Search

MCL, Mincle and Dectin‐2 are C‐type lectin receptors expressed by subsets of myeloid cells, and their genes cluster together in the APLEC/Dectin‐2 gene complex. We have previously shown that MCL and Mincle form a heterodimer in the rat, and others have shown that MCL and Dectin‐2 form a heterodimer in the mouse. In the rat, Dectin‐2 is a pseudogene, but here, we examine the association of the three receptors in human. In co‐transfection experiments analyzed with flow cytometry and immunoprecipitation, we here show that human MCL and Mincle form a disulphide‐linked heterodimer that associates with the signalling adaptor molecule FcεRIγ, in accordance with our previous findings in the rat. In contrast to previous findings in the rat, data in this paper indicate a direct association of MCL with FcεRIγ, as previously shown for mouse MCL. We were unable to demonstrate the formation of a heterodimer between human MCL and Dectin‐2. Thus, despite similarities, there may be important differences in the conformation of these receptors between rat, mouse and human, and this may have functional consequences. [ABSTRACT FROM AUTHOR]

The first ideas leading to The Two‐Signal Model of lymphocyte activation were published 50 years ago, but the model was not realized in one sitting. I describe the three phases that led to its contemporary formulations. A motivation underlying all these models was to generate a minimal description of what is required for antigen to inactivate and activate mature lymphocytes that, at the same time, accounts for how peripheral tolerance is achieved. I suggest the two signal model has not only provided a substantiated framework for understanding how antigen interacts differently with B cells and CD8 T cells, to result in their inactivation and activation, but its postulates are pertinent to contemporary issues concerning the inactivation and activation of CD4 T cells. [ABSTRACT FROM AUTHOR]

Psoriasis is an inflammatory disease that arises in genetically predisposed individuals. Chronic skin lesions that contain activated immune cells can persist for years. Systemic inhibition of TNF, IL‐17 and IL‐23 cytokines has revolutionized psoriasis care during the recent decades. Unfortunately, local relapse of disease is common at previously inflamed sites after cessation of treatment. This highlights that fundamental pathologic alterations of the affected tissues are not completely resolved during clinical remission. Here, we present arguments for a local disease memory located in both dermis and epidermis in psoriasis skin. We decipher different cellular components and intercellular crosstalk that sustain local disease memory and amplify disease relapse in human psoriasis. Decrypting the mechanisms underlying the establishment and persistence of pathogenic memory cells in resolved psoriasis may provide new therapeutic perspectives aimed at long‐term remission of psoriasis. [ABSTRACT FROM AUTHOR]

Osteoclasts are responsible for bone destruction in rheumatoid arthritis (RA), and adipose‐derived mesenchymal stromal cells (ADSCs) can inhibit experimental collagen‐induced arthritis model. This study aims to determine whether ADSCs also suppresses osteoclastogenesis and bone erosion in collagen‐induced arthritis (CIA). Osteoclasts were induced from bone marrow‐derived CD11b+ cells with receptor activator of nuclear factor‐κ B ligand (RANKL) and macrophage colony‐stimulating factor (M‐CSF) stimulation and assessed with tartrate‐resistant acid phosphatase (TRAP) staining. For human cells, osteoclasts were produced from human CD14+ cells. ADSCs were generated and added to cultures with different ratios with CD11b+ cells. Transwell and antibody blockade experiments were performed to define the mechanism of action. NF‐κB and RANKL expression were determined by Western blotting and RT‐qPCR. About 2 × 106 ADSCs or fibroblast cells were adoptively transferred to DBA1/J mice on day 14 after immunization with type II collagen/complete Freund's adjuvant (CII/CFA) while the onset and severity of the CIA were monitored. Adipose‐derived mesenchymal stromal cells but not fibroblast cells completely suppressed osteoclastogenesis in vitro for human and mice. ADSCs injected after immunization and before of onset of CIA significantly suppressed disease development. Treatment with ADSCs dramatically decreased the levels of NF‐κB p65/p50 in osteoclasts in vitro and P65/50 and RANKL expression by synovial tissues in vivo. We have demonstrated that ADSCs can inhibit RANKL‐induced osteoclasts genesis via CD39 signals. Our findings also suggest that ADSCs can inhibit osteoclasts genesis without the involvement of regulatory T cells. ADSCs might represent a promising strategy for stem cell‐based therapies for RA. Thus, manipulation of ADSCs may have therapeutic effects on RA and other bone erosion–related diseases. [ABSTRACT FROM AUTHOR]

To understand functional role of PD‐1‐expressing MAIT cells during tuberculosis infection in humans, sorted PD‐1+ and PD‐1− MAIT cells from pleural effusions of patients with pleural tuberculosis were subjected to transcriptome sequencing. PD‐1‐expressing MAIT cells were analysed by flow cytometry and their phenotypic and functional features were investigated. Transcriptome sequencing identified 144 genes that were differentially expressed between PD‐1+ and PD‐1− MAIT cells from tuberculous pleural effusions and CXCL13 was the gene with highest fold difference. The level of PD‐1‐expressing MAIT cells was associated with extent of TB infection in humans. PD‐1‐expressing MAIT cells had increased production of CXCL13 and IL‐21 as determined by flow cytometry. PD‐1highCXCR5− MAIT cells were significantly expanded in pleural effusions from patients with pleural tuberculosis as compared with those from peripheral blood of both patients with tuberculosis and healthy controls. Although PD‐1highCXCR5− MAIT cells from tuberculous pleural effusions had reduced IFN‐γ level and increased expression of Tim‐3 and GITR, they showed activated phenotype and had higher glucose uptake and lipid content. It is concluded that PD‐1‐expressing MAIT cells had reduced IFN‐γ level but increased production of both CXCL13 and IL‐21. [ABSTRACT FROM AUTHOR]

Abstract: Mast cells play a central role in inflammatory and allergic reactions by releasing inflammatory mediators through 2 main pathways, immunoglobulin E‐dependent and E‐independent activation. In the latter pathway, mast cells are activated by a diverse range of basic molecules (collectively known as basic secretagogues) through Mas‐related G protein‐coupled receptors (MRGPRs). In addition to the known basic secretagogues, here, we discovered several endogenous protein and enzyme fragments (such as chaperonin‐10 fragment) that act as bioactive peptides and induce immunoglobulin E‐independent mast cell activation via MRGPRX2 (previously known as MrgX2), leading to the degranulation of mast cells. We discuss the possibility that MRGPRX2 responds various as‐yet‐unidentified endogenous ligands that have specific characteristics, and propose that MRGPRX2 plays an important role in regulating inflammatory responses to endogenous harmful stimuli, such as protein breakdown products released from damaged or dying cells. [ABSTRACT FROM AUTHOR]