Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1; Department of Comparative Biology and Experimental Medicine, Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada T2N 4N1.
Free Radic Biol Med. 2018 Sep;125:53-61. doi: 10.1016/j.freeradbiomed.2018.03.040. Epub 2018 Mar 22.
In addition to debris clearance and antimicrobial function, versatile organelles known as phagosomes play an essential role in the processing of exogenous antigen in antigen presenting cells. While there has been much attention on human leukocyte antigen haplotypes in the determination of antigenic peptide repertoires, the lumenal biochemistries within phagosomes and endosomes are emerging as equally-important determinants of peptide epitope composition and immunodominance. Recently, the lumenal redox microenvironment within these degradative compartments has been shown to impact two key antigenic processing chemistries: proteolysis by lysosomal cysteine proteases and disulfide reduction of protein antigens. Through manipulation of the balance between oxidative and reductive capacities in the phagosome-principally by modulating NADPH oxidase (NOX2) and γ-interferon-inducible lysosomal thiol reductase (GILT) activities-studies have demonstrated changes to antigen processing patterns leading to modified repertoires of antigenic peptides available for presentation, and subsequently, altered disease progression in T cell-driven autoimmunity. This review focuses on the mechanisms and consequences of redox-mediated phagosomal antigen processing, and the potential downstream implications to tolerance and autoimmunity.
除了清除碎片和抗菌功能外，多功能细胞器即吞噬体在抗原提呈细胞中外源抗原的加工中也起着至关重要的作用。虽然在确定抗原肽库方面，人类白细胞抗原单倍型受到了广泛关注，但吞噬体和内体腔内的腔室生物化学也同样成为影响肽表位组成和免疫显性的重要决定因素。最近，这些降解隔室的腔内氧化还原微环境已被证明会影响两种关键的抗原加工化学：溶酶体半胱氨酸蛋白酶的蛋白水解作用和蛋白质抗原的二硫键还原。通过调节吞噬体中的氧化还原能力平衡（主要通过调节 NADPH 氧化酶 (NOX2) 和 γ-干扰素诱导的溶酶体硫醇还原酶 (GILT) 的活性），研究已经证明了抗原处理模式的变化导致了可供呈递的抗原肽的组成发生变化，随后改变了 T 细胞驱动的自身免疫中的疾病进展。这篇综述重点介绍了氧化还原介导的吞噬体抗原加工的机制和后果，以及对耐受和自身免疫的潜在下游影响。
