Under conditions of cellular stress, proteins can be post-translationally modified causing them to be recognized by the immune system. One such stress-induced post-translational modification (siPTM) is citrullination, the conversion of arginine residues to citrulline by peptidylarginine deiminase (PAD) enzymes. PAD enzymes are activated by millimolar concentrations of calcium which can occur during apoptosis, leading to precipitation of proteins, their subsequent uptake by B cells and stimulation of antibody responses. Detection of anti-citrullinated protein antibodies (ACPAs) is a diagnostic of rheumatoid arthritis (RA), where immune complexes stimulate inflammation around the joints. More recently, autophagy has been shown to play a role in the presentation of citrullinated peptides on MHC class II molecules to CD4⁺ helper T cells, suggesting that citrullination may be a way of alerting immune cells to cellular stress. Additionally, inflammation-induced IFNγ and concomitant MHC class II expression on target cells contributes to immune activation. Stressful conditions in the tumor microenvironment induce autophagy in cancer cells as a pro-survival mechanism. Cancer cells also over express PAD enzymes and in light of this the hypothesis that citrullinated peptides stimulate CD4⁺ T cell responses that would recognize these siPTM’s produced during autophagy has been investigated. The induction of potent citrullinated peptide-specific CD4 responses has been shown in both humans and HLA transgenic mouse models. Responses in mouse models resulted in potent anti-tumour responses against tumours expressing either constitutive or IFNγ-inducible MHC class II. The anti-tumour effect relied upon direct recognition of tumours by specific CD4 T cells suggesting that citrullinated peptides are attractive targets for cancer vaccines.

在细胞紧张的条件下，蛋白质可以被翻译后修饰，从而使其被免疫系统识别。此类应激诱导的翻译后修饰（siPTM）之一是瓜氨酸化，即肽酰精氨酸脱亚氨酶（PAD）酶将精氨酸残基转化为瓜氨酸。PAD酶被钙离子浓度激活，而钙离子浓度可能会在细胞凋亡期间发生，从而导致蛋白质沉淀，随后被B细胞摄取以及刺激抗体反应。抗瓜氨酸化蛋白抗体（ACPAs）的检测是类风湿关节炎（RA）的诊断，其中的免疫复合物会刺激关节周围的炎症。最近，研究表明自噬在将MHC II类分子上的瓜氨酸化肽呈递给CD4 ^+时发挥了作用辅助性T细胞，提示瓜氨酸化可能是提醒免疫细胞注意细胞应激的一种方法。另外，炎症诱导的IFNγ和靶细胞上伴随的II类MHC表达也有助于免疫活化。肿瘤微环境中的应激条件会诱导癌细胞自噬，这是一种生存机制。癌细胞也过表达PAD酶，因此，瓜氨酸肽刺激CD4 ⁺的假说已经研究了识别自噬过程中产生的siPTM的T细胞反应。在人和HLA转基因小鼠模型中均显示了诱导有效的瓜氨酸化肽特异性CD4应答。小鼠模型中的反应导致针对表达组成型或IFNγ诱导的II类MHC的肿瘤的有效抗肿瘤反应。抗肿瘤作用依赖于特异性CD4 T细胞对肿瘤的直接识别，提示瓜氨酸化肽是癌症疫苗的引人注目的靶标。