Smith-Jensen T, Burgoon M P, Anthony J, Kraus H, Gilden D H, Owens G P
Department of Neurology, University of Colorado Health Sciences Center, Denver 80262, USA.
Neurology. 2000 Mar 28;54(6):1227-32. doi: 10.1212/wnl.54.6.1227.
To better understand B-cell activation in MS by analyzing the immunoglobulin (Ig)G heavy chain variable region (VH) repertoire found in MS brains and comparing it with brain VH sequences in individuals with subacute sclerosing panencephalitis (SSPE)--a chronic encephalitis produced by measles virus (MV)-and characterized by an antigen-driven oligoclonal IgG response to MV antigens.
The specificity of oligoclonal IgG in MS CSF and plaques, and their relevance to the pathogenesis of MS is unknown.
Nested PCR was used to amplify and sequence the rearranged IgG heavy-chain VH repertoire in plaques of three acute MS brains and in three SSPE brains. A representative population of VH sequences from each tissue was aligned to the known 51 functional VH germline segments. From this the authors determined the closest VH family germline segment, and the degree and location of somatic mutations for each unique IgG.
As expected for an antigen-driven response against MV antigens, most VH sequences from the SSPE brains were mutated extensively compared with their closest germline segments. Furthermore, SSPE VH sequences accumulated replacement mutations preferentially in the complementary-determining regions (CDRs) relative to framework regions-features normally observed during antigen-driven selection. A comparison of VH family and germline usage also demonstrated that each SSPE brain had its own unique IgG response. When the authors compared the VH response in MS plaques with SSPE, MS VH sequences were also mutated extensively, displayed a preferential accumulation of replacement mutations in CDRs, and were unique in each MS brain.
The presence of an antigen-driven response in MS, rather than a nonconventional mechanism of B-cell activation, warrants additional analysis of the specificity of IgG in MS brain and CSF.
通过分析多发性硬化症（MS）患者大脑中发现的免疫球蛋白（Ig）G重链可变区（VH）库，并将其与亚急性硬化性全脑炎（SSPE）患者大脑中的VH序列进行比较，以更好地了解MS中的B细胞活化。SSPE是一种由麻疹病毒（MV）引起的慢性脑炎，其特征是针对MV抗原的抗原驱动寡克隆IgG反应。
MS脑脊液和斑块中寡克隆IgG的特异性及其与MS发病机制的相关性尚不清楚。
采用巢式PCR扩增并测序三个急性MS患者大脑斑块和三个SSPE患者大脑斑块中重排的IgG重链VH库。将每个组织中具有代表性的VH序列群体与已知的51个功能性VH种系区段进行比对。据此，作者确定了最接近的VH家族种系区段，以及每个独特IgG的体细胞突变程度和位置。
正如对抗MV抗原的抗原驱动反应所预期的那样，与最接近的种系区段相比，SSPE患者大脑中的大多数VH序列发生了广泛的突变。此外，相对于框架区，SSPE的VH序列在互补决定区（CDR）优先积累置换突变，这是抗原驱动选择过程中通常观察到的特征。VH家族和种系使用情况的比较还表明，每个SSPE患者大脑都有其独特的IgG反应。当作者将MS斑块中的VH反应与SSPE进行比较时，MS的VH序列也发生了广泛的突变，在CDR中显示出置换突变的优先积累，并且在每个MS患者大脑中都是独特的。
MS中存在抗原驱动反应，而非B细胞活化的非常规机制，这使得有必要对MS大脑和脑脊液中IgG的特异性进行进一步分析。
