McCluskey J, Farris A D, Keech C L, Purcell A W, Rischmueller M, Kinoshita G, Reynolds P, Gordon T P
Department of Microbiology and Immunology, University of Melbourne, Parkville, Victoria, Australia.
Immunol Rev. 1998 Aug;164:209-29. doi: 10.1111/j.1600-065x.1998.tb01222.x.
Spreading of the immune response is a common theme in organ-specific and systemic autoimmune diseases. We evaluated whether some of the mixed antinuclear antibody patterns characteristic of systemic autoimmunity might be the result of determinant spreading from a single initiating event. Immunisation of healthy mice with individual protein components of the La/Ro ribonucleoprotein (RNP) targeted in systemic lupus erythematosus and primary Sjögren's syndrome induced autoantibodies recognising Ro60 (SS-A), Ro52 (SS-A) and La (SS-B) and in some cases the molecular chaperones calreticulin and Grp78. The endogenous antigen(s) driving determinant spreading might be derived from physiological apoptosis which could explain the involvement of some chaperone proteins in the autoimmune response. Diversified anti-La/Ro antibody responses were initiated by challenge with a single subdominant T epitope of La even though some self epitopes of La were efficiently tolerised. The pattern of autoantibody responses in primary Sjögren's syndrome was strongly influenced by HLA class II phenotype which we speculate controls activation of T cells recognising defined peptides from the La/Ro RNP. In this way, HLA class II alleles may be critical in influencing initiation and spreading of systemic autoimmune reactions. Molecular mimicry of such determinants by exogenous agents might readily initiate spreading of an autoimmune response in genetically susceptible hosts.
免疫反应的扩散是器官特异性和全身性自身免疫性疾病的一个共同特征。我们评估了全身性自身免疫中一些混合抗核抗体模式是否可能是单一起始事件决定簇扩散的结果。用系统性红斑狼疮和原发性干燥综合征中靶向的La/Ro核糖核蛋白（RNP）的单个蛋白质成分免疫健康小鼠，可诱导出识别Ro60（SS-A）、Ro52（SS-A）和La（SS-B）的自身抗体，在某些情况下还可诱导出分子伴侣钙网蛋白和Grp78。驱动决定簇扩散的内源性抗原可能来源于生理性凋亡，这可以解释一些伴侣蛋白参与自身免疫反应的原因。即使La的一些自身表位被有效耐受，单一的La亚优势T表位激发也能引发多样化的抗La/Ro抗体反应。原发性干燥综合征中的自身抗体反应模式受到HLA II类表型的强烈影响，我们推测该表型控制识别来自La/Ro RNP特定肽段的T细胞的激活。通过这种方式，HLA II类等位基因可能在影响全身性自身免疫反应的起始和扩散方面至关重要。外源性因子对这类决定簇的分子模拟可能很容易在遗传易感宿主中引发自身免疫反应的扩散。
