Miller D J, Hanson K D, Carman J A, Hayes C E
Department of Biochemistry, College of Agricultural and Life Sciences, University of Wisconsin-Madison 53706.
Eur J Immunol. 1992 Feb;22(2):373-9. doi: 10.1002/eji.1830220213.
Antigen-stimulated B lymphocytes either differentiate into IgM-secreting plasma cells or into memory B cells that secrete other immunoglobulin isotypes upon antigen restimulation. The mechanisms that generate and maintain memory B cells are poorly understood. Previously, we described a severe B lymphocyte deficiency in adult strain A/WySnJ mice compared to subline A/J. Here we show that the single, autosomal co-dominant locus responsible for the deficiency also diminishes IgG-secreting B cell formation without interfering with IgM-secreting plasma cell differentiation. A/WySnJ secondary IgG1 responses to the protein antigens hemocyanin, bovine gamma-globulin, ovalbumin, lysozyme and beta-galactosidase were 6- to 50-fold lower than A/J responses. The defect also decreased secondary IgG2a and IgG3 responses, and primary IgG1 and IgG2a responses. The reduced A/WySnJ secondary IgG1 response was not due to differential response kinetics or dose responsiveness, and could not be augmented to A/J levels by repeated immunizations. Serum IgG1, IgG2a and IgG3 levels from nonimmune A/WySnJ mice were similarly reduced. The secondary IgG1 response and splenic B cell percentage showed significant positive correlation (r = 0.72) in F2 mice, suggesting that a single locus controlled both traits. In contrast, A/WySnJ mice made good primary IgM responses to hemocyanin, beta-galactosidase, and the thymus-independent antigen trinitrophenyl-Ficoll. The A/WySnJ splenic adherent cells were competent in antigen-presenting function, and A/WySnJ immune T cells proliferated in response to antigen and provided the requisite B cell stimulatory signals for an IgG1 response. Together, our results suggest that A/WySnJ mice have a genetic lesion that causes a selective IgG immune response dysfunction. The absence of IgG-secreting cell precursors or a defect in precursor activation or differentiation are two possible mechanisms which could precipitate a selective IgG response dysfunction. We propose that the defective A/WySnJ and normal A/J strain pair offer the opportunity to use a natural genetic variation as a tool to investigate B lymphocyte development and function.
抗原刺激的B淋巴细胞要么分化为分泌IgM的浆细胞，要么分化为记忆B细胞，后者在抗原再次刺激时分泌其他免疫球蛋白同种型。产生和维持记忆B细胞的机制目前还知之甚少。此前，我们描述了成年A/WySnJ品系小鼠与A/J亚系相比存在严重的B淋巴细胞缺陷。在此我们表明，导致该缺陷的单个常染色体共显性基因座也会减少分泌IgG的B细胞形成，而不干扰分泌IgM的浆细胞分化。A/WySnJ对蛋白质抗原血蓝蛋白、牛γ球蛋白、卵清蛋白、溶菌酶和β-半乳糖苷酶的二次IgG1应答比A/J应答低6至50倍。该缺陷还降低了二次IgG2a和IgG3应答以及初次IgG1和IgG2a应答。A/WySnJ降低的二次IgG1应答并非由于不同的应答动力学或剂量反应性，并且通过重复免疫也无法提高到A/J水平。非免疫A/WySnJ小鼠的血清IgG1、IgG2a和IgG3水平同样降低。在F2小鼠中，二次IgG1应答与脾脏B细胞百分比呈显著正相关（r = 0.72），表明单个基因座控制这两个性状。相比之下，A/WySnJ小鼠对血蓝蛋白、β-半乳糖苷酶和胸腺非依赖性抗原三硝基苯基-菲可产生良好的初次IgM应答。A/WySnJ脾脏黏附细胞具有抗原呈递功能，并且A/WySnJ免疫T细胞在抗原刺激下增殖，并为IgG1应答提供必要的B细胞刺激信号。总之，我们的结果表明，A/WySnJ小鼠存在一种遗传病变，导致选择性IgG免疫应答功能障碍。缺乏分泌IgG的细胞前体或前体激活或分化缺陷是可能导致选择性IgG应答功能障碍的两种机制。我们提出，有缺陷的A/WySnJ品系和正常的A/J品系为利用自然遗传变异作为工具来研究B淋巴细胞发育和功能提供了机会。
