- Immune landscape of hepatocellular carcinoma microenvironment: implications for prognosis and therapeutic applications. [Journal Article]
- LILiver Int 2019 Jul 17
- The development of immunotherapy for solid tumors has boosted interest in the contexture of tumor immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumor c…
The development of immunotherapy for solid tumors has boosted interest in the contexture of tumor immune microenvironment (TIME). Several lines of evidence indicate that the interplay between tumor cells and TIME components is a key factor for the evolution of hepatocellular carcinoma (HCC) and for the likelihood of response to immunotherapeutics. The availability of high-resolution methods will be instrumental for a better definition of the complexity and diversity of TIME with the aim of predicting disease outcome, treatment response, and possibly new therapeutic targets. Here we review current knowledge about the immunological mechanisms involved in shaping the clinical course of HCC. Effector cells, regulatory cells and soluble mediators are discussed for their role defining TIME and as targets for immune modulation, together with possible immune signatures for optimization of immunotherapeutic strategies. This article is protected by copyright. All rights reserved.
- The Edwardsiella piscicida thioredoxin-like protein inhibits ASK1-MAPKs signaling cascades to promote pathogenesis during infection. [Journal Article]
- PPPLoS Pathog 2019; 15(7):e1007917
- It is important that bacterium can coordinately deliver several effectors into host cells to disturb the cellular progress during infection, however, the precise role of effectors in host cell cytoso…
It is important that bacterium can coordinately deliver several effectors into host cells to disturb the cellular progress during infection, however, the precise role of effectors in host cell cytosol remains to be resolved. In this study, we identified a new bacterial virulence effector from pathogenic Edwardsiella piscicida, which presents conserved crystal structure to thioredoxin family members and is defined as a thioredoxin-like protein (Trxlp). Unlike the classical bacterial thioredoxins, Trxlp can be translocated into host cells, mimicking endogenous thioredoxin to abrogate ASK1 homophilic interaction and phosphorylation, then suppressing the phosphorylation of downstream Erk1/2- and p38-MAPK signaling cascades. Moreover, Trxlp-mediated inhibition of ASK1-Erk/p38-MAPK axis promotes the pathogenesis of E. piscicida in zebrafish larvae infection model. Taken together, these data provide insights into the mechanism underlying the bacterial thioredoxin as a virulence effector in downmodulating the innate immune responses during E. piscicida infection.
- A predicted Francisella tularensis DXD-motif glycosyltransferase blocks immune activation. [Journal Article]
- VVirulence 2019; 10(1):643-656
- Pathogens enhance their survival during infections by manipulating host defenses. Francisella tularensis evades innate immune responses, which we have found to be dependent on an understudied gene yb…
Pathogens enhance their survival during infections by manipulating host defenses. Francisella tularensis evades innate immune responses, which we have found to be dependent on an understudied gene ybeX (FTL_0883/FTT_0615c). To understand the function of YbeX, we sought protein interactors in F. tularensis subsp. holarctica live vaccine strain (LVS). An unstudied Francisella protein co-immunoprecipitated with recombinant YbeX, which is a predicted glycosyltransferase with a DXD-motif. There are up to four genomic copies of this gene with identical sequence in strains of F. tularensis pathogenic to humans, despite ongoing genome decay. Disruption mutations were generated by intron insertion into all three copies of this glycosyltransferase domain containing gene in LVS, gdcA1-3. The resulting strains stimulated more cytokines from macrophages in vitro than wild-type LVS and were attenuated in two in vivo infection models. GdcA was released from LVS during culture and was sufficient to block NF-κB activation when expressed in eukaryotic cells. When co-expressed in zebrafish, GdcA and YbeX were synergistically lethal to embryo development. Glycosyltransferases with DXD-motifs are found in a variety of pathogens including NleB, an Escherichia coli type-III secretion system effector that inhibits NF-κB by antagonizing death receptor signaling. To our knowledge, GdcA is the first DXD-motif glycosyltransferase that inhibits NF-κB in immune cells. Together, these findings suggest DXD-motif glycosyltransferases may be a conserved virulence mechanism used by pathogenic bacteria to remodel host defenses.
- The evolving role of cytoreductive nephrectomy: incorporating genomics of metastatic renal cell carcinoma into treatment decisions. [Journal Article]
- COCurr Opin Urol 2019 Jul 15
- CONCLUSIONS: Genetic alterations may help select patients for cytoreductive nephrectomy and optimize timing of treatment. Intratumor heterogeneity and genetic discordance between primary and metastatic tumors may limit clinical applicability. Future studies should evaluate approaches to overcome these limitations.
- Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes. [Journal Article]
- JLJ Leukoc Biol 2019 Jul 16
- Alterations in the composition of the intestinal microbiota have been associated with development of type 1 diabetes (T1D), but little is known about changes in intestinal homeostasis that contribute…
Alterations in the composition of the intestinal microbiota have been associated with development of type 1 diabetes (T1D), but little is known about changes in intestinal homeostasis that contribute to disease pathogenesis. Here, we analyzed oral tolerance induction, components of the intestinal barrier, fecal microbiota, and immune cell phenotypes in non-obese diabetic (NOD) mice during disease progression compared to non-obese diabetes resistant (NOR) mice. NOD mice failed to develop oral tolerance and had defective protective/regulatory mechanisms in the intestinal mucosa, including decreased numbers of goblet cells, diminished mucus production, and lower levels of total and bacteria-bound secretory IgA, as well as an altered IEL profile. These disturbances correlated with bacteria translocation to the pancreatic lymph node possibly contributing to T1D onset. The composition of the fecal microbiota was altered in pre-diabetic NOD mice, and cross-fostering of NOD mice by NOR mothers corrected their defect in mucus production, indicating a role for NOD microbiota in gut barrier dysfunction. NOD mice had a reduction of CD103+ dendritic cells (DCs) in the MLNs, together with an increase of effector Th17 cells and ILC3, as well as a decrease of Th2 cells, ILC2, and Treg cells in the small intestine. Importantly, most of these gut alterations precede the onset of insulitis. Disorders in the intestinal mucosa of NOD mice can potentially interfere with the development of T1D due the close relationship between the gut and the pancreas. Understanding these early alterations is important for the design of novel therapeutic strategies for T1D prevention.
- Inhibition of KHSRP sensitizes colorectal cancer to 5-fluoruracil through miR-501-5p-mediated ERRFI1 mRNA degradation. [Journal Article]
- JCJ Cell Physiol 2019 Jul 16
- K-homology (KH)-type splicing regulatory protein (KHSRP) is an RNA binding protein that participates in RNA variable splicing and stability, and facilitates the biogenesis of miRNAs that target mRNA.…
K-homology (KH)-type splicing regulatory protein (KHSRP) is an RNA binding protein that participates in RNA variable splicing and stability, and facilitates the biogenesis of miRNAs that target mRNA. However, to date, the role of KHSRP in colorectal cancer (CRC) progression has not been reported. In this study, the function of KHSRP in CRC proliferation and 5-fluoruracil (5-FU) resistance was investigated. The upregulation of KHSRP expression was confirmed in CRC patient tissues and two CRC cell lines. Manipulating KHSRP expression altered cell proliferation and 5-FU resistance in CRC cells. ERRFI1, a downstream effector of KHSRP in CRC cells, reduced CRC cell proliferation. Sensitivity to 5-FU mediated by KHSRP knockdown was reversed by ERRFI1 knockdown. We found that KHSRP decreased ERRFI1 mRNA expression indirectly. By screening KHSRP-regulated miRNAs, we further found that miR-501-5p directly combines with KHSRP in CRC cells. Mechanistically, the results of a luciferase assay suggested that miR-501-5p directly binds to the ERRFI1 3'-untranslated region. Taken together, our data indicated that modification of ERRFI1 by KHSRP occurs through miR-501-5p, an essential mechanism driving CRC proliferation and 5-FU resistance. Insight into this mechanism may provide novel targets for overcoming drug resistance in CRC.
- Assessment of CD40 and CD40L expression in rheumatoid arthritis patients, association with clinical features and DAS28. [Journal Article]
- CEClin Exp Med 2019 Jul 16
- The predominance of the effector mechanisms by CD4 + T cells is a characteristic of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). The CD40/CD40L costimulatory pathway contribute…
The predominance of the effector mechanisms by CD4 + T cells is a characteristic of inflammatory autoimmune diseases such as rheumatoid arthritis (RA). The CD40/CD40L costimulatory pathway contributes to these pathogenic mechanisms by promoting autoantibody production and inflammation. Aberrant expression of CD40 and CD40L in RA patients has been shown, the latter prevailing in females. However, contrasting results have emerged regarding the clinical associations of these findings. We determined the association of CD40 and CD40L expression with the clinical activity evaluated through DAS28 in RA patients. A total of 38 female RA patients and 10 age- and sex-matched control subjects were included. CD40 and CD40L mRNA expression was quantified by real-time qPCR, cell surface proteins were determined by flow cytometry, and protein soluble forms were determined by ELISA. The expansion of a CD4 + T cell subpopulation expressing CD40 was identified in the RA group. In addition, high frequencies of CD4 + CD40L + T cells expressing high levels of CD40L, increased levels of sCD40L and overexpression of CD40L mRNA were observed in these patients. Moreover, there was a gradual increase in CD40L when data were stratified according to DAS28, except for very active patients. No correlation was observed between the levels of mRNA, cell surface protein and soluble protein of CD40 and CD40L with the clinical features of RA patients. There is an altered expression of CD40L in female RA patients in association with clinical activity assessed by DAS28, these findings support the evidence that suggests CD40L as a marker of clinical activity.
- Interferon beta increases NK cell cytotoxicity against tumor cells in patients with nasopharyngeal carcinoma via tumor necrosis factor apoptosis-inducing ligand. [Journal Article]
- CICancer Immunol Immunother 2019 Jul 16
- CONCLUSIONS: Increased cytotoxicity of NK cells against NPC cells and increased serum levels of biologically active TRAIL in patients treated with IFNβ could be a means to eliminate micrometastatic disease and explain the low systemic relapse rate in this patient group.
- Sclerostin domain-containing protein 1 is dispensable for the differentiation of follicular helper and follicular regulatory T cells during acute viral infection. [Journal Article]
- AJAm J Transl Res 2019; 11(6):3722-3736
- T follicular helper (TFH) cells are crucial for effective humoral immunity by providing the required signals to cognate B cells and promoting germinal center (GC) formation. Many intrinsic and extrin…
T follicular helper (TFH) cells are crucial for effective humoral immunity by providing the required signals to cognate B cells and promoting germinal center (GC) formation. Many intrinsic and extrinsic factors have been reported to be involved in the multistage, multifactorial differentiation process of TFH cells. By comparing gene expression between TFH cells and TH1 cells based on published GEO data, we found selective and high expression of sclerostin domain-containing protein 1 (SOSTDC1) in TFH cells but not in TH1 cells; however, it is unclear whether SOSTDC1 is important for the differentiation and/or function of TFH cells. Using a mouse model of acute lymphocytic choriomeningitis virus (LCMV) infection, we confirmed the selective expression of SOSTDC1 in TFH cells compared to that in TH1 cells, but the ablation of SOSTDC1 did not affect TFH cell differentiation or effector function. Thus, our results indicate that the SOSTDC1 protein is merely a specific marker of TFH cells but does not play a functional role in the differentiation of TFH cells during acute viral infection.
New Search Next
- Recalling the Future: Immunological Memory Toward Unpredictable Influenza Viruses. [Review]
- FIFront Immunol 2019; 10:1400
- Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protectiv…
Persistent and durable immunological memory forms the basis of any successful vaccination protocol. Generation of pre-existing memory B cell and T cell pools is thus the key for maintaining protective immunity to seasonal, pandemic and avian influenza viruses. Long-lived antibody secreting cells (ASCs) are responsible for maintaining antibody levels in peripheral blood. Generated with CD4+ T help after naïve B cell precursors encounter their cognate antigen, the linked processes of differentiation (including Ig class switching) and proliferation also give rise to memory B cells, which then can change rapidly to ASC status after subsequent influenza encounters. Given that influenza viruses evolve rapidly as a consequence of antibody-driven mutational change (antigenic drift), the current influenza vaccines need to be reformulated frequently and annual vaccination is recommended. Without that process of regular renewal, they provide little protection against "drifted" (particularly H3N2) variants and are mainly ineffective when a novel pandemic (2009 A/H1N1 "swine" flu) strain suddenly emerges. Such limitation of antibody-mediated protection might be circumvented, at least in part, by adding a novel vaccine component that promotes cross-reactive CD8+ T cells specific for conserved viral peptides, presented by widely distributed HLA types. Such "memory" cytotoxic T lymphocytes (CTLs) can rapidly be recalled to CTL effector status. Here, we review how B cells and follicular T cells are elicited following influenza vaccination and how they survive into a long-term memory. We describe how CD8+ CTL memory is established following influenza virus infection, and how a robust CTL recall response can lead to more rapid virus elimination by destroying virus-infected cells, and recovery. Exploiting long-term, cross-reactive CTL against the continuously evolving and unpredictable influenza viruses provides a possible mechanism for preventing a disastrous pandemic comparable to the 1918-1919 H1N1 "Spanish flu," which killed more than 50 million people worldwide.