Immune Pathology I PDF

Immune Pathology I Part I – Concepts in Chronic Inflammation BMS 150 Week 4 e-learning Video Links Video 1 Video 2 Video 3 Chronic Inflammation - Objectives Compare and contrast the pathophysiologic processes and histologic characteristics of...

Immune Pathology I Part I – Concepts in Chronic Inflammation BMS 150 Week 4 e-learning Video Links Video 1 Video 2 Video 3 Chronic Inflammation - Objectives Compare and contrast the pathophysiologic processes and histologic characteristics of acute and chronic inflammation Briefly describe the pathophysiologic link between chronic inflammation and insulin resistance List categories of conditions that give rise to chronic inflammation Describe the involvement of classically-activated vs. alternatively activated macrophages in the general processes of inflammation and repair Describe the major steps in wound healing in terms of time course, order of occurrence, and major tissue and cellular events for each step Describe the histologic appearance and pathophysiologic development of granulomatous inflammation Chronic inflammation Obviously long-term inflammation… Lasts weeks – months – years Usually all of the following coexist: inflammation tissue injury tissue repair (different from regeneration) Can be due to: inability to resolve acute inflammation autoimmune disease continual damage to an organ or tissue Chronic Inflammation There are many pathologies that, although not classified as autoimmune or allergic, do have a chronic inflammatory component Alzheimer disease Atherosclerosis Obesity and the metabolic syndrome Chronic Inflammation and obesity Visceral obesity is well-recognized to be a risk factor for a wide range of diseases diabetes, atherosclerosis, metabolic syndrome cancer  Chronic Inflammation and obesity Why is visceral obesity so bad for you? ▪ excessive lipid build- up can stress the adipocyte (ROS) ▪ free fatty acids in high concentrations may bind to PAMP-R within the adipocyte both of the above can lead to the As shown above, pro- production of IL-6 and TNF-alpha by the inflammatory cytokines lead adipocyte to insulin resistance, and eventually type II diabetes Chronic inflammation: Causes Persistent infections ▪ The pathology of inflammation differs as a tissue is exposed to infectious agents over longer periods of time ▪ Chronic inflammatory cells predominate Macrophages and lymphocytes ▪ Parenchyma that dies is replaced by fibrotic tissue ▪ Cells that replace damaged cells do not necessarily have normal functions i.e. thickening of the respiratory membrane and development of granulomas Impairs gas exchange and restricts the movement of the lungs Chronic Inflammation Acute Inflammation Chronic Inflammation: Causes Immune-mediated inflammatory diseases ▪ Can be divided into autoimmune and allergic diseases Autoimmune diseases result when immune cells/mediators attack tissues inappropriately over long periods of time ▪ They’re considered to be mediated largely by the adaptive immune system, though there are often innate components Allergic diseases result when immune cells respond excessively to exogenous allergens (considered more acute) ▪ Allergic diseases are typically Th2-mediated, in general ▪ More when we talk about hypersensitivity disorders Chronic Inflammation: Causes Prolonged exposure to toxins ▪ Can be exogenous (i.e. silica) ▪ Can be endogenous (i.e. oxidized LDL) Pathological characteristics can vary widely depending on the location of the inflammation and the type of insult ▪ Both silicosis and atherosclerosis appear very differently under the microscope ▪ Also true of autoimmune disease – compare Crohn’s disease and ulcerative colitis Chronic inflammation – the macrophage Part of a system known as the reticuloendothelial system ▪ Monocytes ➔ Macrophages ▪ Resident macrophages Langerhans cells, microglia, Kupffer cells, alveolar macrophages ▪ Dendritic cells After 48 hours – 1 week of inflammation, often macrophages are the predominant cell type in inflamed tissue Chronic inflammation – the macrophage Pro-inflammatory macrophage functions: ▪ Lysosomal enzymes, free radicals destroy bacteria ▪ Efficient and proficient phagocytes ▪ Secretion of cytokines & growth factors IL-1, TNF-alpha ▪ Secretion of inflammatory mediators Leukotrienes and prostaglandins ▪ Secretion of chemotactic factors Leukotriene B4 and chemokines Chronic inflammation – the macrophage Macrophage functions of particular interest in chronic inflammation: ▪ Destruction of bacteria/removal of cellular debris Free radical production and secretion of proteases contribute to the destruction of normal tissue ▪ Secretion of cytokines and growth factors Contribute to activation of lymphocytes Growth factors stimulate cell division, deposition of connective tissue (fibrosis), and angiogenesis Macrophage responses can evolve as inflammation and damage continues in a tissue: “Classically-activated” macrophages: recruit other leukocytes damage pathogens often damage “bystander” host cells “Alternatively-activated” macrophages: Angiogenesis Pro-fibrotic growth factors/cytokines Growth factors/cytokines that stimulate repair or regeneration Classical and alternative macrophage activation Classically-activated macrophages are induced by microbial products and cytokines, particularly IFN-gamma phagocytose and destroy microbes and dead tissues, increase inflammation Alternatively-activated macrophages are induced by other cytokines and are important in tissue repair and resolution of inflammation Repair and the macrophage Angiogenesis 1. Vasodilation ▪ VEGF, NO, other dilators 2. Pericyte separation and endothelial migration 3. Proliferation of endothelial cells behind the leading cell tip (sprout) 4. Pericytes/smooth muscle cells as well as basement membrane surround the “tube” Fibrosis and chronic inflammation Chronic inflammation - lymphocytes Cytotoxic T-cells are particularly implicated in chronic inflammation ▪ Recruited to sites of chronic inflammation by macrophages that continue to respond to the inflammatory stimulus Plasma cells may be recruited to inflamed areas ▪ Plasma cells, macrophages, and lymphocytes can form lymphatic nodule-appearing regions in an area of chronic inflammation ▪ Known as tertiary lymphoid organs Mucosal tissues – large lymphoid follicles in lamina propria, “overdevelopment” of MALT In joint, produces redundant, inflamed synovium known as pannus ▪ Prominent in some autoimmune diseases (i.e. rheumatoid arthritis) Healing… vs. Scarring What are the steps? Phases of Healing – Skin, Connective Tissue Hemostasis – Phase I ▪ Blood extravasation into a tissue → platelet activation and blood coagulation Platelets contain a wide variety of growth factors Initial vasoconstriction (got to stop blood loss) followed by vasodilation (prostaglandins, complement, bradykinin, etc. Inflammation – Phase II ▪ Neutrophils, macrophages kill microbes ▪ Near the end of this phase macrophages transition from classically to alternatively activated Increasing fibrosis, angiogenesis Phases of Healing Proliferation - Phase III ▪ Recruitment of fibroblasts which produce a network of collagen, proteoglycans (ground substance) and fibronectin (forms framework for tissue) Lots of type III collagen laid down, less type I (weak) Myofibroblasts cause wound contraction ▪ Continued angiogenesis ▪ Exuberant angiogenesis + connective tissue matrix development = granulation Maturation - Phase IV ▪ Remodelling of connective tissue, regression of “unnecessary” angiogenesis Type III → Type I collagen transition as well as improved “organization of connective tissue fibres ▪ increased strength of wound Granulation tissue https://en.wikipedia.org/wiki/Wound_healing#/media/File:Wound_healing_phases.png Repair and Scarring - Muscle Steps in repair by scar formation Injury to a tissue, such as muscle (which has limited regenerative capacity), first induces inflammation, which clears dead cells and microbes Followed by the formation of vascularized granulation tissue and then the deposition of extracellular matrix to form the scar Repair and Fibrosis Figure 3-31 Mechanisms of fibrosis. Persistent tissue injury leads to chronic inflammation and loss of tissue architecture Cytokines produced by macrophages and other leukocytes stimulate the migration and proliferation of fibroblasts and myofibroblasts also results in the deposition of collagen and other extracellular matrix proteins. The net result is replacement of normal tissue by fibrosis Chronic inflammation – the granuloma Granuloma = an attempt by lymphocytes and macrophages to “wall off” an inflammatory stimulus ▪ Infectious causes ▪ Autoimmune causes Thought that granuloma formation develops because the insult (microbe, foreign body) is difficult to eradicate or it elicits a Th1 +/- Th17 response Granuloma-causing conditions include: ▪ Tuberculosis ▪ Leprosy ▪ Syphilis ▪ Sarcoidosis ▪ Crohn’s disease Chronic inflammation – the granuloma A granuloma is a focus of chronic inflammation consisting of a microscopic aggregation of macrophages that are transformed into epithelium- like cells ▪ Surrounded by lymphocytes and occasionally plasma cells ▪ Epitheloid macrophage = macrophages resemble epithelial cells ▪ giant cells = macrophages that develop into large “supercells” – they perform most of the “walling-off” function of a granuloma Many macrophages that fuse together  Chronic inflammation – the granuloma Immune granulomas involve the adaptive immune system A cell-mediated immune response is elicited (Type IV hypersensitivity) ▪ Inflammatory stimulus causes recruitment of macrophages and T- cells ▪ The inflammatory stimulus is ingested, antigen is presented to T- cells ▪ T-cells produce IL-2 and IFN-gamma ▪ IFN gamma contributes to activation of macrophages, leading to further antigen presentation, inflammation…. ▪ If the insult cannot be cleared, then a granuloma of epitheloid, activated macrophages and T-cells forms around the site Chronic inflammation – the granuloma Foreign-body granulomas: ▪ Usually a large foreign body that cannot be effectively phagocytosed is surrounded by macrophages – frustrated phagocytosis ▪ Frustrated phagocytosis can still lead to production of free radicals and proteases, which can damage extracellular matrix and viable cells Tuberculosis In the beginning of the 20th century, was the leading cause of death. ▪ Major manifestation is pneumonia, which results in large, widely-disseminated granulomas that destroy lung tissue and lead to pleural effusions ▪ TB can also spread to virtually any organ in the body – we will cover more in the respiratory system Pathological hallmark is the caseating granuloma ▪ Epitheloid macrophages and lymphocytes surround a necrotic core of caseous (“cheesy”) cellular debris – no distinct cellular structures can be seen with this type of necrosis