A murine Ig light chain transgene reveals IGKV3 gene contributions to anti-collagen types IV and II specificities.
A murine Ig light chain transgene reveals IGKV3 gene contributions to anti-collagen types IV and II specificities.
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DOI：
10.1016/j.molimm.2017.08.015
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发表时间：
2017-11
影响因子：
3.6
通讯作者：
Foster MH
中科院分区：
文献类型：
--
作者：
Clark AG;Worni-Schudel IM;Korte FM;Foster MH
一部分自身免疫性疾病是由靶向基质胶原表位的自身抗体引起的。研究最广泛的是破坏肾脏和肺部的抗肾小球基底膜肾小球肾炎（或其系统性对应的Goodpasture病），以及导致致残性关节炎的类风湿性关节炎。这些疾病的自身抗体分别结合在肾小球和肺泡基底膜IV型[alpha3(IV)NC1]胶原的alpha3链的非胶原结构域1 （NC1）和关节软骨的天然或citrullinated II型胶原（CII）上的进化上保守的构象表位。这些疾病中致病性抗胶原B细胞的遗传起源尚不清楚，但从小鼠模型中观察到，尽管存在不同的体内免疫病理，但它们可能重叠。从免疫过alpha3(IV)NC1胶原或CII的小鼠中分离的单克隆自身抗体显示，IGKV3亚群（以前的Vk21家族）基因编码的Ig轻链（LC）与多种Ig重链配对。为了进一步探索这种关系，并确定单个小鼠IGKV3 LC是否独立地倾向于两种抗胶原反应，我们产生了一种新的转基因（Tg） C57BL/6小鼠，该小鼠表达高效重排的IGKV3编码LC，称为mLCV3-Tg，并与内源性重排的Ig重链结合。Tg小鼠的内源性kappa链也存在遗传缺陷，无法追踪mLCV3转基因。我们发现mLCV3-Tg小鼠对两种胶原链的体液自身免疫都很敏感。在未处理Tg小鼠的血清中检测到抗α 3(IV)NC1胶原，但不检测到抗cii， mlcv3编码的Ig，而toll样受体配体诱导脾细胞分泌两种胶原特异性的mLCV3-Tg自身抗体。这表明mLCV3-Tg B细胞的发育存活与每种抗原反应，并且与不同B细胞群产生的两种抗胶原蛋白自身ig相一致。减少的B细胞数量、低血清Ig κ pa水平、低细胞表面Ig κ pa密度以及丰富的内源性lambda链表达表明，igkv3编码的B细胞亚群在体内受到包括缺失、能量和LC编辑在内的机制的调节。这些结果支持了这样一种观点，即小鼠IGKV3 LCs有助于抗原结合位点的结构适应性，这些抗原结合位点支持多种抗胶原自身免疫反应，这些反应在体内受到调节，并且这些细胞可以很容易地逃避免疫调节。
A subset of autoimmune diseases result from autoantibodies targeting epitopes on matrix collagen. The most extensively studied are anti-glomerular basement membrane glomerulonephritis (or its systemic counterpart Goodpasture’s disease) that destroys kidneys and lungs, and rheumatoid arthritis that leads to disabling arthritis. Autoantibodies in these disorders bind evolutionarily conserved conformational epitopes on the noncollagenous domain 1 (NC1) of the alpha3 chain of type IV [alpha3(IV)NC1] collagen in glomerular and alveolar basement membranes, and on native or citrullinated type II collagen (CII) in joint cartilage, respectively. The genetic origins of pathogenic anti-collagen B cells in these diseases is unknown, but observations from murine models raise the possibility that they overlap despite distinct in vivo immunopathologies. Monoclonal autoantibodies isolated from mice immunized with alpha3(IV)NC1 collagen or CII show a biased use of Ig light chains (LC) encoded by genes of the IGKV3 subgroup (previously Vk21 family), paired with diverse Ig heavy chains. To further explore this relationship and determine if a single murine IGKV3 LC independently predisposes to both anti-collagen responses, we generated a novel transgenic (Tg) C57BL/6 mouse that expresses a productively rearranged IGKV3-encoded LC, termed mLCV3-Tg, in conjunction with endogenously rearranged Ig heavy chains. Tg mice are also genetically deficient in endogenous kappa chains to permit tracking of the mLCV3 transgene. We show that mLCV3-Tg mice are susceptible to humoral autoimmunity against both collagen chains. Anti-alpha3(IV)NC1 collagen, but not anti-CII, mLCV3-encoded Ig are detected in serum of unmanipulated Tg mice, while Toll-like receptor ligands induce secretion of mLCV3-Tg autoantibodies of both collagen specificities from splenocytes ex vivo. This indicates developmental survival of mLCV3-Tg B cells reactive with each antigen, and is consistent with production of the two anti-collagen autoIg from distinct B cell populations. Reduced B cell numbers, low serum Ig kappa levels, low cell surface Ig kappa density, and abundant endogenous lambda chain expression suggest that subsets of IGKV3-encoded B cells are regulated in vivo by mechanisms that include deletion, anergy, and LC editing. These results support the notion that murine IGKV3 LCs contribute structural fitness to antigen binding sites that support diverse anti-collagen autoimmune responses, that these responses are regulated in vivo, and that these cells can nonetheless readily escape immune regulation.
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DOI：
10.1084/jem.20061918
发表时间：
2007-01-22
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Casellas R;Zhang Q;Zheng NY;Mathias MD;Smith K;Wilson PC
通讯作者：
Wilson PC
影响因子：
20.1
作者：
Dart ML;Jankowska-Gan E;Huang G;Roenneburg DA;Keller MR;Torrealba JR;Rhoads A;Kim B;Bobadilla JL;Haynes LD;Wilkes DS;Burlingham WJ;Greenspan DS
通讯作者：
Greenspan DS
影响因子：
4.9
作者：
Lindh I;Snir O;Lönnblom E;Uysal H;Andersson I;Nandakumar KS;Vierboom M;'t Hart B;Malmström V;Holmdahl R
通讯作者：
Holmdahl R
影响因子：
6
作者：
Nandakumar, KS;Svensson, L;Holmdahl, R
通讯作者：
Holmdahl, R
影响因子：
4.4
作者：
Clark, Amy G.;Mackin, Katherine M.;Foster, Mary H.
通讯作者：
Foster, Mary H.