Guo Jin, McLachlan Sandra M, Pichurin Pavel N, Chen Chun-Rong, Pham Nancy, Aliesky Holly A, David Chella S, Rapoport Basil
Autoimmune Disease Unit, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite B-131, Los Angeles, California 90048, USA.
Endocrinology. 2005 Nov;146(11):4961-7. doi: 10.1210/en.2005-0760. Epub 2005 Aug 4.
We investigated the relationship between thyroid peroxidase (TPO) antibody and T lymphocyte epitopes in TPO-adenovirus (TPO-Ad) immunized BALB/c mice and mice transgenic for the human class II molecule DR3 associated with human thyroid autoimmunity. TPO autoantibodies are largely restricted to an immunodominant region (IDR). BALB/c mice immunized with fewer (10(7) vs. 10(9)) TPO-Ad particles developed TPO antibodies with lower titers that displayed greater restriction to the IDR. However, as with higher-dose TPO-Ad immunization, T cell epitopes (assessed by splenocyte interferon-gamma response to TPO in vitro) were highly diverse and variable in different animals. In contrast, DR3 mice immunized the higher TPO-Ad dose (10(9) particles) had high TPO antibody levels that showed relative focus on the IDR. Moreover, T cell epitopes recognized by splenocytes from DR3 mice showed greater restriction than BALB/c mice. Antibody affinities for TPO were higher in DR3 than in BALB/c mice. The present study indicates that weak TPO-Ad immunization of BALB/c mice (with consequent low TPO antibody titers) is required for enhanced IDR focus yet is not associated with T cell epitopic restriction. Humanized DR3 transgenic mice, despite stronger TPO-Ad immunization, develop higher titer TPO antibodies that do focus on the autoantibody IDR with T cells that recognize a more limited range of TPO peptides. These data suggest a relationship between major histocompatibility complex class II molecules and the development of antibodies to the IDR, a feature of human thyroid autoimmunity.
我们研究了甲状腺过氧化物酶（TPO）抗体与T淋巴细胞表位在TPO腺病毒（TPO-Ad）免疫的BALB/c小鼠以及转染了与人类甲状腺自身免疫相关的人类II类分子DR3的小鼠中的关系。TPO自身抗体主要局限于一个免疫显性区域（IDR）。用较少数量（10^7对10^9）的TPO-Ad颗粒免疫的BALB/c小鼠产生的TPO抗体滴度较低，且对IDR的限制性更强。然而，与高剂量TPO-Ad免疫一样，T细胞表位（通过体外脾细胞对TPO的干扰素-γ反应评估）在不同动物中高度多样且可变。相比之下，用较高剂量TPO-Ad（10^9颗粒）免疫的DR3小鼠具有较高的TPO抗体水平，且相对集中于IDR。此外，DR3小鼠脾细胞识别的T细胞表位比BALB/c小鼠表现出更强的限制性。DR3小鼠中TPO的抗体亲和力高于BALB/c小鼠。本研究表明，对BALB/c小鼠进行弱TPO-Ad免疫（从而导致低TPO抗体滴度）对于增强IDR聚焦是必需的，但与T细胞表位限制性无关。人源化DR3转基因小鼠尽管进行了更强的TPO-Ad免疫，但仍产生更高滴度的TPO抗体，这些抗体确实聚焦于自身抗体IDR，且T细胞识别的TPO肽范围更有限。这些数据表明主要组织相容性复合体II类分子与针对IDR的抗体产生之间存在关联，这是人类甲状腺自身免疫的一个特征。
