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Endotoxin, or LPS tolerance, is an immunomodulatory mechanism that protects the host against secondary LPS exposure and may prevent endotoxic shock. During the development of tolerance, LPS binds to TLR4 and signals the release of cytokines including type I IFN, which has shown to have immunomodulator properties. The role of type I IFN in the induction of LPS tolerance was the topic of interest in a recent publication by Dr. Ali Ashkar’s research group. The study, led by former undergraduate thesis student Yalda Karimi, suggests that type I IFN does not play a role in LPS tolerance in vitro. Examining peritoneal macrophages from both wild type and IFNR KO mice in vitro, they showed that there is comparable, reduced cytokine production after secondary LPS exposure. In addition, both strains of mice received small doses of LPS to induce tolerance, and were then protected from a lethal dose of LPS. The results from this study show that unlike what was expected, type I IFN does not seem to play a role in endotoxin tolerance, and further studies are required to understand the exact mechanisms leading to tolerance. Read the full study here.

 

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Individuals who are allergic to foods such as nuts and shellfish, suffer from these allergies for the entirety of their lives, with no disease-transforming therapies currently available. Better understanding food allergy is an important area of research in Dr. Manal Jordana’s lab and a recent study led by post-doctoral fellow Dr. Rodrigo Jiménez-Saiz that was published in the Journal of Allergy and Clinical Immunology, looks at the underlying mechanisms involved in allergic responses to food allergens. The conventional belief is that lifelong IgE in food allergy is due to the generation of IgE-producing plasmablasts by germinal center B cells.

These IgE-producing plasmablasts travel to the bone marrow, where they secrete IgE for the rest of an allergic individual’s life. However, this study shows a novel mechanism to explain persistent IgE in allergic responses. Using various animal models and in vitro assays, Jiménez-Saiz et al. showed that lifelong food allergy is the result of the activation of allergen-specific long-lived memory B-cells, which upon allergen re-exposure, replenish allergen-specific IgE-secreting plasma cells in an IL-4-producing CD4 T cell dependent manner. This is a novel finding, and is especially impressive due to the extremely rare population of antigen-specific IgE+ memory cells that Drs. Jiménez-Saiz and Chu were able to study in the animals across a prolonged period of time.

Furthermore, this work suggests that lifelong food allergies may be the result of re-exposure to allergens which recurrently activate memory B and CD4 T cells, and that the mechanisms involved in activating and maintaining these memory responses should be targeted in the search of potential therapies for IgE-mediated food allergies.  The paper is now available to read online here. Congratulations to Rodrigo, and the entire Jordana lab for this great work and achievement! 

Although NK cells are known to play a critical role in protecting against the development of cancer, NK cells become dysfunction due to the tumor microenvironment. The mechanisms by which the local tumor environment inhibits NK cell function are not well described. A study by Dr. Ali Ashkar’s group examining the interactions between the tumor microenvironment and murine NK cells recently reported that both M2-polarized macrophages and tumor-associated macrophages (TAMs) inhibit NK cell expression and cytotoxicity in a contact-dependent manner. Furthermore, they showed that the suppressive effective of these macrophages was due to TGF-β. This study presents a novel method to describe macrophage-mediated regulation of NK cells in a tumor.  

MIRC is an excellent research facility largely thanks to extremely talented trainees who work tirelessly to help progress research in their respective fields of work. As such, we would like to highlight these hardworking individuals on our website and share their stories with all of you. If you are interested in participating in this series or would like to nominate a peer, please contact Puja Bagri (This email address is being protected from spambots. You need JavaScript enabled to view it.). We look forward to featuring the excellence of our talented trainees very soon! 

Humanized mouse models, where human tissues are housed in the background of a mouse, allow researchers to directly examine human cells in a biological system. Development of this model has enabled the study of human-specific pathogens, and has considerably expanded the ability to conduct mechanistic, basic science research. MIRC members are fortunate to have access to humanized mice, thanks to the work being done in Dr. Ali Ashkar’s lab. A recent paper from Dr. Ali Ashkar’s research group provides greater detail about their highly regarded humanized mouse model. They compared two different methods of human stem cell engraftment, were mice were engrafted with human cord blood intravenously as adults or intrahepatically as newborns. They found that mice engrafted as newborns initially had higher levels of human CD3+ T cells and lower levels of human B cells in the blood. However, levels of human CD45 cells were comparable long-term in both adult and newborn mice, suggesting there is very little difference in human immune cell reconstitution between the two methods. When looking at reconstitution in different immunological tissues, they found significant levels of human immune cell reconstitution in all sites, including mesenteric lymph nodes and the liver. This is an interesting finding, as not much has been shown about the reconstitution of lymph nodes and the liver. Furthermore, this study suggests that this humanized mouse model can be used as a relevant pre-clinical model to study the human immune system in the gastrointestinal tract.

The annual Medical Sciences Research Day took place on January 25th and several MIRC trainees were selected to feature their work at this day-long research event. From oral talks, to poster presentations, students did a great job representing MIRC and their respective research groups. Lisa Newhook (Bramson), Joanne Hammill (Bramson), Sara Dizzell (Kaushic) and Puja Bagri (Kaushic) all gave excellent oral presentations, while Donald Basin (Wan), Jessica Breznik (Bowdish), Grace Teskey (Bowdish), Anisha Dubey (Richards) and Danielle Vitali (Kaushic) did an exceptional job with their poster presentations. Congratulations to all presenters for a job well done! Just a reminder, all MIRC graduate students are welcome to submit abstracts for the upcoming Health Sciences Research Plenary, which will be taking place in May. 

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Culture systems that model host-pathogen interactions in the vaginal mucosal epithelium have certain limitations in accurately mimicking in vivo conditions. Yung Lee, an undergraduate student in Dr. Charu Kaushic’s lab, recently published his first paper where he used an improved model to study the effects of female sex hormones on susceptibility to HSV-2 infection. Typically, a liquid-liquid interface (LLI) cell culture model, where both the apical and basolateral surfaces are submerged in growth medium, is used, however, this model is limited in its capacity to simulate physiological conditions. In the current study, immortalized vaginal cells were grown in an air-liquid interface (ALI), more closely simulating the in vivo conditions of the female reproductive tract. The vaginal cells grown in both LLI and ALI models were compared in regards to their growth, differentiation and susceptibility to HSV-2. Additionally, the effects of female sex hormones progesterone (P4) and estrogen (E2) were also examined. Lee et al. found that in comparison to LLI conditions, the ALI model induced cells to grow into multi-layers, which better resembles vaginal cells in vivo. They then used the ALI model to assess the effect of hormones and found that in the presence of P4, cells were more susceptible to HSV-2 infection. This is consistent with many studies showing that P4 can increase susceptibility to sexually transmitted infections. Overall, these results suggest an alternative model for studying host-pathogen interactions that is more physiological relevant to in vivo conditions of the female reproductive tract. Read more here.

Thanks everyone for supporting The Good Samaritan Children's Home in Nairobi, Kenya at yesterday's Bake Sale!

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Recently, Matthew Miller's group in collaboration with Dr. Caitlin Mullarkey and a PhD candidate, Wengqian He have looked at the critical role of epitope specificity in regulating cell mediated cytotoxicity against influenza A virus. In addition to neutralizing antigens, antibodies are also capable of stimulating cellular responses through Fc–Fc receptor interactions. The type of response stimulated by these interactions is influenced by both the Fc receptor type expressed on the effector cell and the isotype of antibody to which it is bound. However, how antibody specificity influences Fc receptor functions, and how antibodies of different specificities interact to modulate these functions, remain unknown. Using influenza A virus as a model, we demonstrate that antibody specificity profoundly influences the induction of antibody-dependent cell-mediated cytotoxicity by effector cells. In addition, we show that interactions among antibodies that bind to discrete epitopes on the same antigen can influence the induction of Fc-dependent effector functions. Read more here.

Chronic cigarette smoke exposure is known to damage pulmonary lipids, resulting in innate inflammatory responses. Cigarette smoke is also known to activate the adaptive immune system, however, the role of these adaptive immune processes has yet to be fully understood.  A study by Danya Thayaparan, a Masters student from Dr. Stampfli’s lab, reports a link between damaged lipids and the production of autoantibodies. Thayaparan et al. showed, using a mouse model, that chronic exposure to cigarette smoke led to the induction of antibodies against oxidized low-density lipoproteins (OxLDL). To examine the potential function of autoantibodies against OxLDL, they used a monoclonal antibody against oxidized phosphatidylcholine (OxPC), the most prevalent phospholipid in lung surfactant. Overall, they found that antibodies against OxPC do not exacerbate cigarette smoke-induced inflammation, and instead, promote lipid and particle uptake by pulmonary macrophages, even after smoking cessation. Altogether, this study suggests a protective function for autoantibodies induced by chronic cigarette smoke exposure. Read more here.

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