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

CD^&lt；5+&gt；B细胞因参与自身免疫和B细胞型慢性淋巴细胞白血病(B-CLL)而备受关注。B-CLL是一种白血病，最常发生在近亲中，部分与主要组织相容性复合体(MHC)有关，MHC与自身免疫性疾病有关。我们建立了MHC(H-2)-同源NZB X NZW(NZB/W)F1小鼠(H-2^&lt；d/z&gt；，H-2^&lt；z/z&gt；和H-2^&lt；d/d&gt；)，随着动物年龄的增长，只有H-2^&lt；d/z&gt；杂合子才会发生严重的SLE，并伴随着抗DNA抗体。这种与年龄相关的变化发生在脾CD^&lt；5+&gt；B细胞减少的同时。相反，H-2^&lt；z/z&gt；纯合子没有发生SLE，但反过来，CD^&lt；5+&gt；B细胞发生了明显的克隆性增殖，类似于B-CLL。H-2^&lt；d/d&gt；纯合子也没有发生典型的系统性红斑狼疮，CD5^-B频率中等。尽管发现三株H-2-同源NZB/W F1株都产生了IgM抗DNA抗体，但只有H-2^&d/z&gt；杂合子产生了IgG抗体。而主要的IgM产生菌表面表型为CD5^+Sigm^+，而免疫球蛋白G产生菌表面表型为CD5-Sigm^-。遗传学和细胞学分析支持我们的观点，即在杂合子中，CD5^+B细胞可能发生了从IgM到IgG的同型转换，并且这一事件与CD5分子的丢失有关。由于缺乏分化所需的遗传元件(H-2^&lt；d/Z&gt；)，在H-2^&lt；z/z&gt；纯合子中，只有增殖信号在CD5^+B细胞中起作用。这些观察推断，某些不同但相关的MHC单倍型可能在近亲中易患B-CLL或自身免疫性疾病。

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.