Browsing by Subject "Brain homeostasis"

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    Harnessing the Potential of Human iPSC‐derived Microglia‐like Cells as Antigen Presenting Cells for MAIT Cells to Study AD Pathology
    (Wiley, 2025-01-03) Afify, Reham; Brutkiewicz, Randy R.; Medical and Molecular Genetics, School of Medicine
    Background: Microglia are dominant immune cells residing in the brain that regulate brain homeostasis and T‐cell responses. An important immune function of microglia involves presenting microbial antigens to mucosal‐associated invariant T (MAIT) cells; MAIT cells recognize microbial vitamin B‐derived metabolites presented by the MHC class I‐like molecule, MR1. Our recent findings highlighted a detrimental role for the MR1/MAIT cell axis in Alzheimer’s disease (AD) using the 5XFAD mouse model. Here, our work is focused on how the MR1/MAIT cell innate immune axis in humans contributes to AD, using iPSC‐derived human microglia‐like cells (iMG) to provide potential mechanistic insights underlying the MR1/MAIT cell axis in AD. As an initial evaluation, we have assessed the activation of iMG and their potential as functional antigen presenting cells (APC) to MAIT cells when exposed to a microbe that can provide a MR1‐presented, MAIT cell‐specific antigen, such as from E. coli. Methods: Initially, we will generate iMG from healthy donors that will be incubated with E. coli for the assessment TNF‐α levels using ELISA as a readout of microglial activation. Subsequently, coculture experiments with human MAIT cells and E. coli‐stimulated iMG will provide an initial evaluation of microglial MR1‐dependent MAIT cell activation via MR1‐dependent antigen presentation, monitored by MAIT cell production of various cytokines measured by ELISA. Results: We expect that iMG will produce increased levels of TNF‐α in response to E. coli compared to the control group. Similarly, we anticipate elevated cytokine levels secreted by MAIT cells via an MR1‐dependent pathway. Conclusions: These experiments will allow us to apply our human iPSC‐based model to studying human microglia as APC and pave the way for a broader understanding of the contributions of the MR1/MAIT cell axis in AD. To our knowledge, our proposed study will be the first of its kind to utilize iMG as APC for human MAIT cells.
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    Recurrent duplications of the annexin A1 gene (ANXA1) in autism spectrum disorders
    (Springer Nature, 2014-04-10) Correia, Catarina T.; Conceição, Inês C.; Oliveira, Bárbara; Coelho, Joana; Sousa, Inês; Sequeira, Ana F.; Almeida, Joana; Café, Cátia; Duque, Frederico; Mouga, Susana; Roberts, Wendy; Gao, Kun; Lowe, Jennifer K.; Thiruvahindrapuram, Bhooma; Walker, Susan; Marshall, Christian R.; Pinto, Dalila; Nurnberger, John I.; Scherer, Stephen W.; Geschwind, Daniel H.; Oliveira, Guiomar; Vicente, Astrid M.; Psychiatry, School of Medicine
    Background: Validating the potential pathogenicity of copy number variants (CNVs) identified in genome-wide studies of autism spectrum disorders (ASD) requires detailed assessment of case/control frequencies, inheritance patterns, clinical correlations, and functional impact. Here, we characterize a small recurrent duplication in the annexin A1 (ANXA1) gene, identified by the Autism Genome Project (AGP) study. Methods: From the AGP CNV genomic screen in 2,147 ASD individuals, we selected for characterization an ANXA1 gene duplication that was absent in 4,964 population-based controls. We further screened the duplication in a follow-up sample including 1,496 patients and 410 controls, and evaluated clinical correlations and family segregation. Sequencing of exonic/downstream ANXA1 regions was performed in 490 ASD patients for identification of additional variants. Results: The ANXA1 duplication, overlapping the last four exons and 3'UTR region, had an overall prevalence of 11/3,643 (0.30%) in unrelated ASD patients but was not identified in 5,374 controls. Duplication carriers presented no distinctive clinical phenotype. Family analysis showed neuropsychiatric deficits and ASD traits in multiple relatives carrying the duplication, suggestive of a complex genetic inheritance. Sequencing of exonic regions and the 3'UTR identified 11 novel changes, but no obvious variants with clinical significance. Conclusions: We provide multilevel evidence for a role of ANXA1 in ASD etiology. Given its important role as mediator of glucocorticoid function in a wide variety of brain processes, including neuroprotection, apoptosis, and control of the neuroendocrine system, the results add ANXA1 to the growing list of rare candidate genetic etiological factors for ASD.