Innate Immunity and Non-Communicable Diseases (Need to go over powerpoint slides)

Learning Objectives

  • Understand the growing epidemic of non-communicable diseases (NCDs) and their global impact.

  • Explore the intricate connection between inflammation and the development and progression of NCDs.

  • Investigate the role of danger-associated molecular patterns (DAMPs) in triggering inflammation and immune responses.

  • Examine atherosclerosis as a detailed example of how inflammation contributes to the pathogenesis of NCDs.

  • Learn about the concept of trained immunity and its implications in chronic inflammatory conditions.

Incidence of Diseases
Communicable Diseases

  • Review data illustrating the decline in the incidence of communicable diseases from 1950 to 2000, including diseases such as rheumatic fever, hepatitis A, mumps, measles, and tuberculosis. Note the public health measures and vaccination programs that contributed to this decline.

Non-Communicable Diseases

  • Analyze data showing the increasing incidence of immune disorders from 1950 to 2000, including multiple sclerosis, Crohn's disease, type 1 diabetes, and asthma. Discuss the factors that may be contributing to this rise, such as environmental changes, lifestyle factors, and improved diagnostic capabilities.

Non-Communicable Diseases (NCDs)

  • Define NCDs as chronic diseases of long duration that are not infectious.

  • Explain that NCDs result from a complex interplay of genetic, physiological, environmental, and behavioral factors.

  • Discuss how rapid unplanned urbanization, the globalization of unhealthy lifestyles, and population aging contribute to the increasing prevalence of NCDs.

Chronic Diseases and Income Levels

  • Highlight that deaths from chronic diseases are disproportionately rising in low-income countries, contributing to health disparities.

  • Analyze a chart that presents data on deaths by cause type and national income level (low, lower-middle, upper-middle, high income) from 2000 to 2015. Compare the burden of communicable diseases, injuries, and chronic diseases across different income levels over time.

COVID-19 Impact on Deaths

  • Examine the impact of the COVID-19 pandemic on mortality rates, noting that COVID-19 was responsible for 37% of deaths in England and Wales in January 2021, compared to 2% in July 2021.

  • Break down total deaths by cause, including dementia/Alzheimer's, heart disease, COVID-19, strokes, lung cancer, respiratory disease, and other causes. Discuss the implications of these data for public health planning and resource allocation.

  • Clarify that strokes include all diseases related to blood flow to the brain, such as aneurysms and thrombosis, and respiratory diseases include COPD, emphysema, bronchitis, and asthma.

The Role of Inflammation

  • Discuss how modern lifestyles, including diets, behavior, microbial patterns, and pollutants, influence mood, behavior, development, and degeneration, contributing to chronic inflammation.

  • Explain the interconnectedness of gastrointestinal inflammation, metabolic responses, stress, and HPA (Hypothalamic-pituitary-adrenal axis) responses in the context of NCDs.

  • Emphasize that these factors lead to inflammation and altered immune function, increasing the risk of NCDs. Discuss the multisystem effects, impacting cardiovascular responses, joints and tissues, stroma, lung development and function, tissue damage, oxidative stress, and tissue repair, all influenced by genetic susceptibility.

Chronic Inflammation and Diseases

  • Detail the association between chronic inflammation and a variety of diseases, including cardiovascular disease (atherosclerosis, heart failure, stroke, hypertension), autoimmune disorders (IBD, Crohn's disease, colitis, lupus, multiple sclerosis, type I diabetes), all cancer stages, neurological diseases (depression, Alzheimer's, Parkinson's, multiple sclerosis), diabetic complications (neuropathy, retinopathy, hypertension, atherosclerosis, heart disease), metabolic disorders (type II diabetes, fatty liver disease, renal failure), bone & joint disease (osteoarthritis, rheumatoid arthritis, osteopenia, osteoporosis), and pulmonary disease (asthma, COPD, hay fever, bronchitis).

Innate Immunity and Inflammation

  • Describe how innate immunity involves pathogen-associated molecular patterns (PAMPs) interacting with pattern recognition receptors (PRRs) on antigen-presenting cells (APCs), macrophages, and PMNs.

  • Explain that stressed cells release danger-associated molecular patterns (DAMPs), which also interact with PRRs, leading to cytokine/chemokine release, immune cell recruitment, inflammation, adaptive immunity, and tissue repair.

Tissue Injury and Repair

  • Explain that tissue injury leads to the passive release or active secretion of DAMPs like HMGB1 and ATP.

  • Discuss how these DAMPs promote the migration and proliferation of stem cells, immune cells, endothelial cells, and epithelial cells, contributing to tissue repair.

  • Describe how angiogenesis is activated through endothelial cell activation and secretion of proangiogenic factors, supporting tissue repair.

Danger Associated Molecular Patterns (DAMPs)

  • Provide a detailed table of DAMPs, including their receptors, release mechanisms, and roles in inflammation/immunity and tissue repair.

  • List examples of DAMPs, such as histones, genomic DNA, HMGB1, IL1a, IL33, ATP, F-actin, Cyclophilin A, HSPs, Uric acid crystals, S100s, mitochondrial DNA, mitochondrial transcription factor A, and Calreticulin.

  • Include receptors like TLR2, TLR4, TLR9, RAGE, TIM3, IL-1R, ST2, P2Y2, P2X7, DNGR1, CD147, CD91, SREC1, FEEL1, and NLRP3.

  • Specify release mechanisms as passive release (P), active secretion (A), and surface exposure (S).

Tissue Homeostasis

  • Illustrate tissue homeostasis with a diagram showing the balance between pro-inflammatory and anti-inflammatory mediators.

  • Identify innate and adaptive immune cells at steady state, including M2 macrophages, dendritic cells (DC), pDC, CD14lowCD16+ cells, Treg, and MDSC.

  • Describe activated innate immune cells in a pro-inflammatory environment, such as M1 macrophages, PMN, CD14highCD16- cells, and iPMN.

Turning Off Inflammation

  • Present a diagram depicting the activity of different immune cells over time during inflammation.

  • Indicate that neutrophils, inflammatory macrophages, and dendritic cells are active during activation and trigger phases.

  • Note that eosinophils, resident macrophages, and regulatory T cells are involved in resolution.

  • Explain that chronification, tissue damage, autoimmunity, genetics, and barrier disruption can influence the inflammatory response.

Macrophage Phenotypes

  • Discuss how macrophage phenotypes can be associated with dysfunction linked to diseases ranging from systemic infection and sepsis to a permissive tumor microenvironment.

  • Define AR as adenosine receptor, IC as immune complexes, and GC as glucocorticoids.

Aberrant Mitochondrial DNA Synthesis in Macrophages

  • Present a research paper abstract discussing how aberrant mitochondrial DNA synthesis in macrophages exacerbates inflammation and atherosclerosis.

  • Explain that cellular metabolism governs inflammation, and inflammation contributes to the progression of atherosclerosis.

  • Note that the study investigates whether mitochondrial DNA synthesis affects macrophage inflammation and atherosclerosis.

Atherosclerosis

  • Describe atherosclerosis as an inflammatory disease and a global health threat, serving as the main pathological basis for most CVDs.

  • Emphasize that CVDs are the leading cause of morbidity and mortality worldwide.

  • Explain that atherosclerosis involves the hardening/thickening of arteries and plaque formation.

  • Detail that plaque consists of immune cells, mesenchymal cells, lipids, and extracellular matrix.

Atherosclerosis Development

  • Illustrate the stages of atherosclerosis with a diagram, from fatty streak to ruptured plaque.

  • Identify key components, including endothelial cells, intima, media, macrophage foam cells, dendritic cells, smooth muscle cells, extracellular matrix, necrotic core, T cells, ApoB-LP, and thrombus.

Endothelial Dysfunction

  • Explain that factors like mechanical stress, hyperlipidemia, damaging factors (smoking, pathogens), and hyperglycemia cause endothelial dysfunction.

  • Describe how endothelial dysfunction leads to increased permeability, lipid infiltration, leukocyte recruitment and adhesion, oxidative stress, and reduced eNOS.

  • Explain that endothelial activation results in inflammation and atherogenesis.

Low Density Lipoproteins (LDL)

  • Illustrate the structure and types of LDL and other lipoproteins (chylomicron, VLDL, IDL, Lp(a)) with diagrams.

  • Explain that LDL consists of a polar surface (phospholipids, unesterified cholesterol, Apolipoprotein B) and an apolar core (cholesteryl ester).

Oxidative Modification of LDL

  • Describe how LDL undergoes lipid peroxidation and modification of apoB with oxidized products, becoming MM-LDL and OxLDL.

  • Explain that OxLDL is enriched with OxPC and recognized by scavenger receptors.

Oxidative Stress

  • Explain oxidative stress as an imbalance between oxidants and antioxidants using a diagram.

  • Differentiate between physiological levels (oxidative eustress) and excessive levels (oxidative distress).

  • List endogenous sources of oxidants, including electron transport chains, NADPH oxidases, peroxidases, and nitric oxide synthases.

  • List exogenous sources, including particulates, radiation, ozone, oxidized diet, combustion processes, nitrogen oxides, and sulfur oxides.

  • List antioxidants, including catalase, superoxide dismutase, glutathione peroxidase, glutathione transferase, heme oxygenase-1, redox proteins, glutathione, vitamin C, vitamin E, carotenoids, and flavonoids.

  • Describe how oxidative stress can lead to DNA oxidation (8-oxoguanine, transversion mutation, carcinogenesis, mitochondrial dysfunction), protein oxidation (fragmentation of peptide chain, proteasome, susceptible to proteolysis), and lipid peroxidation (membrane lipid bilayer disrupted, inactivation of receptors and enzymes).

Macrophage Uptake of Oxidised LDL

  • Explain that macrophages take up oxidised LDL, leading to cholesterol crystal formation in lysosomes, activating the inflammasome and causing pyroptosis.

  • Describe that excess cholesterol can be esterified and stored as cholesterol esters in lipid droplets.

  • Note that cholesterol oxidation leads to oxysterols that trigger LXR, driving cholesterol efflux and altered expression of pro-inflammatory genes.

Monocyte and Macrophage Interactions

  • Illustrate monocyte capture, rolling, arrest, diapedesis, and phagocytosis in the intima with a diagram.

  • Explain that monocytes differentiate into macrophages (foam cells) upon uptake of aggregated ApoB-LPs.

  • Describe that this process is amplified by smooth muscle cells, dendritic cells, and extracellular matrix, leading to foam cell formation and chemokine release.

TLR4/SYK-Dependent Macrophage Activation

  • Note that mmLDL (minimally oxidized low-density lipoprotein) induces TLR4/SYK-dependent macrophage activation.

Plaque Progression

  • Detail plaque progression with a diagram, including monocyte recruitment and differentiation into macrophages, T cell involvement, LDL oxidation, foam cell formation, and necrotic core formation.

  • List key molecules involved, such as IFN-γ, TNF-α, CCL-21, CCL-19, PSGL-1, VLA-4, S-selectin, VCAM-1, ICAM-1, ROS, SR-A, CD36, KLF-4, TLR4/TLR6, TLR2, MyD88, TRIF, NLRP3, CD40/CD40L, MMP, and Fas-L.

NCD Risk Factors

  • List major NCDs, including cardiovascular disease, cancer, chronic respiratory diseases, diabetes, and mental/neurological conditions.

  • List risk factors, including unhealthy diet, tobacco use, harmful use of alcohol, physical inactivity, and air pollution.

Western Diet and Trained Immunity

  • Explain that long-term epigenetic programming of innate immune cells to microbes (trained immunity) alters cell function.

  • Describe how a Western diet triggers systemic inflammation, augmenting cellular responses and inducing trained immunity.

Trained Immunity and Tolerance

  • Explain that infections or sterile tissue triggers induce inflammation and the activation of immune effector mechanisms.

  • Describe how concomitant anti-inflammatory mechanisms are provoked to prevent overshooting inflammation and tissue damage and to limit the inflammatory response in time.

  • Define trained immunity as involving epigenetic and metabolic reprogramming of the innate immune cells, allowing qualitatively and quantitatively adjusted responses of innate immune cells to subsequent time-delayed heterologous stimulation.

  • Explain that misguided trained immunity responses can contribute to disease progression, resulting in either a chronic hyperinflammatory state or a persistent state of decreased activity of the immune system.

Trained Immunity Definition

  • Define trained immunity as the phenomenon where innate immune cells can develop an exacerbated response and long-term inflammatory phenotype following brief exposure to insult.

  • Explain that this elicits an altered response to a second challenge, defining trained immunity.

Trained Immunity Mechanisms

  • Illustrate the mechanisms of trained immunity with a diagram, including bone marrow involvement, exposure to beta-glucan, BCG, or diet (oxLDL).

  • Describe that sensors in bone marrow cells (MPP) lead to increased IGF1R, mevalonate, mTOR, glycolysis, and cell