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Löfgren’s syndrome is an acute form of sarcoidosis that is characterized by the activation of CD4+ T helper cells. In this issue of JEM, Greaves et al. (2021. J. Exp. Med.https://doi.org/10.1084/jem.20210785) identified a peptide derived from an airborne mold species that stimulates T cells of Löfgren’s syndrome patients in an HLA-DR3–restricted manner. An increased serum IgG antibody response to the full-length protein was also observed in those patients, indicating that the fungus Aspergillus nidulans might be the elusive microbial agent that drives acute sarcoidosis.

Introduction: Sarcoidosis is a systemic granulomatous disease of unknown etiology mostly affecting lungs and lymph nodes. Previous whole-exome sequencing (WES) studies have shown that autophagy and especially Ras-related C3 botulinum toxin substrate 1 (RAC1) and mammalian target of rapamycin (mTOR) pathways were possibly implicated in sarcoidosis (Pacheco et al. Trends Immunol 2020 Accepted manuscript). Aims: The SARCFAM (familial sarcoidosis) cohort gathered families aggregating sarcoidosis cases. We hypothesized that relevant genes variants in patients with sarcoidosis and uveitis phenotype were also related to autophagy. Methods: A WES study was performed on 20 patients in 6 families out of the SARCFAM cohort compared with 10 internal controls among siblings. 2 genomic subtractions were performed to compare uveitis and sarcoidosis phenotype to sarcoidosis without uveitis phenotype and to healthy controls. Results: 4 of the 20 patients presented uveitis phenotype. In 3 different families, 38, 142 and 104 variants concerning autophagy were found and respectively 12, 40 and 34 were associated with the uveitis clinical phenotype. Most relevant genes were NOD2, UNC93B, NLRP14, UBQLNL and those related to Toll-like receptors (TLR5). All genes were shown to be related to autophagy/mTOR/RAC1 pathways. NLRP14/NOD2 polymorphisms were respectively found to be related to Behcet uveitis and Blau syndrome. These proteins are targets for various environmental antigens (viruses, mycobacteria) suggesting imbrication of genetic predisposition and environmental triggers. Conclusion: Autophagy could be a major key point in the pathophysiology of sarcoidosis and mTOR may represent an interesting target to treat sarcoidosis.

Sarcoidosis is an enigmatic multisystem disease characterized by the development and accumulation of granulomas: a compact collection of macrophages that have differentiated into epithelioid cells and which are associated with T helper (Th)1 and Th17 cells. Although no single causative factor has been shown to underlie sarcoidosis in humans, its etiology has been related to microbial, environmental, and genetic factors. We examine how these factors play a role in sarcoidosis pathogenesis. Specifically, we propose that dysfunction of mTOR, Rac1, and autophagy-related pathways not only hampers pathogen or nonorganic particle clearance but also participates in T cell and macrophage dysfunction, driving granuloma formation. This concept opens new avenues for potentially treating sarcoidosis and may serve as a blueprint for other granulomatous disorders.

Background Sarcoidosis (OMIM 181000) is a multi-systemic granulomatous disorder of unknown origin. Despite multiple genome-wide association (GWAS) studies, no major pathogenic pathways have been identified to date. To find out relevant sarcoidosis predisposing genes, we searched for de novo and recessive mutations in 3 young probands with sarcoidosis and their healthy parents using a whole-exome sequencing (WES) methodology. Methods From the SARCFAM project based on a national network collecting familial cases of sarcoidosis, we selected three families (trios) in which a child, despite healthy parents, develop the disease before age 15 yr. Each trio was genotyped by WES (Illumina HiSEQ 2500) and we selected the gene variants segregating as 1) new mutations only occurring in affected children and 2) as recessive traits transmitted from each parents. The identified coding variants were compared between the three families. Allelic frequencies and in silico functional results were analyzed using ExAC, SIFT and Polyphenv2 databases. The clinical and genetic studies were registered by the ClinicalTrials.gov - Protocol Registration and Results System (PRS) (https://clinicaltrials.gov) receipt under the reference NCT02829853 and has been approved by the ethical committee (CPP LYON SUD EST – 2 – REF IRB 00009118 – September 21, 2016). Results We identified 37 genes sharing coding variants occurring either as recessive mutations in at least 2 trios or de novo mutations in one of the three affected children. The genes were classified according to their potential roles in immunity related pathways: 9 to autophagy and intracellular trafficking, 6 to G-proteins regulation, 4 to T-cell activation, 4 to cell cycle and immune synapse, 2 to innate immunity. Ten of the 37 genes were studied in a bibliographic way to evaluate the functional link with sarcoidosis. Conclusions Whole exome analysis of case-parent trios is useful for the identification of genes predisposing to complex genetic diseases as sarcoidosis. Our data identified 37 genes that could be putatively linked to a pediatric form of sarcoidosis in three trios. Our in-depth focus on 10 of these 37 genes may suggest that the formation of the characteristic lesion in sarcoidosis, granuloma, results from combined deficits in autophagy and intracellular trafficking (ex: Sec16A, AP5B1 and RREB1), G-proteins regulation (ex: OBSCN, CTTND2 and DNAH11), T-cell activation (ex: IDO2, IGSF3), mitosis and/or immune synapse (ex: SPICE1 and KNL1). The significance of these findings needs to be confirmed by functional tests on selected gene variants. Electronic supplementary material The online version of this article (10.1186/s12920-018-0338-x) contains supplementary material, which is available to authorized users.

Sarcoidosis is a multifactorial disease induced by environmental and genetic factors. Whole exome sequencing in 5 familial cases of the disease suggest that genetic defects in Rac1 and mTor functional hubs may be relevant to sarcoidosis pathogenesis. http://bit.ly/2xooHx3

Summary: DC-SIGN+ monocyte-derived dendritic cells (mo-DCs) play important roles in bacterial infections and inflammatory diseases, but the factors regulating their differentiation and proinflammatory status remain poorly defined. Here, we identify a microRNA, miR-181a, and a molecular mechanism that simultaneously regulate the acquisition of DC-SIGN expression and the activation state of DC-SIGN+ mo-DCs. Specifically, we show that miR-181a promotes DC-SIGN expression during terminal mo-DC differentiation and limits its sensitivity and responsiveness to TLR triggering and CD40 ligation. Mechanistically, miR-181a sustains ERK-MAPK signaling in mo-DCs, thereby enabling the maintenance of high levels of DC-SIGN and a high activation threshold. Low miR-181a levels during mo-DC differentiation, induced by inflammatory signals, do not support the high phospho-ERK signal transduction required for DC-SIGNhi mo-DCs and lead to development of proinflammatory DC-SIGNlo/− mo-DCs. Collectively, our study demonstrates that high DC-SIGN expression levels and a high activation threshold in mo-DCs are linked and simultaneously maintained by miR-181a. : DC-SIGN+ mo-DCs play important roles in bacterial infections and inflammatory diseases, but the factors regulating differentiation and activation remain poorly defined. Lim et al. show that miR-181a simultaneously fine-tunes DC-SIGN+ mo-DC differentiation/activation by promoting ERK-MAPK signaling, which sustains DC-SIGN expression and limits its responsiveness to TLR4 triggering and inflammatory stimuli. Keywords: DC-SIGN, inflammation, monocyte-derived, mo-DC, ulcerative colitis, DC-SIGN+ mo-DC, miR-181a, terminal mo-DC differentiation