Rizzi M, Ferrera F, Filaci G, Indiveri F
Center of Excellence for Biomedical Research, University of Genoa, Italy.
Autoimmun Rev. 2006 Feb;5(2):145-7. doi: 10.1016/j.autrev.2005.09.001. Epub 2005 Sep 13.
The mechanism underlying the generation of T and B autoreactive clones in autoimmune diseases is still unknown. Among genetic factors implicated in autoimmunity, Autoimmune Regulator gene (AIRE) is one of the candidates to better understand the complex scenario of autoimmune manifestations. AIRE mutations are responsible for the development of autoimmune polyendocrinopathy candidiasis ectodermal dystrophy (APECED) with monogenic autosomal recessive inheritance; it has been shown that AIRE regulates the negative selection of autoreactive T cells clones, driving the transcription of tissue-specific antigens in thymic epithelial cells. In various autoimmune manifestations correlated or not to APECED, AIRE variants act in a semidominant manner, leading to a reduction in AIRE protein amount per cell, and consequently to a marked decrease in ectopic proteins expression in the thymus. The co-occurrence of autoimmune diseases in the same individual has prompted several studies aimed to recognize shared patho-physiological mechanisms; in this scenario small reductions in function could explain the predisposition to autoimmunity in AIRE-heterozygous carriers of missense mutations; further studies to investigate whether the AIRE gene is involved in determining these autoimmune manifestations should be carried out.
自身免疫性疾病中T和B自身反应性克隆产生的潜在机制仍不清楚。在与自身免疫相关的遗传因素中，自身免疫调节基因（AIRE）是更好地理解自身免疫表现复杂情况的候选基因之一。AIRE突变导致具有单基因常染色体隐性遗传的自身免疫性多内分泌腺病念珠菌病外胚层营养不良（APECED）的发生；研究表明，AIRE调节自身反应性T细胞克隆的阴性选择，驱动胸腺上皮细胞中组织特异性抗原的转录。在各种与APECED相关或不相关的自身免疫表现中，AIRE变异以半显性方式起作用，导致每个细胞中AIRE蛋白量减少，进而导致胸腺中异位蛋白表达显著降低。同一个体中自身免疫性疾病的共同出现促使了多项旨在识别共同病理生理机制的研究；在这种情况下，功能的微小降低可以解释错义突变的AIRE杂合携带者易患自身免疫性疾病的原因；应该开展进一步的研究来调查AIRE基因是否参与了这些自身免疫表现的决定过程。
