Fingolimod Alters Tissue Distribution and Cytokine Production of Human and Murine Innate Lymphoid Cells

Sphingosine-1 phosphate receptor 1 (S1PR1) is expressed by lymphocytes and regulates their egress from secondary lymphoid organs. Innate lymphoid cell (ILC) family has been expanded with the discovery of group 1, 2 and 3 ILCs, namely ILC1, ILC2 and ILC3. ILC3 and ILC1 have remarkable similarity to CD4+ helper T cell lineage members Th17 and Th1, respectively, which are important in the pathology of multiple sclerosis (MS). Whether human ILC subsets express S1PR1 or respond to its ligands have not been studied. In this study, we used peripheral blood/cord blood and tonsil lymphocytes as a source of human ILCs. We show that human ILCs express S1PR1 mRNA and protein and migrate toward S1P receptor ligands. Comparison of peripheral blood ILC numbers between fingolimod-receiving and treatment-free MS patients revealed that, in vivo, ILCs respond to fingolimod, an S1PR1 agonist, resulting in ILC-penia in circulation. Similarly, murine ILCs responded to fingolimod by exiting blood and accumulating in the secondary lymph nodes. Importantly, ex vivo exposure of ILC3 and ILC1 to fingolimod or SEW2871, another S1PR1 antagonist, reduced production of ILC3- and ILC1- associated cytokines GM-CSF, IL-22, IL-17, and IFN-γ, respectively. Surprisingly, despite reduced number of lamina propria-resident ILC3s in the long-term fingolimod-treated mice, ILC3-associated IL-22, IL-17A, GM-CSF and antimicrobial peptides were high in the gut compared to controls, suggesting that its long term use may not compromise mucosal barrier function. To our knowledge, this is the first study to investigate the impact of fingolimod on human ILC subsets in vivo and ex vivo, and provides insight into the impact of long term fingolimod use on ILC populations

Recombinant entomopathogenic agents: a review of biotechnological approaches to pest insect control

Although the use of chemical pesticides has decreased in recent years, it is still a common method of pest control. However, chemical use leads to challenging problems. The harm caused by these chemicals and the length of time that they will remain in the environment is of great concern to the future and safety of humans. Therefore, developing new pest control agents that are safer and environmentally compatible, as well as assuring their widespread use is important. Entomopathogenic agents are microorganisms that play an important role in the biological control of pest insects and are eco-friendly alternatives to chemical control. They consist of viruses (non-cellular organisms), bacteria (prokaryotic organisms), fungi and protists (eukaryotic organisms), and nematodes (multicellular organisms). Genetic modification (recombinant technology) provides potential new methods for developing entomopathogens to manage pests. In this review, we focus on the important roles of recombinant entomopathogens in terms of pest insect control, placing them into perspective with other views to discuss, examine and evaluate the use of entomopathogenic agents in biological control

S1P analogues SEW2871, BAF312 and FTY720 affect human Th17 and Treg generation ex vivo

© 2022 Elsevier B.V.Multiple Sclerosis is an immune-mediated neurodegenerative disease. IL-23-mediated signaling and Th17 cells play critical roles in disease pathogenesis in murine models of disease and humans. Sphingosine 1 phosphate (S1P) regulates migration of several types of immune cells including Th17 cells. S1P analogues (fingolimod (FTY720) and Siponimod (BAF312)) have been approved and currently used for MS treatment. Immunomodulatory roles for FTY720 have been defined, however, how different S1P analogues impact human Th17 and Treg cell generation and cytokine production, and IL-23-mediated signaling have not yet been explored in detail. In the current study, we investigated the effects of S1P receptor 1 (S1P1) specific S1P analogue SEW2871, S1P1 and S1P5 specific BAF312, and non-selective FTY720 on human Th17 and Treg differentiation and IL-23-mediated signaling. All three S1P analogues directly inhibited Th17 cell differentiation ex vivo while increasing Treg differentiation from naive CD4 + T cells. All three S1P analogues suppressed IL-23-mediated STAT4, NF-kB and AKT activation. Lastly, all three S1P analogues also inhibited Dectin-1 expression by both mature and immature monocyte-derived dendritic cells (moDCs) and in turn curdlan-mediated production of IL-23p19, p40, IL-6 and IL-1β cytokines. Our results provide novel insight into the immunomodulatory roles of different S1P analogues on human Th17 and Treg cell biology

Molecular characterization of the chitinase genes of native Bacillus thuringiensis isolates and their antagonistic activity against three important phytopathogenic fungi

Bacillus spp. can promote the growth of plants and reduce plant disease incidence or severity by triggering induced systemic resistance to plant pathogens. In addition, bacteria of this genus are chitinase enzyme producers. Chitinase inhibits the growth of fungi by breaking down the chitin-containing cell wall of plant pathogenic fungi. In this study, 270 native Bacillus spp., isolated from various habitats in Kayseri and Adana, Turkey, were screened by PCR for the chitinase gene and 66 of them were found to have this gene. Nine Bacillus thuringiensis (Bt) isolates showing high insecticidal activity against insect pests in our previous studies were selected from 66 isolates containing the chitinase gene. Chitinases with different molecular weights ranging from similar to 40 to 113 kDa were determined by SDS-PAGE. To determine the antagonistic effects against plant pathogenic fungi (Fusarium oxysporum f.sp. niveum, Verticillium dahliae and Aspergillus niger), a dual culture assay was used with nine native and two standard strains of Bt, and radial growth inhibition was calculated as a percentage. Of all the tested isolates, SY33.3 showed the strongest antagonistic activity and thus, can be used as an effective biological control agent against plant pathogenic fungi.Erciyes University Scientific Project UnitErciyes University [FBD-08-540]This project was funded by Erciyes University Scientific Project Unit under the codes of FBD-08-540.WOS:0006598086000012-s2.0-8510747767

IL-15 negatively regulates curdlan-induced IL-23 production by human monocyte-derived dendritic cells and subsequent Th17 response

OBJECTIVE: In this study, we aimed to assess the effects of long- and short-term IL-15 cytokine exposure of human monocyte-derived curdlan-matured dendritic cells (DCs) on the production of Th17 cell-polarizing cytokine IL-23 and subsequent Th17 cell activation

A novel missense mutation outside the DNAJ domain of DNAJC21 is associated with Shwachman-Diamond syndrome

Shwachman-Diamond Syndrome (SDS) and related bone marrow failure disorders are characterized by early onset pancytopenia with a hypocellular bone marrow, short stature, and pancreatic insufficiency, along with an increased risk for myeloid malignancies. Recently, several cases with an SDS-like syndrome have been reported to harbor mutations in the DNAJ domain of DNAJC21. Here, we report an intriguing case of a 13.5 years-old female born to Turkish consanguineous parents with a novel missense mutation occurring outside the DNAJ domain of the DNAJC21 gene. Whole-exome and Sanger sequencing confirmation revealed a homozygous missense mutation in DNAJC21 gene c.463T>C, p.W155R which was considered as pathogenic in in silico analyses. Initially, this patient's vague and atypical symptoms led to uncertainty of the underlying diagnosis. Upon confirmation of the genetic mutation, a number of functional studies such as diepoxibutane test, proliferation test from peripheral blood mononuclear cells, and cytokinesis-block micronucleus cytome assay performed with the patient cells confirmed the likely diagnosis of an SDS-like syndrome attributable to DNAJC21 dysfunction. Through the analysis of this rare case, we illuminate the pleiotropic features of this unique bone marrow failure syndrome and emphasize the paramount role of genomic testing to discriminate a range of closely related bone marrow failure disorders

A NOVEL MISSENSE MUTATION OUTSIDE DNAJ DOMAIN OF DNAJC21 IS ASSOCIATED WITH SHWACHMAN-DIAMOND SYNDROME

Shwachman-Diamond Syndrome (SDS) and related bone marrow failure disorders are characterized by early onset pancytopenia with a hypocellular bone marrow, short stature, and pancreatic insufficiency, along with an increased risk for myeloid malignancies. Recently, several cases with an SDS-like syndrome have been reported to harbor mutations in the DNAJ domain of DNAJC21. Here, we report an intriguing case of a 13.5 years-old female born to Turkish consanguineous parents with a novel missense mutation occurring outside the DNAJ domain of the DNAJC21 gene. Whole-exome and Sanger sequencing confirmation revealed a homozygous missense mutation in DNAJC21 gene c.463T>C, p.W155R which was considered as pathogenic in in silico analyses. Initially, this patient's vague and atypical symptoms led to uncertainty of the underlying diagnosis. Upon confirmation of the genetic mutation, a number of functional studies such as diepoxibutane test, proliferation test from peripheral blood mononuclear cells, and cytokinesis-block micronucleus cytome assay performed with the patient cells confirmed the likely diagnosis of an SDS-like syndrome attributable to DNAJC21 dysfunction. Through the analysis of this rare case, we illuminate the pleiotropic features of this unique bone marrow failure syndrome and emphasize the paramount role of genomic testing to discriminate a range of closely related bone marrow failure disorders

Characterization of cord blood CD3(+)TCRV alpha 7.2(+)CD161(high) T and innate lymphoid cells in the pregnancies with gestational diabetes, morbidly adherent placenta, and pregnancy hypertension diseases

Problem Although pregnant women with gestational diabetes (GD), morbidly adherent placenta (MAP), and pregnancy hypertension (pHT) diseases lead to intrauterine growth restriction (IUGR), little is known about their effect on mucosal-associated invariant T (MAIT) and innate lymphoid cells (ILC) in the umbilical cord. This study aimed to quantify and characterize MAIT cells and ILCs in the cord blood of pregnant women with GD, MAP, and pHT diseases. Method of study Cord blood mononuclear cells (CBMCs) were isolated by Ficoll-Paque gradient. CD3(+)TCRV alpha 7.2(+)CD161(high) cells and ILC subsets were quantified by flow cytometry. CBMCs were stimulated with PMA/Ionomycin and Golgi Plug for 4 h and stained for IFN-gamma, TNF-alpha, and granzyme B. The stained cells were analyzed on FACS ARIA III. Results Compared with healthy pregnancies, in the cord blood of the pHT group, elevated number of lymphocytes was observed. Moreover, the absolute number of IFN-gamma producing CD4(+) or CD4(-) subsets of CD3(+)TCRV alpha 7.2(+)CD161(high) cells as well as those producing granzyme B were significantly elevated in the pHT group compared to healthy controls suggesting increased MAIT cell activity in the pHT cord blood. Similarly, in the MAP group, the absolute number of total CD3(+)TCRV alpha 7.2(+)CD161(high) cells, but not individual CD4(+) or negative subsets, were significantly increased compared with healthy controls' cord blood. Absolute numbers of total CD3(+)TCRV alpha 7.2(+)CD161(high) cells and their subsets were comparable in the cord blood of the GD group compared with healthy controls. Finally, the absolute number of total ILCs and ILC3 subset were significantly elevated in only pHT cord blood compared with healthy controls. Our data also reveal that IFN-gamma(+) or granzyme B+ cell numbers negatively correlated with fetal birth weight. Conclusions CD3(+)TCRV alpha 7.2(+)CD161(high) cells and ILCs show unique expansion and activity in the cord blood of pregnant women with distinct diseases causing IUGR and may play roles in fetal growth restriction