Journal of mucosal immunology research最新文献

Immune cell infiltration into tumors, intratumoral cellular organization, and the cell-specific expression patterns of chemokines and chemokine receptors greatly influence the efficacy of immunotherapeutic treatment strategies. In our recent review article, we shined a light on the deciding role of the chemokine network between immune mediated tumor regression or immune evasion of the tumor. Current T cell centric immunotherapeutic strategies primarily rely on increasing cellular activation and decreasing cellular inhibition, with the overall goal of enhancing effector cell function. These strategies neglect to account for the presence of the T cells within the tumor, hardly boosting immune cell infiltration. Chemokines and chemokine receptors are the regulators of recruitment, migration, and intratumoral compartmentalization. Yet, utilizing the chemokine network to recruit immune cells that will drive tumor regression is not a straightforward path, as tumor cells often hijack these pathways in the effort of immune evasion. Many novel therapeutic strategies involving chemokine targeting are under trial for many diverse tumor types. As a field, we can learn from both the successes and failures of these trials in order to push forward the next generation of immunotherapeutic strategies that include augmented T cell trafficking.

ELL2 was previously discovered as a member of the Super Elongation Complex. It is involved in driving the maturation of B cells to plasma cells through shifting patterns of RNA processing, favoring generation of the secretory form of heavy chain immunoglobulin (IgH) associated with plasma cells. ELL2 influences the expression and splicing patterns of more than 4,000 genes in antibody secreting cells. The ELL2 gene has been implicated in cancers such as multiple myeloma and salivary gland carcinoma. A member of the ELL family (ELL1) was recently proven to act as an E3 ubiquitin ligase to known proto-oncogene, c-Myc, through a highly conserved cysteine residue in the C-terminal CEYLH region. Comparison of sequence homology shows this region is conserved between the three members of the ELL family, leading us to hypothesize that the other two ELLs (2 and 3) could serve the same role. In this review, we summarize what is known about ELL2 with respect to its role in driving B cell to plasma cell differentiation as well as its potential role in tumor suppression.

A significant amount of correlational evidence has linked increased levels of IL-18 with allergic diseases in both human and animal models, and, as mast cells are major mediators of allergies, we hypothesized that IL-18 may have a role in mast cell biology. Rationale for our hypothesis is based on the evidence that IL-3 deficient mice are not devoid of mast cells, even though IL-3 is a major differentiation and growth factor for mast cells. Accordingly, we cultured IL-18 responsive bone marrow CD34+ cells in vitro under a variety of conditions and cytokine combinations to examine mast cell differentiation and maturation using flow cytometry, quantitative PCR,and immunostaining techniques. Additionally, in vivo mast cell transformation and maturation were also analysed using endogenous IL-18 gene-deficient or Fabpi-IL-18 overexpressed mice. Our data indicate that both IL-3 and IL-18 exposed CD34+ bone marrow precursors differentiate and mature into mast cells. Further, we observed that IL-18 differentiates mast cells independent of IL-3, as pharmacologic blockade of IL-3 does not prevent in vitro IL-18-driven mast cell differentiation. Further, we found that endogenous IL-18 deficiency restricts maturation of IL-3 generated mast cells and IL-18 derived mast cells require IL-3 for their survival. Additionally, we observed IL-18 intestinal overexpression promotes tissue mast cell proliferation and mucosal mast cell development. Taken together, we provide the evidence that IL-18 has an important contributory role in mast cell differentiation, maturation and in vivo development of mucosal mast cells. Therefore, IL-18 may represent a future pharmacologic target for treating mast cell-mediated allergic diseases.

CXCR3 is a chemokine receptor expressed on a wide range of leukocytes, and it is involved in leukocyte migration throughout the blood and lymphatics. Specifically, CXCR3 is required for lymphocyte homing to the genital mucosa. When compared to wild type (WT) mice, CXCR3 deficiency (CXCR3-/-) mice infected with Chlamydia muridarum (C. muridarum) did not display impaired clearance and resolution of infection. However, they possessed significantly higher bacterial burden and lower levels of IFN-γ-producing TH1 cells. The knockouts also demonstrated a significant decrease in the level of activated conventional dendritic cells in the GT, ultimately leading to the decrease in activated TH1 cells. In addition, few activated plasmacytoid dendritic cells, which possess an inflammatory phenotype, were found in the lymph node of infected mice. This reduction in pDCs may be responsible for the decrease in neutrophils, which are acute inflammatory cells, in the CXCR3-/- mice. Due to the significantly reduced level of acute inflammation, these mice also possess a decrease in dilation and pathology in the oviduct. This demonstrates that the CXCR3-/- mice possess the ability to clear C. muridarum infections, but they do so without the increased inflammation and pathology in the GT.