Barbera Betancourt Ariana, Lyu Qingkang, Broere Femke, Sijts Alice, Rutten Victor P M G, van Eden Willem
Faculty of Veterinary Medicine, Department of Infectious Diseases and Immunology, Utrecht University, Utrecht, Netherlands.
Front Immunol. 2017 Oct 26;8:1408. doi: 10.3389/fimmu.2017.01408. eCollection 2017.
Failing immunological tolerance for critical self-antigens is the problem underlying most chronic inflammatory diseases of humans. Despite the success of novel immunosuppressive biological drugs, the so-called biologics, in the treatment of diseases such rheumatoid arthritis (RA) and type 1 diabetes, none of these approaches does lead to a permanent state of medicine free disease remission. Therefore, there is a need for therapies that restore physiological mechanisms of self-tolerance. Heat shock proteins (HSPs) have shown disease suppressive activities in many models of experimental autoimmune diseases through the induction of regulatory T cells (Tregs). Also in first clinical trials with HSP-based peptides in RA and diabetes, the induction of Tregs was noted. Due to their exceptionally high degree of evolutionary conservation, HSP protein sequences (peptides) are shared between the microbiota-associated bacterial species and the self-HSP in the tissues. Therefore, Treg mechanisms, such as those induced and maintained by gut mucosal tolerance for the microbiota, can play a role by targeting the more conserved HSP peptide sequences in the inflamed tissues. In addition, the stress upregulated presence of HSP in these tissues may well assist the targeting of the HSP induced Treg specifically to the sites of inflammation.
对关键自身抗原的免疫耐受失败是大多数人类慢性炎症性疾病的根本问题。尽管新型免疫抑制生物药物（即所谓的生物制剂）在治疗类风湿性关节炎（RA）和1型糖尿病等疾病方面取得了成功，但这些方法都无法实现无药状态下的疾病永久缓解。因此，需要恢复自身耐受生理机制的疗法。热休克蛋白（HSPs）在许多实验性自身免疫疾病模型中通过诱导调节性T细胞（Tregs）表现出疾病抑制活性。在RA和糖尿病的基于HSP的肽的首次临床试验中，也观察到了Tregs的诱导。由于其极高的进化保守程度，HSP蛋白序列（肽）在与微生物群相关的细菌物种和组织中的自身HSP之间共享。因此，诸如由肠道黏膜对微生物群的耐受性诱导和维持的Treg机制，可以通过靶向炎症组织中更保守的HSP肽序列发挥作用。此外，这些组织中应激上调的HSP的存在很可能有助于将HSP诱导的Treg特异性靶向炎症部位。
