Dighiero G
Unité d'Immuno-Hématologie et d'Immunopathologie, Institut Pasteur, Paris.
Bull Acad Natl Med. 1999;183(6):1153-63; discussion 1163-4.
In 1900, the group from Metchnikoff suggested the concept of autoimmunization by demonstrating the presence of autoantibodies in normal conditions; which was opposed to the concept of horror autotoxicus raised by Ehrlich. Landsteiner's description of the transfusion compatibility rules and 50 year-later work from Burnett's and Medawar's groups lead to the clonal deletion theory as a general explanation of tolerance and autoimmunity. However, more recent work succeeded demonstrating that autoreactive B cells constitute a substantial part of the B-cell repertoire and that this autoreactive repertoire secretes the so-called natural autoantibodies (NAA) characterized by their broad reactivity mainly directed against very well conserved public epitopes. They fulfill the definition of an autoantibody since they are self-reactive, but they are not self-specific. As yet, NAA directed against determinants of polymorphism have not been reported. The presence of this repertoire in normal conditions challenges the clonal deletion theory as a unique explanation for self-tolerance. However, if we take into account that this autoreactive B-cell repertoire is not self-specific, this contradiction may not be a real one opposition. Indeed, the Lansteiner's rule that a subject belonging to group A will never produce anti-A antibodies and will always produce natural antibodies against the B-cell group, could never be challenged. Clonal deletion is probably accounting for this phenomenon. However, the serum of healthy adult individuals frequently exhibits low titers of anti-I antibodies, which is a precursor molecule of AB0 antigen system. The mechanism accounting for deletion of B cells directed against critical determinants like antigens A and B in the red blood cell system and allowing the production of autoantibodies against I remains elusive.
1900年，梅契尼科夫团队通过证明正常情况下自身抗体的存在，提出了自身免疫的概念；这与埃尔利希提出的“恐自身中毒”概念相悖。兰德施泰纳对输血相容性规则的描述以及伯内特和梅达沃团队50年后的研究成果，催生了克隆清除理论，作为对耐受性和自身免疫的一般性解释。然而，最近的研究成功证明自身反应性B细胞构成了B细胞库的重要组成部分，并且这个自身反应性库分泌所谓的天然自身抗体（NAA），其特点是具有广泛的反应性，主要针对高度保守的公共表位。它们符合自身抗体的定义，因为它们是自身反应性的，但并非自身特异性的。迄今为止，尚未报道针对多态性决定簇的NAA。正常情况下这种库的存在对克隆清除理论作为自身耐受性的唯一解释提出了挑战。然而，如果我们考虑到这种自身反应性B细胞库并非自身特异性的，那么这种矛盾可能并非真正的对立。事实上，兰德施泰纳法则指出，属于A组的个体永远不会产生抗A抗体，而总是会产生针对B细胞组的天然抗体，这一法则从未受到挑战。克隆清除可能是这种现象的原因。然而，健康成年个体的血清中经常显示出低滴度的抗I抗体，I是AB0抗原系统的前体分子。解释红细胞系统中针对抗原A和B等关键决定簇的B细胞如何被清除，同时又允许产生针对I的自身抗体的机制仍然难以捉摸。
