Two immunoglobulin (Ig) diversification mechanisms collaborate to provide protective humoral immunity. Combinatorial assembly of IgH and IgL V region exons from gene segments generates preimmune Ig repertoires, expressed as B cell receptors (BCRs). Secondary diversification occurs when Ig V regions undergo somatic hypermutation (SHM) and affinity-based selection toward antigen in activated germinal center (GC) B cells. Secondary diversification is thought to only ripen the antigen-binding affinity of Igs that already exist (i.e., cognate Igs) because of chance generation during preimmune Ig diversification. However, whether stochastic activation of noncognate B cells can generate new affinity to antigen in GCs is unclear. Using a mouse model whose knock-in BCR does not functionally engage with immunizing antigen, we found that chronic immunization induced antigen-specific serological responses with diverse SHM-mediated antibody affinity maturation pathways and divergent epitope targeting. Thus, intrinsic GC B cell flexibility allows for somatic, noncognate B cell evolution, permitting de novo antigen recognition and subsequent antibody affinity maturation without initial preimmune BCR engagement.

两种免疫球蛋白（Ig）多样化机制协同作用，以提供保护性体液免疫。来自基因片段的IgH和IgL V区外显子的组合组装产生了免疫前的Ig曲目，表达为B细胞受体（BCR）。当Ig V区经历体细胞超突变（SHM）和对生发中心（GC）B细胞中的抗原进行基于亲和力的选择时，发生二级多样化。二级多样化被认为只会使免疫前Ig产生机会而已存在的Ig（即同源Ig）的抗原结合亲和力成熟。多样化。但是，尚不清楚非同源B细胞的随机激活是否可以对GC中的抗原产生新的亲和力。使用其敲入BCR不能与免疫抗原功能结合的小鼠模型，我们发现慢性免疫可以通过多种SHM介导的抗体亲和力成熟途径和不同的表位靶向来诱导抗原特异性血清学反应。因此，内在的GC B细胞柔韧性允许体细胞性，非同源性的B细胞进化，允许从头进行抗原识别和随后的抗体亲和力成熟，而无需最初的免疫前BCR参与。