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

MHC 对自身免疫和 B-CLL 中 CD5 B 细胞的控制

• 批准号: 02454170
• 负责人: SHIRAI Toshikazu
• 金额: $ 4.22万
• 依托单位: Juntendo University School of Medicine
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for General Scientific Research (B)
• 财政年份: 1990
• 资助国家: 日本
• 起止时间: 1990 至 1991
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-02454170/
• 关键词: B-CLL; CD5 B cell; H-2-congenic mouse; autoimmunity; MHC; MHC class II molecule; New Zealand mice; SLE; CD5B細胞; クロ-ナル増殖; New zealandマウス; Hー2 congenicマウス; I領域遺伝子

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.

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。

项目成果

Okabe,T.,Abe,M.,Takiura,F.,Hirose,S.& Shirai,T.: "Destinct surface phenotypes of B cells responsible for spontaneous production of IgM and IgGーDNA antibodies in autoimmuneーprone NZB X Fl mice." Autoimmunity. 7. 109-120 (1990)

Okabe, T.、Abe, M.、Takiura, F.、Hirose, S. 和 Shirai, T.：“B 细胞的特定表面表型负责在自身免疫倾向的 NZB X Fl 中自发产生 IgM 和 IgG-DNA 抗体7. 109-120（1990）

Ogawa,S.,Nishimura,H.,Awaji,M.,Nozawa,S.,Hirose,S. & Shirai,T.: "Nucleotide sequence analysis of MHC class II gene autoimmuneーprone (NZB X NZW)F1 mice." Immunogenetics. 32. 63-67 (1990)

Okawa, S.、Nishimura, H.、Awaji, M.、Nozawa, S.、Hirose, S. 和 Shirai, T.：“MHC II 类基因自身免疫倾向 (NZB X NZW)F1 小鼠的核苷酸序列分析。 “免疫遗传学。32。63-67（1990）

Shirai,T.,Hirose,S.,Okada,T.& Nishimura,H.: "Immunological Disorders in Mice." CRC Press,Inc., 42 (1991)

白井 T.、广濑 S.、冈田 T.

Ogawa,S.,Nishimura,H.,Awaji,M.,Nozawa,S.,Hirose,S.& Shirai,T.: "Nucleotide sequence analysis of MHC class II gene in autoimmuneprone (NZB X NZW)F1 mice." Immunogenetics. 32. 63-67 (1990)

小川，S.，西村，H.，淡路，M.，野泽，S.，广濑，S.

Ogawa, S., Nishimura, H., Awaji, M., Nozswa, S., Hirose, S. & Shirai, T.: "Nucleotide sequence analysis of MHC class II gene in autoimmune-prone (NZB X NZW) Fl mice." Immunogenetics. 33. 413-414 (1990)

小川，S.，西村，H.，淡路，M.，Nozswa，S.，广濑，S.