CONTROL OF AUTOANTIBODY AFFINITY BY SELECTION AGAINST AMINO-ACID REPLACEMENTS IN THE COMPLEMENTARITY-DETERMINING REGIONS
CONTROL OF AUTOANTIBODY AFFINITY BY SELECTION AGAINST AMINO-ACID REPLACEMENTS IN THE COMPLEMENTARITY-DETERMINING REGIONS
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DOI：
10.1073/pnas.91.26.12917
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发表时间：
1994-12-20
影响因子：
11.1
通讯作者：
THOMPSON, KM
中科院分区：
文献类型：
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作者：
BORRETZEN, M;RANDEN, I;THOMPSON, KM
类风湿因子（RF）自身抗体可以在健康个体感染或免疫后产生，从而逃避正常的耐受机制。目前尚不清楚这些自身抗体是否能经历体细胞超突变和类似于外源抗原抗体的亲和成熟。我们通过分析免疫后从供体获得的杂交瘤单克隆IgM RFs序列，研究了这些自身抗体是如何在正常个体中调节的。可变区经历广泛的高突变，但与针对外源抗原的抗体相反，对突变的强烈选择导致高变区或互补性决定区氨基酸的替代。此外，我们发现这些RFs的亲和力没有随着突变的积累而增加。这表明高亲和力变异在超突变过程中是耐受的，并且存在一种在某些自身反应性B细胞上运行的外周机制，该机制虽然没有删除所有自身反应性细胞的失能，但阻止了高亲和力自身抗体的产生。用V(H)1 DP-10重链可变区片段比较正常人和类风湿关节炎（RA）患者的RF，提示RA患者的RF可能不受这种控制机制的影响。
Rheumatoid factor (RF) autoantibodies can be produced in healthy individuals after infections or immunizations and thus escape normal tolerization mechanisms. It has not been clear whether such autoantibodies can undergo somatic hypermutation and affinity maturation similar to antibodies to exogenous antigens. We have investigated how these autoantibodies are regulated in normal individuals by analyzing the sequences of monoclonal IgM RFs obtained as hybridomas from donors after immunization. The variable regions undergo extensive hypermutation, but in contrast to antibodies against exogenous antigens, there is a strong selection against mutations that result in replacement of amino acids in the hypervariable, or complementarity-determining, regions. Furthermore, we found no increase in affinity of these RFs with the accumulation of mutations. This suggests that high-affinity variants are tolerized during the hypermutation process and there is a peripheral mechanism operating on certain autoreactive B cells that, while not deleting of anergizing all autoreactive cells, prevents the generation of high-affinity autoantibodies. Comparison of RFs by using the V(H)1 DP-10 heavy chain variable region segment from both normal individuals and rheumatoid arthritis (RA) patients suggests that RF from RA patients may not be subject to such a controlling mechanism.