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Periodontal disease has been reported to be associated with diabetes mellitus. However, the direction of the association and the influence of bias are not clear. Thus, the aim of this systematic review and meta-analysis was to summarize the existing evidence on the bidirectional prospective association between periodontal disease and diabetes mellitus by accounting for the risk of bias of the original studies. The literature search was conducted on the electronic data sources PubMed and Web of Science up to February 9th, 2021. We included observational studies, which investigated the prospective association between diabetes mellitus and periodontal disease or vice versa. The risk of bias of the primary studies was evaluated by applying the Quality in Prognosis Studies (QUIPS) tool. Random effects models were used to calculate summary relative risk (SRR) with 95% CI. Subgroup analyses were applied to investigate heterogeneity and the robustness of the finding. In total, 15 studies were included . The SRR for incident diabetes mellitus was 1.26 (95% CI 1.12, 1.41; I2: 71%, n = 10; participants = 427,620; identified cases = 114,361), when comparing individuals with periodontitis to individuals without periodontitis. The SRR for incident periodontitis was 1.24 (95% CI 1.13, 1.37; I2: 92%, n = 7; participants = 295,804; identified cases: > 22,500), comparing individuals with diabetes to individuals without diabetes. There were no significant differences between subgroups after stratification for risk of bias. The findings show a positive bidirectional association between periodontal disease and diabetes mellitus, and thus, underline the need for screening of patients with periodontitis regarding diabetes mellitus and vice versa. The main limitation of the study is the high unexplained heterogeneity between the studies including the different assessment methods of the disease diagnosis.

Autoimmune diseases develop when autoantigens activate previously quiescent self-reactive lymphocytes. Gene–gene interaction between certain HLA class I risk alleles and variants of the endoplasmic reticulum aminopeptidase ERAP1 controls the risk for common immune-mediated diseases, including psoriasis, ankylosing spondylitis, and Behçet disease. The functional mechanisms underlying this statistical association are unknown. In psoriasis, HLA-C*06:02 mediates an autoimmune response against melanocytes by autoantigen presentation. Using various genetically modified cell lines together with an autoreactive psoriatic TCR in a TCR activation assay, we demonstrate in this study that in psoriasis, ERAP1 generates the causative melanocyte autoantigen through trimming N-terminal elongated peptide precursors to the appropriate length for presentation by HLA-C*06:02. An ERAP1 risk haplotype for psoriasis produced the autoantigen much more efficiently and increased HLA-C expression and stimulation of the psoriatic TCR by melanocytes significantly more than a protective haplotype. Compared with the overall HLA class I molecules, cell surface expression of HLA-C decreased significantly more upon ERAP1 knockout. The combined upregulation of ERAP1 and HLA-C on melanocytes in psoriasis lesions emphasizes the pathogenic relevance of their interaction in patients. We conclude that in psoriasis pathogenesis, the increased generation of an ERAP1-dependent autoantigen by an ERAP1 risk haplotype enhances the likelihood that autoantigen presentation by HLA-C*06:02 will exceed the threshold for activation of potentially autoreactive T cells, thereby triggering CD8+ T cell–mediated autoimmune disease. These data identify ERAP1 function as a central checkpoint and promising therapeutic target in psoriasis and possibly other HLA class I–associated diseases with a similar genetic predisposition.

Arakawa et al. discovered that the autoimmune response in psoriasis is directed against melanocytes. They show that the main psoriasis risk allele HLA-C*06:02 mediates melanocyte-specific autoimmunity and identify ADAMTSL5 as a melanocyte autoantigen, which stimulates IL-17 and IFN-γ production in CD8+ T cells., Psoriasis vulgaris is a common T cell–mediated inflammatory skin disease with a suspected autoimmune pathogenesis. The human leukocyte antigen (HLA) class I allele, HLA-C*06:02, is the main psoriasis risk gene. Epidermal CD8+ T cells are essential for psoriasis development. Functional implications of HLA-C*06:02 and mechanisms of lesional T cell activation in psoriasis, however, remained elusive. Here we identify melanocytes as skin-specific target cells of an HLA-C*06:02–restricted psoriatic T cell response. We found that a Vα3S1/Vβ13S1 T cell receptor (TCR), which we had reconstituted from an epidermal CD8+ T cell clone of an HLA-C*06:02–positive psoriasis patient specifically recognizes HLA-C*06:02–positive melanocytes. Through peptide library screening, we identified ADAMTS-like protein 5 (ADAMTSL5) as an HLA-C*06:02–presented melanocytic autoantigen of the Vα3S1/Vβ13S1 TCR. Consistent with the Vα3S1/Vβ13S1-TCR reactivity, we observed numerous CD8+ T cells in psoriasis lesions attacking melanocytes, the only epidermal cells expressing ADAMTSL5. Furthermore, ADAMTSL5 stimulation induced the psoriasis signature cytokine, IL-17A, in CD8+ T cells from psoriasis patients only, supporting a role as psoriatic autoantigen. This unbiased analysis of a TCR obtained directly from tissue-infiltrating CD8+ T cells reveals that in psoriasis HLA-C*06:02 directs an autoimmune response against melanocytes through autoantigen presentation. We propose that HLA-C*06:02 may predispose to psoriasis via this newly identified autoimmune pathway.

Nintedanib is a triple angiokinase inhibitor approved with docetaxel for adenocarcinoma non-small cell lung cancer after first-line chemotherapy (FLT). In the phase III LUME-Lung 1 study, overall survival (OS) was significantly longer with nintedanib/docetaxel than with placebo/docetaxel in all adenocarcinoma patients and those with time from start of FLT (TSFLT)

Argonaute (Ago) proteins interact with small regulatory RNAs such as microRNAs (miRNAs) and facilitate gene-silencing processes. miRNAs guide Ago proteins to specific mRNAs leading to translational silencing or mRNA decay. In order to understand the mechanistic details of miRNA function, it is important to characterize Ago protein interactors. Although several proteomic studies have been performed, it is not clear how the Ago interactome changes on miRNA or mRNA binding. Here, we report the analysis of Ago protein interactions in miRNA-containing and miRNA-depleted cells. Using stable isotope labeling in cell culture in conjunction with Dicer knock out mouse embryonic fibroblasts, we identify proteins that interact with Ago2 in the presence or the absence of Dicer. In contrast to our current view, we find that Ago-mRNA interactions can also take place in the absence of miRNAs. Our proteomics approach provides a rich resource for further functional studies on the cellular roles of Ago proteins.