Koelsch Kristi, Zheng Nai-Ying, Zhang Qingzhao, Duty Andrew, Helms Christina, Mathias Melissa D, Jared Mathew, Smith Kenneth, Capra J Donald, Wilson Patrick C
Molecular Immunogenetics Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104, USA.
J Clin Invest. 2007 Jun;117(6):1558-65. doi: 10.1172/JCI27628. Epub 2007 May 17.
Determination of the origin and fate of autoreactive B cells is critical to understanding and treating autoimmune diseases. We report that, despite being derived from healthy people, antibodies from B cells that have class switched to IgD via genetic recombination (and thus become class switched to C delta [C delta-CS] cells) are highly reactive to self antigens. Over half of the antibodies from C delta-CS B cells bind autoantigens on human epithelioma cell line 2 (HEp-2) cells or antinuclear antigens, and a quarter bind double-stranded DNA; both groups of antibodies are frequently polyreactive. Intriguingly, some C delta-CS B cells have accumulated basic residues in the antibody variable regions that mediate anti-DNA reactivity via somatic hypermutation and selection, while other C delta-CS B cells are naturally autoreactive. Though the total percentage was appreciably less than for C delta-CS cells, a surprising 31% of IgG memory cell antibodies were somewhat autoreactive, and as expected, about 24% of naive cell antibodies were autoreactive. We interpret these findings to indicate either that autoreactive B cells can be induced to class switch to IgD or that autoreactive B cells that use IgD as the B cell receptor are not effectively deleted. Determination of the mechanism by which the majority of C delta-CS B cells are autoreactive may be important in understanding peripheral tolerance mechanisms and may provide insight into the enigmatic function of the IgD antibody.
确定自身反应性B细胞的起源和命运对于理解和治疗自身免疫性疾病至关重要。我们报告称,尽管来自健康个体,但通过基因重组已类别转换为IgD(从而成为类别转换为Cδ[Cδ-CS]细胞)的B细胞所产生的抗体对自身抗原具有高度反应性。超过一半的来自Cδ-CS B细胞的抗体与人上皮瘤细胞系2(HEp-2)细胞上的自身抗原或抗核抗原结合,四分之一的抗体与双链DNA结合;这两组抗体通常具有多反应性。有趣的是,一些Cδ-CS B细胞在抗体可变区积累了碱性残基,这些残基通过体细胞超突变和选择介导抗DNA反应性,而其他Cδ-CS B细胞则天然具有自身反应性。尽管总百分比明显低于Cδ-CS细胞,但令人惊讶的是,31%的IgG记忆细胞抗体有一定程度的自身反应性,正如预期的那样,约24%的幼稚细胞抗体具有自身反应性。我们对这些发现的解释是,要么自身反应性B细胞可被诱导类别转换为IgD,要么以IgD作为B细胞受体的自身反应性B细胞未被有效清除。确定大多数Cδ-CS B细胞具有自身反应性的机制可能对理解外周耐受机制很重要,并可能为IgD抗体的神秘功能提供见解。