IgE-primed mast cells in peripheral tissues, including the skin, lung, and intestine, are key initiators of allergen-triggered edema and inflammation. Particularly in severe forms of allergy, this ...inflammation becomes strongly neutrophil dominated, and yet how mast cells coordinate this type of response is unknown. We and others have reported that activated mast cells--a hematopoietic cell type--can produce IL-33, a cytokine known to participate in allergic responses but generally considered as being of epithelial origin and driving Type 2 immune responses (e.g., ILC2 and eosinophil activation). Using models of skin anaphylaxis, our data reveal that mast cell-derived IL-33 also initiates neutrophilic inflammation. We demonstrate a cellular crosstalk mechanism whereby activated mast cells crosstalk to IL-33 receptor-bearing basophils, driving these basophils to adopt a unique response signature rich in neutrophil-associated molecules. We further establish that basophil expression of CXCL1 is necessary for IgE-driven neutrophilic inflammation. Our findings thus unearth a new mechanism by which mast cells initiate local inflammation after antigen triggering and might explain the complex inflammatory phenotypes observed in severe allergic diseases. Moreover, our findings (i) establish a functional link from IL-33 to neutrophilic inflammation that extends IL-33-mediated biology well beyond that of Type 2 immunity, and (ii) demonstrate the functional importance of hematopoietic cell-derived IL-33 in allergic pathogenesis.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Comparison of sequencing data from a tumor sample with data from a matched germline control is a key step for accurate detection of somatic mutations. Detection sensitivity for somatic variants is ...greatly reduced when the matched normal sample is contaminated with tumor cells. To overcome this limitation, we developed deTiN, a method that estimates the tumor-in-normal (TiN) contamination level and, in cases affected by contamination, improves sensitivity by reclassifying initially discarded variants as somatic.
Abstract
Identifying robust, patient-specific, and predictive biomarkers presents a major obstacle in precision oncology. To optimize patient-specific therapeutic strategies, here we couple pathway ...knowledge with large-scale drug sensitivity, RNAi, and CRISPR-Cas9 screening data from 460 cell lines. Pathway activity levels are found to be strong predictive biomarkers for the essentiality of 15 proteins, including the essentiality of MAD2L1 in breast cancer patients with high BRCA-pathway activity. We also find strong predictive biomarkers for the sensitivity to 31 compounds, including BCL2 and microtubule inhibitors (MTIs). Lastly, we show that Bcl-xL inhibition can modulate the activity of a predictive biomarker pathway and re-sensitize lung cancer cells and tumors to MTI therapy. Overall, our results support the use of pathways in helping to achieve the goal of precision medicine by uncovering dozens of predictive biomarkers.
Multiple myeloma is a plasma cell malignancy almost always preceded by precursor conditions, but low tumor burden of these early stages has hindered the study of their molecular programs through bulk ...sequencing technologies. Here, we generate and analyze single cell RNA-sequencing of plasma cells from 26 patients at varying disease stages and 9 healthy donors. In silico dissection and comparison of normal and transformed plasma cells from the same bone marrow biopsy enables discovery of patient-specific transcriptional changes. Using Non-Negative Matrix Factorization, we discover 15 gene expression signatures which represent transcriptional modules relevant to myeloma biology, and identify a signature that is uniformly lost in abnormal cells across disease stages. Finally, we demonstrate that tumors contain heterogeneous subpopulations expressing distinct transcriptional patterns. Our findings characterize transcriptomic alterations present at the earliest stages of myeloma, providing insight into the molecular underpinnings of disease initiation.
The role of coinhibition in an immune response is thought to be critical for the contraction of an adaptive immune response in its waning phases. We present evidence that B and T lymphocyte ...attenuator (BTLA) coinhibitory signaling is required to temper early inflammation. Using an in vivo Con A challenge model of acute hepatitis, we observed reduced survival and increased early serum cytokine secretion in BTLA(-/-) mice as compared with wild-type mice. In vitro, liver mononuclear cells from BTLA(-/-) mice are hyperresponsive to anti-CD3, Con A, and alpha-galactosylceramide stimulation and secrete higher levels of TNF-alpha, IFN-gamma, IL-2, and IL-4. We found this was in part due to negative regulation of NKT cells by BTLA, as early cytokine inhibition from whole liver mononuclear cells or purified NKT cells depends upon BTLA signaling. Overall, our data demonstrate that coinhibition is active in early immune responses through BTLA regulation of NKT cells.
Contact sensitivity responses require both effective immune sensitization following cutaneous exposure to chemical haptens and antigen-specific elicitation of inflammation upon subsequent hapten ...challenge. We report that antigen-independent effects of IgE antibodies can promote immune sensitization to haptens in the skin. Contact sensitivity was markedly impaired in IgE
−/− mice but was restored by either transfer of sensitized cells from wild-type mice or administration of hapten-irrelevant IgE before sensitization. Moreover, IgE
−/− mice exhibited impairment in the reduction of dendritic cell numbers in the epidermis after hapten exposure. Monomeric IgE has been reported to influence mast cell function. We observed diminished contact sensitivity in mice lacking FcϵRI or mast cells, and mRNA for several mast cell-associated genes was reduced in IgE
−/− versus wild-type skin after hapten exposure. We speculate that levels of IgE normally present in mice favor immune sensitization via antigen-independent but FcϵRI-dependent effects on mast cells.
LIGHT (homologous to lymphotoxins, inducible expression, competes with herpesvirus glycoprotein D for herpesvirus entry mediator, a receptor expressed on T lymphocytes) is a member of the tumor ...necrosis factor superfamily that contributes to the regulation of immune responses. LIGHT can influence T-cell activation both directly and indirectly by engagement of various receptors that are expressed on T cells and on other types of cells. LIGHT, LIGHT receptors, and their related binding partners constitute a complicated molecular network in the regulation of various processes. The molecular cross-talk among LIGHT and its related molecules presents challenges and opportunities for us to study and to understand the full extent of the LIGHT function. Previous research from genetic and functional studies has demonstrated that dysregulation of LIGHT expression can result in the disturbance of T-cell homeostasis and activation, changing the ability of self-tolerance and of the control of infection. Meanwhile, blockade of LIGHT activity can ameliorate the severity of various T-cell-mediated diseases. These observations indicate the importance of LIGHT and its involvement in many physiological and pathological conditions. Understanding LIGHT interactions offers promising new therapeutic strategies that target LIGHT-engaged pathways to fight against cancer and various infectious diseases.
Coinhibitory pathways are thought to act in later stages of an adaptive immune response, but whether coinhibition contributes to early innate immunity is unclear. We show that engagement of the newly ...discovered coinhibitory receptor B and T lymphocyte attenuator (BTLA) by herpesvirus entry mediator (HVEM) is critical for negatively regulating early host immunity against intracellular bacteria. Both HVEM(-/-) and BTLA(-/-), but not LIGHT(-/-), mice are more resistant to listeriosis compared with wild-type mice, and blockade of the BTLA pathway promotes, while engagement inhibits, early bacterial clearance. Differences in bacterial clearance were seen as early as 1 day postinfection, implicating the initial innate response. Therefore, innate cell function in BTLA(-/-) mice was studied. We show that innate cells from BTLA(-/-) mice secrete significantly more proinflammatory cytokines upon stimulation with heat-killed Listeria. These results provide the first evidence that a coinhibitory pathway plays a critical role in regulating early host innate immunity against infection.
Clonal hematopoiesis results from somatic mutations in cancer driver genes in hematopoietic stem cells. We sought to identify novel drivers of clonal expansion using an unbiased analysis of ...sequencing data from 84,683 persons and identified common mutations in the 5-methylcytosine reader,
, as well as in
,
, and
. We also identified these mutations at low frequency in myelodysplastic syndrome patients.
edited mouse hematopoietic stem and progenitor cells exhibited a competitive advantage
and increased genome-wide intron retention.
mutations potentially link DNA methylation and RNA splicing, the two most commonly mutated pathways in clonal hematopoiesis and MDS.
Receptor-interacting protein (RIP) has been reported to associate with tumor necrosis-associated factor (TRAF)2 and TRAF6. Since TRAF2 and TRAF6 play important roles in CD40 signaling and TRAF6 plays ...an important role in TLR4 signaling, we examined the role of RIP in signaling via CD40 and TLR4. Splenocytes from RIP(-/-) mice proliferated and underwent isotype switching normally in response to anti-CD40-IL-4 but completely failed to do so in response to LPS-IL-4. However, they normally up-regulated TNF-alpha and IL-6 gene expression and CD54 and CD86 surface expression after LPS stimulation. RIP(-/-) splenocytes exhibited increased apoptosis and impaired Akt phosphorylation after LPS stimulation. These results suggest that RIP is essential for cell survival after TLR4 signaling and links TLR4 to the phosphatidylinositol 3 kinase-Akt pathway.
PDF
