs Medical Center, and University of Utah, Salt Lake City, USA.
Arthritis Rheum. 2000 Jun;43(6):1278-89. doi: 10.1002/1529-0131(200006)43:6<1278::AID-ANR10>3.0.CO;2-S.
Collagen-induced arthritis (CIA) is a polygenic model of experimentally induced autoimmunity and chronic joint inflammation. This study maps genetic loci that regulate CIA susceptibility in DA/Bkl (DA) and BN/SsNHsd (BN) rats.
Genome scans covering chromosomes 1-20 and interval mapping techniques using 159 simple sequence-length polymorphism markers were used to identify quantitative trait loci (QTLs) that regulate CIA in (DA x BN)F2 hybrids. Serum antibody titers to type II collagen were determined by enzyme-linked immunosorbent assay.
DA rats were high responders to porcine type II collagen (PII) and developed severe CIA (100%). BN rats were low responders to PII and resistant to CIA (0%). BN genes strongly repressed PII-induced CIA. Only 12% of (DA x BN)F1 rats (7 of 60) and 31% of (DA x BN)F2 rats (307 of 1,004) developed CIA. Three new QTLs (Cia11, Cia12, and Cia13) with significant logarithm of odds (LOD) scores of 5.6, 4.6, and 4.5, respectively, plus a suggestive QTL (Cia14*, LOD 3.0) regulating arthritis severity were identified on chromosomes 3, 12, 4, and 19. A new QTL, Ciaa3, associating with anticollagen antibody titer (antibody to PII LOD 6.5; antibody to rat type II collagen LOD 5.2) mapped to chromosome 9. Of 10 CIA QTLs previously identified in (DA x F344) and (DA x ACI) rats, only Cia1 in the major histocompatibility complex and a region coincident to Cia5 on chromosome 10 (LOD >8.0) influenced CIA severity in (DA x BN)F2 rats.
Since CIA exhibits many of the pathologic features of rheumatoid arthritis, the data indicate that the variety of genetic elements regulating human autoimmune and rheumatic diseases may be much larger and more varied than originally envisioned.
胶原诱导的关节炎（CIA）是一种实验性诱导自身免疫和慢性关节炎症的多基因模型。本研究绘制了调控DA/Bkl（DA）和BN/SsNHsd（BN）大鼠CIA易感性的基因座图谱。
使用覆盖1至20号染色体的基因组扫描以及利用159个简单序列长度多态性标记的区间定位技术，来鉴定调控（DA×BN）F2杂种大鼠中CIA的数量性状基因座（QTL）。通过酶联免疫吸附测定法测定血清中针对II型胶原的抗体滴度。
DA大鼠对猪II型胶原（PII）反应强烈，并发生严重的CIA（100%）。BN大鼠对PII反应较弱且对CIA有抗性（0%）。BN基因强烈抑制PII诱导的CIA。只有12%的（DA×BN）F1大鼠（60只中的7只）和31%的（DA×BN）F2大鼠（1,004只中的307只）发生了CIA。在3号、12号、4号和19号染色体上分别鉴定出三个新的QTL（Cia11、Cia12和Cia13），其显著优势对数（LOD）分数分别为5.6、4.6和4.5，以及一个调控关节炎严重程度的提示性QTL（Cia14*，LOD 3.0）。一个与抗胶原抗体滴度相关的新QTL（抗PII抗体LOD 6.5；抗大鼠II型胶原抗体LOD 5.2）定位于9号染色体。在先前在（DA×F344）和（DA×ACI）大鼠中鉴定出的10个CIA QTL中，只有主要组织相容性复合体中的Cia1以及10号染色体上与Cia5重合的区域（LOD>8.0）影响（DA×BN）F2大鼠的CIA严重程度。
由于CIA表现出类风湿性关节炎的许多病理特征，这些数据表明，调控人类自身免疫和风湿性疾病的多种遗传因素可能比最初设想的要多得多且更加多样。
