Ep. 1: Myeloid Cells and Cardiovascular Health

May 13, 2021

In the kickoff episode of the 2021 Inflammation and Immunopys Series, Dr. Matthias Nahrendorf and Richard Moerschner examine the critical roles of monocytes and macrophages in cardiovascular health and disease, including their distinct functions in atherosclerotic lesions, healthy and injured hearts, and the brain. His research demonstrates that after myocardial infarction, sympathetic nerve activity modulates the hematopoietic stem cell niche to accelerate myeloid progenitor cell migration and proliferation, which paradoxically accelerates atherosclerosis progression and may explain the high incidence of secondary infarcts in patients. Nahrendorf discusses current concepts of immune cell supply, lineage relationships, cross-talk between organ systems, and advanced imaging tools for studying monocytes, macrophages, and their progenitors in cardiovascular disease.

Key Highlights

• Monocytes and macrophages reside and accumulate in atherosclerotic lesions and injured cardiac and cerebral tissue, with distinct subsets pursuing different functions in steady state and disease, ranging from hours to months in tenure with some promoting inflammation while others support tissue repair.
• Following myocardial infarction, increased sympathetic nerve activity modulates the hematopoietic stem cell niche, activating migration and proliferation of myeloid progenitor cells that accelerate atherosclerosis progression, potentially explaining why secondary infarcts are common in post-MI patients.
• Advanced imaging approaches including MR, nuclear, optical, and hybrid imaging enable non-invasive sampling of myeloid cell biology and immune dynamics in cardiovascular disease, providing new insights into atherosclerosis and heart failure pathophysiology.

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Ep. 2: Conversations Between Mucosal Immunity and the Gut Barrier

May 27, 2021

Dr. Jerrold R. Turner, Professor of Pathology and Medicine at Harvard Medical School, examines how intestinal epithelial tight junctions regulate barrier function and mediate crosstalk between the immune system and luminal materials including dietary antigens and microbes. His research demonstrates that tight junction selective permeability is dynamically modulated during development and by physiological stimuli, immune cell signaling, and enteric pathogens, with these changes directly impacting nutrient transport, mucosal immune tone, and pathogen clearance. Turner discusses recent mechanistic advances in tight junction regulation and how barrier modulation influences mucosal homeostasis, disease progression, and resolution.

Key Highlights

• Intestinal epithelial tight junctions form selectively-permeable seals that regulate paracellular flux between the lumen and underlying tissues, serving as the critical barrier separating the immune system from dietary antigens and microbes in the gastrointestinal tract.
• Tight junction permeability is dynamically regulated by physiological stimuli, immune cell signaling, and enteric pathogens, with these biophysical changes modulating nutrient transport, mucosal immune responses, and pathogen clearance to maintain or compromise intestinal homeostasis.
• Understanding mechanisms of tight junction regulation and barrier dysfunction is essential for determining how epithelial barrier impairment contributes to gastrointestinal disease and for developing novel therapeutic strategies to restore barrier function and mucosal health.

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Ep. 3: Engineered T Cells for Cancer

June 17, 2021

Professor Marcela V. Maus, Director of the Cellular Immunotherapy Program and Associate Professor of Medicine at Harvard Medical School, explains the design, engineering components, and mechanisms of chimeric antigen receptor (CAR) T cell therapy for cancer treatment. Her research demonstrates how CAR T cells are modular "living drugs" that undergo rapid expansion and long-term persistence in patients, with CAR design characteristics influencing clinical efficacy more than tumor genotype or prognostic biomarkers. Maus discusses how molecular and genetic engineering approaches including targeted antigen selection, co-stimulation domain optimization, and T cell-engaging antibody molecules overcome challenges of antigen escape, tumor heterogeneity, and immunosuppressive tumor microenvironments in both liquid and solid malignancies.

Key Highlights

• CAR T cells are living drugs that expand rapidly following infusion and persist for months or years, with FDA-approved products including tisagenlecleucel for relapsed/refractory acute lymphoblastic leukemia achieving overall response rates of 83% and median overall survival of 19.1 months compared to 2.5 months with chemotherapy.
• CAR T cell attributes including binding domain, hinge region, transmembrane domain, co-stimulation domain, and activation domain are modular and interchangeable, with these design characteristics influencing clinical activity more than tumor genotype, representing a significant paradigm shift in oncology where T cell properties predict responses better than traditional prognostic biomarkers.
• For solid tumors, engineered T cell engaging antibody molecules (TEAMs) targeting multiple antigens overcome tumor heterogeneity and immunosuppression by locally redirecting regulatory T cells without on-target, off-tumor toxicity, demonstrating how molecular engineering addresses fundamental challenges in CAR T cell therapy across cancer types.

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Ep. 4: Cardiovascular Disease Associated with SARS-CoV-2 and HIV Infections

September 9, 2021

Professor Xuebin Qin, Professor of Medicine at Tulane National Primate Research Center, examines cardiovascular injury associated with SARS-CoV-2 and HIV infections using mouse and nonhuman primate models. For SARS-CoV-2, his research demonstrates direct infection of pulmonary endothelial cells leading to endothelial dysfunction, increased vascular permeability, and multi-organ damage including cardiac involvement in severe COVID-19. For HIV infection, Qin's work establishes that chronic HIV infection alone accelerates atherosclerosis through caspase-1 and indoleamine 2,3-dioxygenase pathway activation, revealing innate immune mechanisms linking viral infection to cardiovascular disease.

‍Key Highlights

• K18-hACE2 transgenic mice infected with SARS-CoV-2 develop severe COVID-19 with progressive body weight loss, lymphocytopenia, eosinopenia, and multi-organ damage including pulmonary endothelial activation characterized by upregulation of VCAM-1 and ICAM-1 and downregulation of VE-cadherin, mirroring pathology observed in human autopsy samples.
• Chronic HIV infection alone accelerates atherosclerosis in Tg26 transgenic mice crossed with apolipoprotein E-deficient mice, with increased caspase-1 activity, elevated serum IL-1 beta and IL-18 levels, and heightened macrophage activation correlating with plaque formation in HIV-infected vasculature.
• Indoleamine 2,3-dioxygenase activity, measured by increased kynurenine-to-tryptophan ratio, is elevated in HIV-infected mice and correlates with atherosclerosis and IL-6 inflammatory cytokine production, with elevated circulating IL-18 in HIV patients with atherosclerotic plaque predicting increased myocardial infarction risk.

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Ep. 5: Premature Vascular Disease in Autoimmunity

October 7, 2021

Dr. Mariana J. Kaplan, Senior Investigator and Branch Chief at the NIH Systemic Autoimmunity Branch, examines mechanisms of premature cardiovascular disease in systemic lupus erythematosus, revealing that cardiovascular complications are the leading cause of death in SLE but only partially explained by traditional risk factors. Her research identifies dysregulation of type I interferon signaling and abnormal neutrophil biology including neutrophil extracellular traps and low-density granulocytes as key drivers of endothelial dysfunction, arterial stiffness, and accelerated atherosclerosis. Kaplan discusses how neutrophil-derived NETs impair high-density lipoprotein function and cholesterol efflux capacity while amplifying vascular inflammation, and presents emerging therapeutic approaches including type I interferon inhibitors and JAK/STAT pathway inhibitors to prevent vascular damage in autoimmunity.

Key Highlights

• Systemic lupus erythematosus causes premature cardiovascular disease including accelerated atherosclerosis, myocardial infarction, and vasculopathy as the leading cause of SLE mortality, with evidence of vascular damage including endothelial dysfunction, arterial stiffness, and plaque formation preceding clinical cardiovascular events.
• Low-density granulocytes and neutrophil extracellular traps are elevated in SLE, with LDG gene signature correlating with severity of vascular damage and coronary atherosclerosis through enhanced NET formation that impairs HDL-mediated cholesterol efflux and amplifies vascular inflammation and coagulation.
• Type I interferon inhibitor Anifrolumab and JAK/STAT inhibitor Tofacitinib reduce circulating low-density granulocytes and NETs, restore HDL cholesterol efflux capacity, and improve lipid profiles in SLE patients, with antimalarials offering additional NET pathway interference without immunosuppressive effects.

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Ep. 6: Immunophysiological Mechanisms that Limit Dissemination of Microbial Signals from the Intestine

November 11, 2021

Dr. Gwendalyn J. Randolph, Emil R. Unanue Professor at Washington University School of Medicine, examines how the intestinal lymphatic system and hepatic filtration regulate microbial signals and inflammatory mediators to prevent systemic dissemination and septic shock. Her research demonstrates that the intestine produces high-density lipoprotein that binds and neutralizes lipopolysaccharide from gram-negative bacteria, restricting toll-like receptor 4 activation in hepatic Kupffer cells, with gut-derived HDL accounting for the vast majority of portal blood HDL-cholesterol. Randolph discusses how lymphoid tissue organization and elevated collecting vessel pressures create physical barriers that confine inflammatory responses to the gut, with dysregulation of these mechanisms contributing to inflammatory bowel disease pathogenesis.

Key Highlights

• The intestine produces HDL that is transported via hepatic portal blood to neutralize lipopolysaccharide through LBP-mediated transfer to lipoproteins, reducing inflammatory signaling through TLR4-MD2 complexes and protecting Kupffer cells from LPS-mediated damage through hepatic first-pass filtering.
• Gut-derived HDL is primarily of the HDL3 subtype and accounts for the vast majority of HDL-cholesterol in hepatic portal blood, functioning as a "backpack" that accepts and releases inflammatory cargo while undergoing remodeling during circulation and tissue transit.
• In inflammatory bowel disease, B cell-rich lymphoid follicles develop near lymphatic valves within draining mesenteric lymph nodes with elevated collecting vessel pressures that create a pressure cuff effect, functioning together with HDL production to restrict inflammatory cells and factors from disseminating away from the gut.

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