Fridkis-Hareli Masha
Department of Cancer Immunology & AIDS, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
J Autoimmune Dis. 2008 Feb 15;5:1. doi: 10.1186/1740-2557-5-1.
Organ-specific autoimmune diseases affect particular targets in the body, whereas systemic diseases engage multiple organs. Both types of autoimmune diseases may coexist in the same patient, either sequentially or concurrently, sustained by the presence of autoantibodies directed against the corresponding autoantigens. Multiple factors, including those of immunological, genetic, endocrine and environmental origin, contribute to the above condition. Due to association of certain autoimmune disorders with HLA alleles, it has been intriguing to examine the immunogenetic basis for autoantigen presentation leading to the production of two or more autoantibodies, each distinctive of an organ-specific or systemic disease. This communication offers the explanation for shared autoimmunity as illustrated by organ-specific blistering diseases and the connective tissue disorders of systemic nature.
Several hypothetical mechanisms implicating HLA determinants, autoantigenic peptides, T cells, and B cells have been proposed to elucidate the process by which two autoimmune diseases are induced in the same individual. One of these scenarios, based on the assumption that the patient carries two disease-susceptible HLA genes, arises when a single T cell epitope of each autoantigen recognizes its HLA protein, leading to the generation of two types of autoreactive B cells, which produce autoantibodies. Another mechanism functioning whilst an epitope derived from either autoantigen binds each of the HLA determinants, resulting in the induction of both diseases by cross-presentation. Finally, two discrete epitopes originating from the same autoantigen may interact with each of the HLA specificities, eliciting the production of both types of autoantibodies.
Despite the lack of immediate or unequivocal experimental evidence supporting the present hypothesis, several approaches may secure a better understanding of shared autoimmunity. Among these are animal models expressing the transgenes of human disease-associated HLA determinants and T or B cell receptors, as well as in vitro binding studies employing purified HLA proteins, synthetic peptides, and cellular assays with antigen-presenting cells and patient's lymphocytes. Indisputably, a bioinformatics-based search for peptide motifs and the modeling of the conformation of bound autoantigenic peptides associated with their respective HLA alleles will reveal some of these important processes.
The elucidation of HLA-restricted immune recognition mechanisms prompting the production of two or more disease-specific autoantibodies holds significant clinical ramifications and implications for the development of more effective treatment protocols.
器官特异性自身免疫性疾病影响身体的特定靶器官，而全身性疾病累及多个器官。这两种自身免疫性疾病可能在同一患者中相继或同时存在，由针对相应自身抗原的自身抗体维持。多种因素，包括免疫、遗传、内分泌和环境因素，都与上述情况有关。由于某些自身免疫性疾病与HLA等位基因相关，因此研究导致产生两种或更多种自身抗体（每种自身抗体分别对应一种器官特异性或全身性疾病）的自身抗原呈递的免疫遗传基础一直很有趣。本通讯解释了器官特异性水疱性疾病和全身性结缔组织疾病所体现的共同自身免疫现象。
已经提出了几种涉及HLA决定簇、自身抗原肽、T细胞和B细胞的假说机制，以阐明在同一个体中诱发两种自身免疫性疾病的过程。其中一种情况是，假设患者携带两个疾病易感HLA基因，当每种自身抗原的单个T细胞表位识别其HLA蛋白时，就会产生两种自身反应性B细胞，它们产生自身抗体。另一种机制是，当来自任一自身抗原的表位与每个HLA决定簇结合时发挥作用，通过交叉呈递诱导两种疾病。最后，源自同一自身抗原的两个离散表位可能与每种HLA特异性相互作用，引发两种自身抗体的产生。
尽管缺乏直接或明确的实验证据支持当前假说，但有几种方法可以更好地理解共同自身免疫。其中包括表达人类疾病相关HLA决定簇和T或B细胞受体转基因的动物模型，以及使用纯化的HLA蛋白、合成肽的体外结合研究，以及与抗原呈递细胞和患者淋巴细胞的细胞分析。无可争议的是，基于生物信息学搜索肽基序以及与各自HLA等位基因相关的结合自身抗原肽构象的建模将揭示其中一些重要过程。
阐明促使产生两种或更多种疾病特异性自身抗体的HLA限制性免疫识别机制具有重要的临床意义，并对开发更有效的治疗方案具有启示作用。
