Controls of MHC on CD5 B cells in autoimmunity and B-CLL

CD^<5+> B细胞由于参与自身免疫和B细胞型慢性淋巴细胞白血病（B-CLL）而引起了广泛关注。B-CLL是一种最常发生在近亲中的白血病，部分与主要组织相容性复合体（MHC）有关，这是一种与自身免疫性疾病相关的发现。我们建立了MHC（H-2）-同源NZB X NZW（NZB/W）F1小鼠（H-2^<d/z>、H-2^<z/z>和H-2^<d/d>），因为随着动物年龄的增长，只有H-2^<d/z>杂合子发展出与IgG抗DNA抗体相关的严重SLE。这种与年龄相关的变化与脾脏CD^<5+> B细胞的减少同时发生。相比之下，H-2^<z/z>纯合子没有发展成SLE，但反过来，CD^<5+> B细胞的明显克隆性增殖确实发生，类似于B-CLL。H-2^<d/d>纯合子也没有发展成典型的SLE，并且中等的CD 5 ^- B频率持续存在。尽管发现所有三个H-2同源NZB/W F1菌株都产生IgM抗DNA抗体，但只有H-2^<d/z>杂合子产生IgG抗体。主要IgM产生者的表面表型为CD 5 ^+ sIgM^+，而IgG产生者的表面表型为CD 5-sIgM^-。遗传和细胞分析支持了我们的论点，即在杂合子中，IgM到IgG同种型转换可能出现在CD 5 ^+ B细胞中，并且该事件与CD 5分子的丢失有关。由于缺乏分化所需的遗传元件（H-2^<d/Z>），在H-2^<z/z>纯合子中，只有增殖信号在CD 5 ^+ B细胞中起作用。这些观察结果表明，某些不同但相关的MHC单倍型可能易患B-CLL或近亲自身免疫性疾病。

CD^<5+> B cells have attracted much attention, because of their involvement in both autoimmunity and B cell-type chronic lymphocytic leukemia(B-CLL). B-CLL is a type of leukemia most often occuring among close relatives and is partly associated with the major histocompatibility complex(MHC), a finding relevant to autoimmune disease. We established MHC(H-2)-congenic NZB X NZW(NZB/W)Fl mice(H-2^<d/z>, H-2^<z/z>, and H-2^<d/d>), in that only H-2^<d/z> heterozygotes developed severe SLE, associated with IgG anti-DNA antibodies, as the animals aged. Such age-associated changes occurred in parallel with the decrease in the splenic CD^<5+> B cells. By contrast, H-2^<z/z> homozygotes did not develop SLE but, in turn, a marked clonal proliferation of CD^<5+> B cells resembling B-CLL did occur. H-2^<d/d> homozygotes also did not develop the typical SLE, and a moderate CD5^- B frequency persisted. Despite the finding that all the three H-2-congenic NZB/W Fl strains produced IgM anti-DNA antibodies, only the H-2^<d/z> heterozygotes produced IgG antibodies. Whereas the surface phenotype of major IgM producers was CD5^+ sIgM^+, that of IgG producers was CD5-sIgM^-. Genetic and cellular analyses supported our thesis that in the heterozygotes IgM to IgG isotype switching probably emerges in CD5^+ B cells and that this event is associated with the loss of CD5 molecules. Because of the lack of genetic elements (H-2^<d/Z>) required for differentiation, only signals for proliferation would be functioning in CD5^+ B cells in the H-2^<z/z> homozygotes. These observations infer that certain different, but related, MHC haplotypes may predispose either to B-CLL orto autoimmune disease in close relatives.