Immunopathology Commons^™

Identification And Characterization Of Novel Immune Modulating Genes In Parkinson's Disease, Kathleen Chaundy Paul Murphy

Dartmouth College Ph.D Dissertations

Parkinson’s disease (PD) is a progressive age-related neurodegenerative disorder characterized by both motor and non-motor symptoms. The poorly understood prodromal period, decades-long progression, and disease-phenotype heterogeneity continue to impede the development of preventive and curative therapies. A growing appreciation of immune system changes during the progression of PD suggests that evaluating peripheral immune cells may help identify signatures relevant to disease etiology. We aimed to expand our understanding of the peripheral immune compartment in PD via two lines of investigation: (1) by employing single-cell RNA sequencing to profile the transcriptomes of peripheral blood mononuclear cells (PBMCs) from a cohort of …

Examining The Ligands, Location, And Function Of Toll-Like Receptor 10, Kiefer Keanu Tam

Master's Theses

Toll-like receptors are a class of innate immune pattern recognition receptors that detect pathogen-associated molecular patterns and regulate downstream inflammatory responses. Toll-like receptor 10 remains the only human TLR whose ligand specificity, cellular localization, and immunological function are not fully defined. Emerging evidence suggests that TLR10 may play an anti-inflammatory role and can heterodimerize with TLR2 to modulate immune signaling. Previous studies from our laboratory demonstrated that stimulation with heat-killed Mycobacterium tuberculosis promotes TLR2-TLR10 heterodimerization and trafficking to the cell surface. In this study, we expanded our ligand panel to include additional gram-positive bacteria, particularly anti-inflammatory probiotic species, to further …

Cell-Free Mitochondrial Dna (Mtdna) Triggers Vascular Dysfunction Via Toll-Like Receptor 9 (Tlr9)-Dependent Activation Of Inflammasomes, Mohin Amin

Senior Theses

Hypertension is the leading global risk factor for mortality and is closely associated with vascular inflammation and dysfunction. Damaged mitochondria release cell-free mitochondrial DNA (cf-mtDNA), which activates toll-like receptor 9 (TLR9). The binding of TLR9 to mtDNA activates the NLRP3 inflammasome pathway, promoting the release of pro-inflammatory cytokines via gasdermin D (GSDMD), therefore worsening inflammation. However, the mechanisms linking mitochondrial injury to inflammation-induced vascular dysfunction remain unclear. We hypothesize that cf-mtDNA triggers TLR9-dependent NLRP3 inflammasome activation contributing to vascular and endothelial dysfunction. To assess that, adult male C57BL/6 were exposed to 28 consecutive days of chronic unpredictable stress (CUS) or …

Comparative Spatial Biology: A Cross-Species Analysis Of Canine Oral Cancers As Models For Human Disease, Ram Pradhyumnan

Honors Undergraduate Theses

Oral squamous cell carcinoma (OSCC), one of the most common malignancies of the oral cavity, remains a clinically challenging disease due to its aggressive behavior, late-stage diagnosis, and limited improvements in therapeutic outcomes over recent decades. A significant barrier to progress in OSCC research and treatment is the lack of suitable preclinical models that recapitulate the complexity and natural progression of the disease. Most current models—including cell lines, xenografts, and genetically engineered mice—fail to capture key features such as the spatial organization of tumor epithelium, interactions with an intact immune system, and the stepwise evolution from normal mucosa to invasive …

The Influence Of Tert-Butylhydroquinone (Tbhq) On Acod1/Irg1-Driven Inflammatory Pathways, Alyssa M. Whisel

All Dissertations

The demand for processed foods has led to increased use of synthetic phenolic antioxidants (SPAs), notably tert-butylhydroquinone (TBHQ), to inhibit lipid oxidation and prolong shelf life. While TBHQ is deemed safe at regulated levels, concerns arise from studies indicating potential adverse effects such as oxidative stress, genotoxicity, and impaired immune function. To investigate TBHQ's immunomodulatory effects, RAW 264.7 murine macrophages were pre-treated with TBHQ and subsequently stimulated with lipopolysaccharide (LPS) or polyinosinic-polycytidylic acid (poly I:C, PIC) to simulate bacterial or viral challenges. Results demonstrated that TBHQ at high non-cytotoxic doses reduced nitric oxide and IL-10 production while promoting phagocytosis and …

Computational Frameworks To Unravel The Immune Landscape, Shan He

Dissertations and Theses (Open Access)

Recent advances in immunotherapy, including immune checkpoint blockade (ICB) and adoptive cell therapy, face challenges such as resistance and immune-related adverse events, partly due to our limited understanding of the immune signaling pathways. While high- throughput genomic data provide unprecedented resolution into these immune pathways, their full potential is limited by the lack of well-annotated, context-specific immune gene sets. To address this need, I developed a workflow to construct immune gene sets by integrating RNA- seq datasets and performing decomposition. Using this approach, I constructed 28 immune- specific gene sets from 83 bulk RNA-seq datasets and 12 Natural Killer (NK) …

Immune Regulation In Fungal Airway Inflammation And Host Defense, Ruoning Wang

Biomedical Sciences ETDs

Asthma is a chronic inflammatory disease of the lungs characterized by complex pathophysiological mechanisms and diverse endotypes, primarily categorized as T helper type 2 cell (Th2)-high and Th2-low asthma. Despite significant advances in understanding asthma pathogenesis, the mechanisms governing the pulmonary immune system’s response to external challenges have not been fully understood. To address these gaps, this comprehensive project was designed to investigate the interplay between fungal infections and specific CD4⁺ T cell populations in asthma. Our findings suggest that fungal infections can contribute to neutrophilic asthma by promoting the migration of platelet-myeloid aggregates into the lungs. We also …

Developing A Murine Model To Investigate The Mechanisms Of Peanut, Cashew, Shrimp Multifood Allergy, Aaron Wilson

NYMC Student Theses and Dissertations

Approximately 32 million people in the United States have food allergies, which is approximately 10 percent of the population. Food allergies can be mild, moderate, or even severe, resulting in anaphylaxis. The most predominant food groups that trigger food allergies include peanuts, tree nuts, fish, and shellfish. Peanuts and tree nuts have some similarities in protein structure. Shellfish is not associated with the protein properties of peanuts or tree nuts, it is the leading cause of adult anaphylaxis and often co-exist with peanut and tree nut allergies Currently, there are few studies that have established a murine model for allergy …

Identification And Preclinical Assessment Of Novel Therapeutic Modalities In Environmental Exposure-Induced Lung Disease, Aaron D. Schwab

Theses & Dissertations

Environmental lung diseases are preventable respiratory conditions either caused or made worse by inhaled environmental exposures. Contemporarily, environmental lung diseases are most associated with workplace exposures given specific occupational processes aerosolize inflammatory agents that can be inhaled at high concentrations. Although a considerable amount is known regarding immunoglobulin (Ig)E-mediated responses to environmental exposures, little is known about non-IgE mediated respiratory conditions resulting from lipopolysaccharide (LPS)-enriched organic dust exposure(s). Chronic respiratory diseases such as asthma, hypersensitivity pneumonitis, chronic obstructive pulmonary disease (COPD), and pulmonary fibrosis have all been identified as environmental lung diseases caused or exacerbated by such environmental dusts. Therapeutic …

Pseudomonas Aeruginosa Exoenzyme Y Enzymatic Activity Inhibits Exoenzyme S-Induced Caspase Activation But Not Cytotoxicity In Pulmonary Microvascular Endothelial Cells, Connor Holm

Honors Theses

Pseudomonas aeruginosa (P. aeruginosa) is the most common cause of ventilator-associated pneumonia in intensive care unit patients. P. aeruginosa utilizes a type III secretion system that injects exoenzymes U, S, T, and/or Y into the host cell cytosol. A majority of clinically isolated P. aeruginosa strains express ExoY often in combination with ExoU and ExoT, or ExoS and ExoT. Host signaling mechanisms in response to intoxication with individual exoenzymes have been extensively studied, yet little is known about host cell response to co-intoxication. In this study, pulmonary microvascular endothelial cells (PMVECs) were infected with P. aeruginosa strains expressing different combinations …

Functional Analysis Of Ligand Binding Domain 2 Of Outer Surface Protein C Of Borreliella Burgdorferi, Gavin Z. Chambers

Theses and Dissertations

Lyme disease, caused by the spirochete Borreliella burgdorferi, is the most common vector-borne infection in North America. A critical determinant of early mammalian infection is outer surface protein C (OspC), a highly variable lipoprotein that is indispensable for spirochete survival but whose precise function remains unresolved. OspC has been proposed to mediate diverse roles, including complement evasion, adhesion, tissue dissemination, and antiphagocytic activity, supporting the view that it is a multifunctional virulence factor. Structural studies have identified two putative ligand-binding domains (LBD1 and LBD2), with LBD2 forming a solvent-exposed crown at the membrane-distal end of the OspC dimer.

To …

Leveraging Epigenomics And Transcriptomics To Develop High-Dimensional Biomarkers Of Neuroinflammation, Steven C. Pike

Dartmouth College Ph.D Dissertations

Neuroinflammation is a critical physiological phenomenon implicated in most neurological disorders, either as a cause or a consequence of pathology. Our understanding of neuroinflammation is limited by the inability to directly profile the cells of interest. Thus, developing biomarkers of neuroinflammation is clinically urgent as we know neuroinflammation correlates with patient outcomes and treatment success. The recent advances in “omics” technologies, particularly epigenomics and transcriptomics, provides the opportunity for high-dimensional profiling of biospecimens for potential biomarkers. Within this dissertation, I demonstrate that biomarkers obtained from “omics” platforms can detect neuroimmunological phenomena in clinical and preclinical settings. In chapter one, DNA …

Combination Therapy Of Ido1 Inhibition And Anti-Pd1 Mediates Anti-Tumor Immunity By Promoting Memory Immunity Development And Cytotoxicity Of Γδ T And Nk Cells Via Il-2 Signaling And By Overcoming Pro-Tumor Effects Of Tgf-Β Signaling, Hyuk Jee

Dartmouth College Master’s Theses

Cutaneous melanoma is the most aggressive form of skin cancer even though it takes only about 1% of all skin cancers. Even among all cutaneous melanomas, NRAS-mutant melanoma is more aggressive than any other, and about 10-25% of all cutaneous melanoma cases have mutations in NRAS. NRAS is a member of the RAS family of proto-oncogenic GTPase proteins, and it plays a key role in signal transduction pathways responsible for cellular survival, proliferation, and metabolism. Immunotherapy is the first line of defense against NRAS-mutant melanoma because, despite tremendous efforts made for decades, it has not been successful to develop small …

Sounding The Alarm: Local Cues That Drive Functional Specialization Of Brain Resident Memory T Cells, Shawn Christopher Musial Jr.

Dartmouth College Ph.D Dissertations

Resident memory T cells are a unique subset of memory T cells that persist within tissues throughout the body, including the brain, optimally positioned to exert local immune activation. Broadly, T cells in the CNS are implicated in a range of neurologic disorders, can protect against reinfection, and even participate in normal CNS homeostasis. Despite this, there remain significant gaps in knowledge about how T cells, specifically resident memory T cells (T_RM), are regulated and function in the unique CNS environment. Here, we leverage a mouse model of acute viral infection to dissect the diversity of brain T …

Molecular Mechanisms Of Exercise-Stimulated Resolution Of Inflammation And Its Dietary Dependence., Ernesto H. Pena Calderin

Electronic Theses and Dissertations

Diet-induced obesity and adipose tissue (AT) inflammation that ensues sets the stage for systemic metabolic inflammation, disrupted insulin signaling, and eventual type 2 diabetes (T2D) development. At the center of this pathology lies a disruption in endogenous inflammation resolution pathways characterized by an imbalance in lipid mediator production (greater abundance of pro-inflammatory to pro-resolving lipids). Additionally, obese states are characterized by adrenergic deficiency, especially in response to physical activity. Inflammatory processes have been experimentally mitigated by either the pharmacological inhibition of pro-inflammatory signals (i.e., Leukotriene B₄ (LTB₄) and its receptor BLT1, which establishes a potent chemotactic stimulus …

Partial Immunity To Mycoplasma Gallisepticum After An Initial Infection Is Long-Lasting And Reduces Transmission In Flocks Of Canaries, Madeline Sudnick

Graduate Theses and Dissertations

Pathology during a second infection can be influenced by immunity and an increase in resistance or tolerance of individuals. Population-level differences in the ability to maintain immunity can lead to contrasting survival outcomes between groups and determine how future outbreaks will spread. However, long term wildlife disease surveillance can be challenging due to lack of infrastructure and host-pathogen specific tests. Calculating disease transmission likelihood requires understanding individual-level heterogeneity in pathology and behavior, and there is limited knowledge in understanding how populations in different stages of an epidemic will transmit disease. In Chapter I, we aim to help fill a gap …

Complement Propagates Visual System Pathology After Traumatic Brain Injury, Davis Marchant Borucki

MUSC Theses and Dissertations

Background: Traumatic brain injury is associated with the development of visual system disorders, including deficits in visual acuity. Visual deficits can present with delay and worsen over time, suggesting that ongoing neuroinflammatory changes contribute to their development and progression. Complement activation is strongly associated with the neuroinflammatory response after TBI and has been shown to contribute to neuronal and synaptic loss. However, the contributions of complement activation after TBI to vision loss remains unclear.

Methods: We employed an open skull controlled cortical impact model of traumatic brain injury in adult male mice to study how TBI affects vision. Animals were …

Pharmacodynamic Effects Of Zsj-0228 On Complement Protein Deposition In The Kidneys Of Focal Segmental Glomerulosclerosis-Afflicted Mice., Braeden Pinkerton

Theses & Dissertations

Chronic inflammation, when left untreated, may result in significant morbidity and in severe cases, mortality. While glucocorticoids (GCs) are still being extensively used clinically as a class of very potent anti-inflammatory agents, they are also notorious for diverse adverse side effects. To mitigate these side effects, we have developed a polyethylene glycol (PEG)-based prodrug (ZSJ-0228) of dexamethasone (Dex). When tested on rodent models of Lupus Nephritis and Focal Segmental Glomerulosclerosis (FSGS), ZSJ-0228 was found to provide potent and sustained therapeutic efficacy without any detectable typical GC-associated side effects. Given ZSJ-0228’s transient renal exposure after systemic administration, it is yet to …

Mucins: Drivers Of Cancer Cell And Microenvironment Crosstalk In Pancreatic Cancer, Xiaoqi Li

Theses & Dissertations

Mucins facilitate the pancreatic cancer (PC) initiation, progression, and metastasis. Among mucins, MUC4 has been reported to inhibit lymphokine-activated cell killing and induce the apoptosis of cytotoxic T-cells. Counterintuitively, MUC4 expression is upregulated by multiple T-cell-secreted cytokines, such as IFN-γ, IL-17, and stroma-secreted factors like retinoic acid. Previously, we have identified that nuclear receptor coactivator 3 (NCOA3) regulates the MUC1 and MUC4 expression by increasing chromatin accessibility and maintaining protein stability. However, the comprehensive crosstalk mediated by MUC4 in cancer cells and T-cells and how its upstream regulator, NCOA3, modifies the cancer cell-intrinsic behavior is still elusive. Here, we show …

The Role Of B Cell Activation State And Sex In Aryl Hydrocarbon Receptor Mediated Induction Of Chemokine Receptor 9 And Alpha4beta7 Expression In Vitro, Logan Bauerle

Master's Theses

Defense of mucosal tissues from microbial infection and allergy is reliant on continual production of antibodies. The aryl hydrocarbon receptor (AhR) is known to regulate B cell development and is associated with suppression of systemic humoral immunity. Recent attention has been paid to the role of the AhR in altering expression of cell adhesion molecules (CAMs). B cells express CAMs and chemokine receptors to migrate around the body for localized secretion of antibodies. AhR agonists promote B cell migration to the small intestine through upregulation of chemokine receptor 9 (CCR9) and integrin α₄β₇. Both the AhR …

Remodeling Anaplastic Thyroid Cancer's Aggressive Profile And Metabolic Signature By Natural Alkaloid Berberine, Tara Elizabeth Jarboe

NYMC Student Theses and Dissertations

Anaplastic thyroid cancer is a rare, fatal cancer with a five-year survival of 4%. Universally diagnosed at stage IV, anaplastic thyroid cancer is characterized by its lack of differentiation, rapid proliferative rate, highly inflammatory tumor microenvironment, and metabolic dysregulation. Refractory to all established therapies, anaplastic thyroid cancer requires a novel therapeutic approach that targets all of these drivers of anaplastic thyroid cancer carcinogenesis. We propose natural alkaloid berberine as a therapeutic with multitarget efficacy to alter mitochondrial metabolism and reprogram anaplastic thyroid cancer’s aggressive phenotype. Our in vitro model uses monocyte cell line U937, anaplastic thyroid cancer cell lines T238 …

The Critical Role Of Nac1 In Triple-Negative Breast Cancer Stemness And Immunosuppression, Chrispus Ngule

Theses and Dissertations--Toxicology and Cancer Biology

Triple-negative breast cancer (TNBC) is a highly heterogeneous and the most lethal breast cancer (BC) subtype. We report here a new role of nucleus accumbens associated protein 1 (NAC1) in maintaining stemness signature and features of TNBC and controlling the status of myeloid-derived suppressor cells, which accounts for its role in tumor progression and metastasis. This report demonstrates increased NAC1 amplification in TNBC metastatic samples compared to nonmetastatic tissues. In vitro, NAC1 depletion in TNBC cells suppressed their proliferation, colony formation, migration, and invasion. In vivo, NAC1 knockdown in TNBC cells reduced tumorigenic ability, diminished tumor growth rate, and abolished …

Sphingosine Kinase 2 Depletion Dysregulates Hepatic Redox Metabolism And Enhances Inflammation In Early Metabolic Dysfunction-Associated Steatohepatitis (Mash), Kaitlyn Georgene Jackson

Theses and Dissertations

Metabolic dysfunction-associated steatotic liver disease (MASLD) currently affects one in three people worldwide; its prevalence is growing alongside other cardiometabolic disorders. Aberrations to redox and sphingolipid metabolism contribute to MASLD pathologic progression. Sphingosine-1-phosphate (S1P) is an active lipid, meaning that S1P participates in biochemical processes within the cell. S1P is generated by two distinct isoenzymes, sphingosine kinase (SphK)1 and SphK2. The localization of the SphK enzyme dictates S1P function. While cytosolic SphK1-generated S1P is well-characterized, nuclear and mitochondrial SphK2-generated S1P is less known. Moreover, SphK2 depletion effects on cellular redox processes and inflammation are not well-defined.

This study defines the …

The Role Of Hdac6 In Periodontal Inflammation, Hannah S. Lohner

Theses and Dissertations

Periodontal disease is a polymicrobial infection-induced chronic inflammatory disease and results in irreversible tissue damage and bone loss. While bacteria play a large role in the initiation of this disease, excessive and prolonged inflammatory immune responses are fundamental for its progression, making host directed therapy (HDT) a possible and potentially valuable treatment. Histone Deacetylase 6 (HDAC6) is an enzyme that removes acetyl groups from both histone and non-histone proteins, giving it a potential role in regulating inflammation initiated by pathogenic oral bacteria. Previous studies indicated that HDACs act as a bivalent regulator in inflammatory responses; however, the role that HDAC6 …

Role Of The Anti-Viral Immune Response In Neural Cell Modulation And Neurological Sequelae Of Childhood Viral Infections, Yashika Kamte

Electronic Theses and Dissertations

Viral infections of the central nervous system (CNS) often result in neurological sequelae and are considered a risk factor for the development of neurological disease. Moreover, the outcomes of a viral infection are largely dependent on the age of the host, with younger hosts developing more profound neuropathology. Perhaps the developing brain coupled with an immature immune system contributes to worse outcomes in the very young. Children suffering from brain infections are more prone to develop enduring neurological impairments even after recovery from the infection. Although majority of the brain growth occurs in utero, neurodevelopment continues throughout the juvenile …

+Protective Roles For Interferon-Gamma In Astrocytes During Chronic Autoimmunity, Brandon C. Smith

ETD Archive

Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS). Infiltrating inflammatory immune cells perpetuate demyelination and axonal damage in the CNS and significantly contribute to pathology and clinical deficits. Interferon (IFN)γ is classically described as deleterious in acute CNS autoimmunity, we and others have shown astrocytic IFNγ signaling also has a neuroprotective role. We found IFNγ signaling on astrocytes upregulates subunits of the immunoproteasome (iP) and programmed death ligand 1 (PD-L1), both of which serve protective roles during autoimmunity. Astrocyte-specific knockouts of Ifngr1 resulted in increased clinical severity in the MS murine model, experimental …

Cellular Mechanism Of Pentagalloyl Glucose-Mediated Prevention And Reversal Of Abdominal Aortic Aneurysms, Greg Halsey

All Dissertations

Abdominal aortic aneurysm (AAA) has been the 15th leading cause of death in persons older than 55 for the past ten years in several Western countries, with rupture resulting in an almost 100% mortality rate. AAA is a focal dilation of the aorta characterized by progressive loss of elastin and vascular smooth muscle cells (SMCs), as well as persistent inflammatory response [1]. The only treatment for AAA is surgery; however, the mortality post-procedure is still 1-4%, with a 15-30% chance of morbidity [2].

Pentagalloyl glucose (PGG) treatment is effective in the reversal of AAA. While its stabilizing interactions with extracellular …

Complement System In Multiple Sclerosis: Its Role In Disease Course And Potential As A Therapeutic Target, Michael R. Linzey

Dartmouth College Ph.D Dissertations

Multiple sclerosis (MS) is a clinically heterogeneous neurological condition characterized by neuroinflammation and neurodegeneration. Relapsing-remitting MS, defined by inflammatory attacks, is the most common initial form of MS and there are currently 23 FDA-approved treatments for these patients. These therapies work primarily by reducing inflammation in the CNS; they do not work well in progressive disease. Therefore, an unmet medical need exists for effective therapeutic options to treat progressive MS (PMS).

In MS, intrathecal immunoglobulins synthesis (IIgS) correlates with disease progression. My goals for this dissertation were to establish the pathological role of IIgS and identify new potential therapeutic …

The Role Of Complement In Stroke And Traumatic Brain Injury, Christine Couch

MUSC Theses and Dissertations

Brain and neural injury are a non-specific disease category that includes traumatic brain injury (TBI) and stroke. Both TBI and stroke are common, costly, and leading causes of severe disability in adults. Both stroke and TBI are responsible for substantial disability in working age adults, with stroke being the second leading cause of death worldwide [1] and TBI a major cause of disability in people younger than their 40's [2]. The immune response after brain injury is multifactorial and involves both local and systemic events at the cellular and molecular level. The complement system is a component of both the …

Temporal, Phenotypic, And Quantitative Characterization Of Thyroid Infiltrating Mononuclear Cells During Development Of Spontaneous Autoimmune Thyroiditis In Obese Strain Chickens, Katelyn M. Clark

Poultry Science Undergraduate Honors Theses

The Obese strain (OS) of chickens spontaneously develops autoimmune thyroiditis and is a well-established biomedical model for Hashimoto’s thyroiditis in humans. Both conditions are characterized by the infiltration of the thyroid glands with mononuclear cells resulting in destruction of the thyroid tissue and impairment of the thyroid’s endocrinological functions. Past studies have described mononuclear cell infiltration in thyroids of the OS chickens, but the time-course, cell composition, and relative amounts of the various mononuclear cells infiltrating the thyroids has not been well defined. In this project, the mononuclear cell infiltrate was characterized phenotypically and quantitatively in OS chickens over the …