Haem oxygenase (HO)-1/carbon monoxide (CO) protects cancer cells from oxidative stress, but the gas-responsive signalling mechanisms remain unknown. Here we show using metabolomics that CO-sensitive methylation of PFKFB3, an enzyme producing fructose 2,6-bisphosphate (F-2,6-BP), serves as a switch to activate phosphofructokinase-1, a rate-limiting glycolytic enzyme. In human leukaemia U937 cells, PFKFB3 is asymmetrically di-methylated at R131 and R134 through modification by protein arginine methyltransferase 1. HO-1 induction or CO results in reduced methylation of PFKFB3 in varied cancer cells to suppress F-2,6-BP, shifting glucose utilization from glycolysis toward the pentose phosphate pathway. Loss of PFKFB3 methylation depends on the inhibitory effects of CO on haem-containing cystathionine β-synthase (CBS). CBS modulates remethylation metabolism, and increases NADPH to supply reduced glutathione, protecting cells from oxidative stress and anti-cancer reagents. Once the methylation of PFKFB3 is reduced, the protein undergoes polyubiquitination and is degraded in the proteasome. These results suggest that the CO/CBS-dependent regulation of PFKFB3 methylation determines directional glucose utilization to ensure resistance against oxidative stress for cancer cell survival.

免疫系统的某些分子如何影响大疱性类天疱疮 Summary 大疱性类天疱疮 (BP) 是一种罕见的皮肤病,主要影响 60 岁以上的人群。患者出现红色斑块和水疱。BP 是一 种自身免疫性皮肤病,即抗体不再攻击它们本应攻击的危险微生物,而会识别并附着在正常皮肤的分子上,导致 炎性反应。 BP 自身抗体靶向的两种自身抗原(分子)是 BP180 和 BP230,两者都是基底膜带(BMZ,皮肤外层和中层之间的连 接)的组成部分。 除了称为 IgG 的自身抗体外,一个 BP 患者子集表明 BMZ 中一种称为 IgE 的不同抗体沉积(存在),但尚未明确 BMZ IgE 与 BP 严重程度之间的关系。 在这项来自日本的研究中,作者分析了 BMZ 中的 IgE 沉积、血清中的 IgE 水平和 BP 患者的疾病严重程度之间 的关系。 首先,作者研究了 53 例大疱性类天疱疮 (BP) 患者的皮肤样本,其中 10 例 BMZ 中的 IgE 沉积较强,13 例沉积 较弱。接下来,在这 53 例 PB 患者中,作者专注于治疗前接受过测试的 15 名患者。根据使用大疱性类天疱疮 疾病面积指数 (PDAI) 评分进行的测量,BMZ IgE 沉积较强的患者相比无 IgE 沉积的患者 BP 更广泛。 在使用称为全身性皮质类固醇的药物治疗后,BMZ IgE 沉积较强或较弱的患者改善时间较长。相比之下,他们 的荨麻疹/红斑 BPDAI 评分没有发现显著差异,该评分测量皮肤发红和荨麻疹等症状。 这表明,BMZ IgE 沉积会影响 BP 患者的水疱形成。与之前的研究一致,结果表明,抗 IgE 疗法(如 omalizmab)不 仅可有效治愈红斑(发红)和荨麻疹(风团疹),对 BP 中的糜烂和水疱也很有效。 本摘要涉及研究: 基底膜带 IgE 沉积与大疱性类天疱疮疾病严重程度和治疗结果相关。 This summary relates to: https://doi.

Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor–transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg3−/− mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.

Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell–cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops.

CD4 + T cells limit pathogenic bystander T cell expansion by suppressing cholesterol biosynthesis via secreted 25-hydroxycholesterol.