Advance Pathology 2024 PDF

# Advance Pathology 2024 ## Inflammation **Ass. Prof. Dr. Ahmed Qassim** Inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from...

# Advance Pathology 2024 ## Inflammation **Ass. Prof. Dr. Ahmed Qassim** Inflammation is a protective response involving host cells, blood vessels, and proteins and other mediators that intended to eliminate the initial cause of cell injury as well as the necrotic cells and tissues resulting from the original insult, and to initiate the process of repair. Inflammation accomplishes its protective mission by first diluting, destroying, or otherwise neutralizing harmful agents (e.g., microbes, toxins). It then sets into motion the events that eventually heal and repair the sites of injury. Without inflammation, infections would go unchecked and wounds would never heal. In the context of infections, inflammation is one component of a protective response that immunologists refer to as innate immunity. Although inflammation helps clear infections and other noxious stimuli and initiates repair, the inflammatory reaction and the subsequent repair process can themselves cause considerable harm. The components of the inflammatory reaction that destroy and eliminate microbes and dead tissues are also capable of injuring normal tissues. The cells and molecules of host defense, including leukocytes and plasma proteins, normally circulate in the blood, and the goal of the inflammatory reaction is to bring them to the site of infection or tissue damage. In addition, resident cells of vascular walls and the cells and proteins of the extracellular matrix (ECM) are also involved in inflammation and repair. ### Components of acute and chronic inflammation | Component | Source of Mediators | Immune Response | Macrophage | Elimination of Microbes, Dead Tissue | |---|---|---|---|---| | Mast Cell | Histamine, Others | | | | | Smooth Muscle | | | | Role in Immune Response | | Polymorphonuclear Leukocyte | | | | | | Plasma Proteins | | | | | | Lymphocyte | | | | | | Monocyte | | | | Source of Mediators (cytokines, others) | | Endothelium | | | | | | Basement Membrane | | | | | | Platelets | | | | Source of Mediators (nitric oxide, cytokines, others) | | | | Complement: mediators of inflammation, elimination of microbes | | Elimination of Microbes, Dead Tissue | | | | Clotting factors and kininogens mediators of inflammation | Fibroblasts | | | | | | Extracellular matrix proteins and cells | | | | | | | Repair | **Figure 2-1** The components of acute and chronic inflammatory responses and their principal functions! The roles of these cells and molecules in inflammation are described in this chapter. ### Acute vs. Chronic Inflammation | Feature | Acute | Chronic | |---|---|---| | Onset | Fast: minutes or hours | Slow: days | | Duration | Few minutes to few days | Days to years | | Cellular Infiltration | Mainly neutrophils | Monocytes/Macrophages & Lymphocytes | | Tissue Injury, Fibrosis | Usually mild and self-limited | Often severe and progressive | | Local and Systemic Signs | Prominent | Less prominent; may be subtle | Inflammation can be acute or chronic. * **Acute inflammation** is rapid in onset and of short duration, lasting from a few minutes to as long as a few days, and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation. * **Chronic inflammation** may be more insidious, is of longer duration (days to years), and is typified by influx of lymphocytes and macrophages with associated vascular proliferation and fibrosis (scarring). However, these two basic forms of inflammation may coexist, and many variables modify their course and histologic appearance. ### Inflammation is induced by chemical mediators Chemical mediators that are produced by host cells in response to injurious stimuli. When a microbe enters a tissue or the tissue is injured, the presence of the infection or damage is sensed by resident cells, mainly macrophages, but also dendritic cells, mast cells, and other cell types. These cells secrete molecules (cytokines and other mediators) that induce and regulate the subsequent inflammatory response. Inflammatory mediators are also produced from plasma proteins that react with the microbes or to injured tissues. Some of these mediators promote the efflux of plasma and the recruitment of circulating leukocytes to the site where the offending agent is located. The recruited leukocytes are activated and they try to remove the offending agent by phagocytosis. ### Steps of the Inflammatory Response 1. Recognition of the injurious agent 2. Recruitment of leukocytes 3. Removal of the agent 4. Regulation (control) of the response, and 5. Resolution (repair) ### Components of the Inflammatory Process * Leukocytes (WBCs) * Plasma proteins * Cell of vascular wall * Extracellular Matrix (ECM) ### The external manifestations of inflammation called cardinal signs of inflammation 1. Heat 2. Redness 3. Swelling 4. Pain 5. Loss of function ### Acute Inflammation Is a rapid response to injury or microbes and other foreign substances (lasting from a few minutes to few days), and is characterized by fluid and plasma protein exudation and a predominantly neutrophilic leukocyte accumulation. ### Stimuli for Acute Inflammation 1. Infections 2. Tissue necrosis 3. Foreign bodies 4. Immune Reactions ### Recognition of microbes, necrotic cells and foreign substances Microbes and dead cells must elicit some sort of "Danger signals" that distinguish them from normal tissues and mobilize the host response. Phagocytes, dendritic cells and many other cells, such as epithelial cells, express receptors that are designed to sense the presence of infectious pathogens and substances released from dead cells. These receptors called “pattern recognition receptors" and the most important families of these receptors are the following: * **Toll-like receptors (TLRs):** are microbial sensors which recognize products of bacteria, viruses and other pathogens. TLRs are located in plasma membranes and endosomes. Recognition of microbes by these receptors activates transcription factors that stimulate the production of number of secreted and membrane proteins including mediators of inflammation, antiviral cytokines (interferons), and proteins that promote lymphocyte activation and even more potent immune responses. * **The inflammasome:** is a multi-protein cytoplasmic complex that recognized products of dead cells, crystals and some microbial products. Triggering of the inflammasome results in activation of an enzyme called caspase-1, which cleaves precursor forms of the inflammatory cytokine interleukin-1ß (IL-1 B) into its biologically active form. IL-1 is an important mediator of leukocyte recruitment in the acute inflammatory response, and leukocytes phagocytose and destroy dead cells. ### Acute inflammation has 2 major components: 1. **Vascular changes:** * **Vasodialtion** (increase blood flow). * **Increase vascular permeability** (permit plasma proteins to leave the circulation). * **Activation of endothelil cells** (increased adhesion of leukocytes and migration of the leukocytes through the vessel wall). 2. **Cellular events:** * **Leukocyte recruitment.** * **Leukocyte activiation.** ### Vascular changes 1. **Vasodilation** • Increased blood flow - engorgement (causes heat and redness) → increased blood viscosity → leukocytes accumulate along the vascular endothelial surface (a process called margination). 2. **Increase vascular permeability** • Increased hydrostatic pressure → Movement of fluid from capillary into the tissue (Transudate), then movement of protein rich fluid and cells (Exudate) into the interstitium [This alteration is responsible for the swelling (tumor) edema]. ### Notes: • **Transudate:** extravascular fluid with low protein content, transudates accumulate in both inflammatory and non inflammatory conditions (e.g. heart failure, liver disease,...etc) • **Exudate:** extravascular fluid of high protein content, with cell debries. Exudates are typically seen in inflammation. • **Edema:** is abnormal accumulation of fluid in the interstitial tissue, beneath the skin or in the cavities of the body, which causes severe pain. ### Causes of increased vascular permeability 1. **Endothelial cell contraction leading to intercellular gaps.** It is a reversible process caused by histamine, bradykinin, leukotrienes......etc. (15-30 minutes). A slower and more prolonged retraction of endothelial cells may be induced by cytokines such as TNF and IL-1 (this reaction may take 4-6 hours to develop and persist for 24 hours or more). 2. **Direct endothelial cells injury (e.g. endothelial cell necrosis and detachment).** Lekage begins immediately after the injury and persists for several hours (or days) until the damaged vessels are thrombosed or repaired. 3. **Increased transcytosis of proteins by way of an intracellular vesicular pathway augments venular permeability, especially after exposure to certain mediators such as vascular endothelial growth factor (VEGF).** Transcytosis occurs through channels formed by fusion of intracellular vesicles. 4. **Leakage from new blood vessels.** Tissue repair involves new blood vessel formation (angiogenesis). These vessel sprouts remain leaky until proliferating endothelial cells mature sufficiently to form intercellular junctions. New endothelial cells also have increased expression of receptors for vasoactive mediators, and some of the factors that stimulate angiogenesis (e.g., VEGF) also directly induce increased vascular permeability. ### Cellular events 1. **Leukocyte recruitment:** • **Margination and rolling:** * **Margination** is the process when leukocytes pushed from the center of blood vessel and accumulated in the periphery of vessels. * **Rolling** is the process when leukocytes tumble on the endothelial surface. The weak adhesions involved in rolling are mediated by a group of adhesive molecules called Selectins. L- selectin (CD62L) present on leukocyte surface bind to their ligand on the surface of endothelial cell (GlyCam-1 also called CD34), p and E selectin (CD62P and CD62E) on the surface of endothelial cells bind to their ligand on the surface of leukocyte (sialyl-Lewis X). • **Adhesion and transmigration:** * **Adhesion:** The firm adhesion of leukocytes to endothelial cells mediated by integrins expressed on leukocyte surface interacting with their ligands on endothelial cells surface (intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1). * **Transmigration:** After adhesion, leukocytes migrate through the vessel wall by squeezing themselves through the endothelial junction (this movement of leukocytes known as Diapedesis). Platelet endothelial cell adhesion molecule-1 (PECAM-1) (also called CD31), which expressed on leukocytes and endothelial cells mediates the binding events needed for leukocytes to traverse the endothelium. After passing through the endothelium, leukocytes secrete Collagenase that enable them to pass through the vascular basement membrane. • **Chemotaxis:** * **Chemotaxis** is the directional movement of WBCs towards chemotactic agents at the site of injury (site of inflammation). The chemotactic agents include: 1. Exogenous substances such as soluble bacterial products. 2. Components of the complement system such as C5a. 3. Cytokines, especially those of the chemokine family (e.g. IL-8 which is chemoattractant for neutrophils). The chemotactic agents bind to specific receptors on leukocytes cell surface and induce their movement. The leukocytes move by anchoring themselves to the extracellular matrix (by pseudopods) and then pull the remainder of the cell after. The type of WBCs seen in the inflammatory response varies with the nature and severity of the injury (cause of inflammation) and the age of the inflammatory_lesion. In most types of acute inflammation, neutrophils predominate in the inflammatory infiltrate during the first 6-24 hours and are replaced by monocytes in 24-48 hours. In some types of acute inflammation such as those induced by hypersensitivity reactions or parasitic infestations, eosinophils are the main inflammatory cell type, while in viral infections lymphocytes may be the first cells to arrive. In chronic inflammation, mononuclear inflammatory cells (macrophages, lymphocytes and plasma cells) are the main cell type. ### Leukocyte activation Leukocyte activation may induced by bacterial or necrotic tissue products which had been sensed by receptors on the surface of WBC such as Toll like receptors and seven-transmembrane G protein coupled receptors. Engagement of these materials induces a number of responses in leukocyte (activation) include: 1. **Phagocytosis:** * Phagocytosis is the process of engulfing and destruction of the microbial agents and necrotic tissue debris by phagocytes such as neutrophils and macrophages. Steps of phagocytosis include: Recognition and Attachment, and Engulfment * **Recognition and attachment** Leukocytes surface have receptors which recognize and engulf microorganisms and dead cells or recognize host cell protein (which called opsonins) which coated the microbes. The most important opsonins are IgG and complement components. * **Engulfment** Pseudopodes from leukocytes are extended around the particle to be engulfed to form a phagocytic vacuole that contains the particle. 2. **Killing and degradation of microbes:** The key steps in this reaction are the production of microbicidal substances within lysosomes and fusion with phagosomes, thus exposing the ingested particles to the destructive mechanisms of the leukocytes. These mechanisms includes the production of reactive oxygen species (such as superoxide and hydrogen peroxide) and lysosomal enzyme. The ultimate step in phagocytosis of bacteria is killing and degradation. There are two forms of bacterial killing * **Oxygen-independent mechanism:** * This is mediate by some of the constituents of the primary and secondary granules of polymorphonuclear leukocytes. These include: Bactericidal permeability increasing protein (BPI) * Lysozymes * Lactoferrin * **Oxygen-dependent mechanism:** * There are two types of oxygen- dependent killing mechanisms * **Non-myeloperoxidase dependent** * The oxygen - dependent killing of microorganisms is due to formation of reactive oxygen species such as hydrogen peroxide (H2O2), super oxide (O2) and hydroxyl ion (HO-) and possibly single oxygen (102). These species have single unpaired electrons in their outer orbits that react with molecules in cell membrane or nucleus to cause damages. The destructive effects of H2O2 in the body are gauged by the action of the glutathione peroxidase and catalase. * **Myloperoxidase-dependent** * The bactericidal activity of H2O2 involves the lysosomal enzyme myeloperoxidase, which in the presence of halide ions converts H2O2 to hypochlorous acid (HOCI). This H2O2 - halide - myecloperoxidease system is the most efficient bactericidal system in neutrophils. A similar mechanism is also effective against fungi, viruses, protozoa and helminths. ### Effects of Inflammation * **Beneficial effects** * Diluting or destroying (neutralizing) of harmful agents * Protective antibodies which lead to lysis of microorganism by the complement system, or to enhance phagocytosis by opsonization. * Fibrin formation may impede the movement of microorganism and facilitate phagocytosis. * Stimulation of immunity when the inflammatory_exudate reach lymph nodes by lymphatic vessels; they stimulate an immune response, which provides antibodies and cellular mechanisms that may appear after few days and remain for years. * **Harmful effects** * Digestion of normal tissue by lysosomal enzymes such as collagenases and proteases which lead to tissue destruction. * Swelling of inflamed tissue may lead to serious mechanical effects, e.g., acute apiglottitis in children may cause suffocation. Also inflammatory swelling in enclosed space like cranial cavity may impair blood flow and leads to ischemic injury e.g. in case of encephalitis and meningitis. * Inappropriate inflammatory response e.g., the inflammatory response against the pollens may cause asthma and dyspnea. This may sometimes be severe enough to cause death. ### Outcome of acute inflammation: 1. Complete Resolution 2. Abscess formation 3. Healing by connective tissue (fibrosis) 4. Progression to chronic inflammation ### Chemical mediators of inflammation: | Mediators | Source | Action | |---|---|---| | Histamine and serotonin | Mast cells | Vasodilation | | Prostaglandins | Mast cells, leukocytes | Pain and fever | | Cyrokines (e.g. TNF, IL-1) | Mast cells, endothelial cells | Endothelial activation and acute phase response | | Chemokines | Leukocytes | Chemotaxis, WBCs activation | | Bradykinin | Plasma mediator | Vasodilation and pain | ### There are different morphologic types of acute inflammation: 1. **Serous inflammation** * This is characterized by an outpouring of a thin fluid that is derived from either the blood serum or secretion of mesothelial cells lining the peritoneal, pleural, and pericardial cavities. * The skin blister resulting from a burn or viral infection is a good example of the accumulation of a serous effusion either within or immediately beneath the epidermis of the skin. * Fluid in a serous cavity is called an effusion. * It resolves without reactions 2. **Fibrinous inflammation** * More severe injuries result in greater vascular permeability that ultimately leads to exudation of larger molecules such as fibrinogens through the vascular barrier. * Histologically, the accumulated extravascular fibrin appears as an eosinophilic meshwork of threads or sometimes as an amorphous coagulum * Fibrinous exudate is characteristic of inflammation in serous body cavities such as the pericardium (butter and bread appearance), pleura and meninges. Course of fibrinous inflammation include:a126 * Such exudates may be degraded by fibrinolysis, and the accumulated debris may be removed by macrophages, resulting in restoration of the normal tissue structure (resolution). * However, extensive fibrin-rich exudates may not be completely removed, and are replaced by an ingrowth of fibroblasts and blood vessels (organization), leading ultimately to scarring that may have significant clinical consequences. For example, organization of a fibrinous pericardial exudates forms dense fibrous scar tissue that bridges or obliterates the pericardial space and restricts myocardial function. 3. **Suppurative (Purulent) inflammation and abscess** * This type of inflammation is characterized by collection of large amounts of purulent exudate (pus). (Pus is a thick creamy liquid, yellowish or blood stained in colour and composed of: A large number of living or dead neutrophils (pus cells) Necrotic tissue debris Edema fluid * Certain organisms (e.g., staphylococci) are more likely to induce such localized suppuration and are therefore referred to as pyogenic (pus-forming). There are two types of suppurative inflammation: * **Abscess formation:** * Abscesses are focal collections of pus that may be caused by seeding of pyogenic organisms into a tissue or by secondary infections of necrotic foci. Abscesses typically have a central, largely necrotic region rimmed by a layer of preserved neutrophils, with a surrounding zone of dilated vessels and fibroblast proliferation indicative of attempted repair. As time passes, the abscess may become completely walled off and eventually be replaced by connective tissue. Because of the underlying tissue destruction, the usual outcome with abscess formation is scarring. * **Acute diffuse (phlegmonous) inflammation** * This is characterized by diffuse spread of the exudate through tissue spaces. It is caused by virulent bacteria (eg. streptococci) without either localization or marked pus formation. Example: Cellulitis. 4. **Ulcer** * Ulecer is a local defect, or excavation, of the surface of an organ or tissue that is produced by necrosis of cells and sloughing (shedding) of necrotic and inflammatory tissue. Ulceration can occur only when tissue necrosis and resultant inflammation exist on or near a surface. Ulcers are most commonly encountered in (1) the mucosa of the mouth, stomach, intestines, or genitourinary tract and (2) in the subcutaneous tissues of the lower extremities in older persons who have circulatory disturbances predisposing affected tissue to extensive necrosis. Ulcerations are best exemplified by peptic ulcer of the stomach or duodenum, in which acute and chronic inflammation coexist. During the acute stage, there is intense polymorphonuclear infiltration and vascular dilation in the margins of the defect. With chronicity, the margins and base of the ulcer develop scarring with accumulation of lymphocytes, macrophages, and plasma cells. 5. **Pseudomembranous inflammation** * The basic elements of pseudomembranous inflammation are extensive confluent necrosis of the surface epithelium of an inflamed mucosa and severe acute inflammation of the underlying tissues. The fibrinogens in the inflamed tissue coagulate within the necrotic epithelium. And the fibrinogen, the necrotic epithelium, the neutrophilic polymorphs, red blood cells, bacteria and tissue debris form a false (pseudo) membrane which forms a white or colored layer over the surface of inflamed mucosa. * Pseudomembranous inflammation is exemplified by Dipthetric infection of the pharynx or larynx and Clostridium difficille infection in the large bowel (Pseudomemranous colitis). # Chronic Inflammation Chronic inflammation is inflammation of prolonged duration (weeks to years), and is it characterized by: 1. Infiltration of mononuclear inflammatory cells i.e., macrophages, lymphocytes and plasma cells. 2. Tissue destruction (induced by the products of the inflammatory cells). 3. Repair, involving angiogenesis and fibrosis. ### Causes of chronic inflammation: * **Persistent infections associated with intracellular infection e.g. tuberculosis, leprosy, certain fungi etc characteristically cause chronic inflammation. These organisms are of low toxicity and evoke delayed hypersensitivity reactions.** * **Immune-mediated inflammatory diseases (e.g. hypersensitivity diseases).** * **Prolonged exposure to toxic agents nondegradable but partially toxic substances either endogenous lipid components which result in atherosclerosis or exogenous substances such as silica, asbestos.** * **Progression from acute inflammation: Acute inflammation almost always progresses to chronic inflammation e.g. persistent suppuration as a result of uncollapsed abscess cavities, foreign body materials (dirt, cloth, wool, etc), sequesterum in osteomylitis, or a sinus/fistula from chronic abscesses.** * **Autoimmuniy.** Autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosis are chronic inflammations from the outset. Chronic inflammation may developed from acute inflammation, or some forms of injury (e.g. viral infections) may stimulate chronic inflammatory response from the onset. ### Types of inflammatory cells in chronic inflammation * **Macrophages:** are the dominant cells of chronic inflammation (derived from circulating blood monocytes after their emigration from blood stream to tissue). Macrophages are normally diffusely scattered in most connective tissues and are also found in organs such as the liver (where they are called Kupffer cells), spleen and lymph nodes (where they are called sinus histiocytes), central nervous system (microglial cells), and lungs (alveolar macrophages). Together these cells constitute the so-called mononuclear phagocyte system, also known by the older name of reticuloendothelial system. In all tissues, macrophages act as filters for particulate matter, microbes, and senescent cells, as well as the effector cells that eliminate microbes in cellular and humoral immune responses. Monocytes arise from precursors in the bone marrow and circulate in the blood for only about a day. Under the influence of adhesion molecules and chemokines, they migrate to a site of injury within 24 to 48 hours after the onset of acute inflammation. When monocytes reach the extravascular tissue, they undergo transformation into macrophages, which are somewhat larger and have a longer lifespan and a greater capacity for phagocytosis than do blood monocytes. Tissue macrophages are activated by diverse stimuli to perform a range of functions. Two major pathways of macrophage activation, classical and alternative. * **Classical macrophage activation** is induced by microbial products such as endotoxin, by T cell-derived signals, importantly the cytokine IFN-y, and by foreign substances including crystals and particulate matter. Classically activated macrophages produce lysosomal enzymes, NO, and ROS, all of which enhance their ability to kill ingested organisms, and secrete cytokines that stimulate inflammation. These macrophages are important in host defense against ingested microbes and in many chronic inflammatory reactions. * **Alternative macrophage activation** is induced by cytokines other than IFN-y, such as IL-4 and IL-13, produced by T lymphocytes and other cells, including mast cells and eosinophils. Alternatively activated macrophages are not actively microbicidal; instead, their principal role is in tissue repair. They secrete growth factors that promote angiogenesis, activate fibroblasts and stimulate collagen synthesis. It may be that in response to most injurious stimuli, macrophages are initially activated by the classical pathway, designed to destroy the offending agents, and this is followed by alternative activation, which initiates tissue repair. However, such a precise sequence is not well documented in most inflammatory reactions Macrophages have several critical roles in host defense and the inflammatory response: * Macrophages ingest and eliminate microbes and dead tissues. Because macrophages respond to activating signals from T lymphocytes, they are the most important phagocytes in the cell-mediated arm of adaptive immune responses. * Macrophages initiate the process of tissue repair and are involved in scar formation and fibrosis. * Macrophages secrete mediators of inflammation, such as cytokines (TNF, IL-1, chemokines, and others) and eicosanolds. These cells are therefore central to the initiation and propagation of all inflammatory reactions. * Macrophages display antigens to T lymphocytes and respond to signals from T cells, thus setting up a feedback loop that is essential for defense against many microbes by cell mediated immune responses. The same bidirectional interactions are central to the development of chronic inflammatory diseases. After the initiating stimulus is eliminated and the inflammatory reaction abates, macrophages eventually die or wander off into lymphatics. In chronic inflammatory sites, however, macrophage accumulation persists, because of continued recruitment from the blood and local proliferation. IFN-y can also induce macrophages to fuse into large, multinucleate giant cells. * **Lymphocytes:** Both classes of lymphocytes migrate into inflammatory sites using some of the same adhesion molecule pairs and chemokines that recruit other leukocytes. In the tissues, B lymphocytes may develop into plasma cells, which secrete antibodies, and CD4+ T lymphocytes are activated to secrete cytokines. By virtue of cytokine secretion, CD4+ T lymphocytes promote inflammation and influence the nature of the inflammatory reaction. There are three subsets of CD4+ helper T cells that secrete different sets of cytokines and elicit different types of inflammation: * **TH1 cells** produce the cytokine IFN-Y, which activates macrophages in the classical pathway. * **TH2 cells** secrete IL-4, IL-5, and IL-13, which recruit and activate eosinophils and are responsible for the alternative pathway of macrophage activation. * **TH17 cells** secrete IL-17 and other cytokines that induce the secretion of chemokines responsible for recruiting neutrophils and monocytes into the reaction. Lymphocytes and macrophages interact in a bidirectional way, and these interactions play an important role in propagating chronic inflammation. Macrophages display antigens to T cells, express membrane molecules (called costimulators), and produce cytokines (IL-12 and others) that stimulate T cell responses. Activated T lymphocytes, in turn, produce cytokines (e.g. Interferon gamma) which recruit and activate macrophages and thus promote more antigen presentation and cytokine secretion. The result is a cycle of cellular reactions that fuel and sustain chronic inflammation. In some strong and prolonged inflammatory reactions, the accumulation of lymphocytes, antigen-presenting cells, and plasma cells may assume the morphologic features of lymphoid organs, and akin to lymph nodes, may even contain well-formed germinal centers. This pattern of lymphoid organogenesis is often seen in the synovium of patients with long-standing rheumatoid arthritis and the thyroid of patients with autoimmune thyroiditis. * **Other Cells** Eosinophils are characteristically found in inflammatory sites around parasitic infections and as part of immune reactions mediated by IgE, typically associated with allergies. Their recruitment is driven by adhesion molecules similar to those used by neutrophils, and by specific chemokines (e.g., eotaxin) derived from leukocytes and epithelial cells. Eosinophil granules contain major basic protein, a highly charged cationic protein that is toxic to parasites but also causes epithelial cell necrosis. Mast cells are sentinel cells widely distributed in connective tissues throughout the body, and they can participate in both acute and chronic inflammatory responses. In atopic persons (those prone to allergic reactions), mast cells are "armed" with IgE antibody specific for certain environmental antigens. When these antigens are subsequently encountered, the IgE-coated mast cells are triggered to release histamines and AA metabolites that elicit the early vascular changes of acute inflammation. IgE armed mast cells are central players in allergic reactions, including anaphylactic shock. Mast cells can also elaborate cytokines such as TNF and chemokines and may play a beneficial role in combating some infections. An important final point: Although the presence of neutrophils is the hallmark of acute inflammation, many forms of chronic inflammation may continue to show extensive neutrophilic infiltrates, as a result of either persistent microbes or necrotic cells, or mediators elaborated by macrophages. Such inflammatory lesions are sometimes called “acute on chronic"-for example, in inflammation of bones (osteomyelitis). ### Classification of chronic inflammation Chronic inflammation can be classified into the following two types based on histologic features: 1. **Nonspecific chronic inflammation: This involves a diffuse accumulation of macrophages and lymphocytes at site of injury that is usually productive with new fibrous tissue formations. e.g. Chronic cholecystitis.** 2. **Specific inflammation (granulomatous inflammation):** * **Definition:** Granulomatous inflammation is characterized by the presence of granuloma. A granuloma is a microscopic aggregate of epithelioid cells. Epithelioid cell is an activated macrophage, with a modified epithelial cell-like appearance (hence the name epithelioid). The epitheloid cells can fuse with each other & form multinucleated giant cells. So, even though, a granuloma is basically a collection of epithelioid cells, it also usually contains multinucleated giant cell & is usually surrounded by a cuff of lymphocytes and occasional plasma cells. There are two types of giant cells: Foreign body-type giant cells and Langhans giant cells in which the nuclei are arranged peripherally in a horse -shoe pattern which is seen typically in tuberculosis, sarcoidosis etc... * **Giant cells** are formed by fusion of macrophages perhaps by a concerted attempt of two or more cells to engulf a single particle. ### Causes of granulomatious inflammation include: * **Bacterial:** Tuberculosis, Leprosy, Syphilis, Cat scratch disease, Yersiniosis * **Fungal:** Histoplasmosis, Cryptococcosis, Coccidioidomycosis, Blastomycosis * **Helminthic:** Schistosomiasis * **Protozoal:** Leishmaniasis, Toxoplasmosis * **Chlamydia:** Lymphogranuloma venerum * **Inorganic material:** Berrylliosis * **Idiopathic:** Acidosis, Cohn's disease, Primary biliary cirrhosis ### Granulomatous inflammation Granulomatous inflammation is a distinctive pattern of chronic inflammation characterized by aggregation of activated macrophages that assume an epithelioid appearance. Epithelioid cell is an activated macrophage, with a modified epithelial cell-like appearance (hence the name epithelioid). The epitheloid cells can fuse with each other & form multinucleated giant cells. So, even though, a granuloma)is basically a collection of epithelioid cells, it also usually contains multinucleated giant cell & is usually surrounded by a cuff of lymphocytes and occasional plasma cells. There are two types of giant cells ### Granulomas: Granulomas are the morphologic and structural units of granulamatous inflammation. They are small collections of epithelioid cells usually surrounded by a rim of lymphocytes and sometimes fibroblasts. * **The granulomas of TB are characterized by central foci of caseation necrosis.** * **The epithelioid cell may fuse together to form multinucleated giant cells.** * **The multinucleated giant cells may or may not be present in the granulomas and thus they are not considered an essential component for the diagnosis of granulamatous inflammation.** * **The multinucleated giant cells may achieve diameters of 40 to 50 micrometers and may contain up to 50 nuclei.** ### **Types of giant cells** There are two morphological variants of multinucleated giant cells depending on distribution of their nuclei: 1. **Langhan's giant cells** in which the nuclei are arranged around the periphery (creating a horseshoe pattern). 2. **Foreign body giant cells** in which the nuclei are scattered randomly. Foreign body giant cells are so named because they are formed in the presence of large amounts of indigestible material (foreign bodies). ### Pathogenesis: There are two types of granulomas, which differ in their pathogenesis. * **A. Foreign body granuloma** These granulomas are initiated by inert foreign bodies such as talc, sutures (nonabsorbable), fibers, etc... that are large enough to preclude phagocytosis by a single macrophage and do not incite an immune response. * **B. Immune granulomas** Antigen presenting cells (macrophages) engulf a poorly soluble inciting agent. Then, the macrophage processes and presents part of the antigen (in association with MHC type2 molecules) to CD4+T helper 1 cells which become activated. The activated CD4+ T-cells produce cytokines (IL-2 and interferon gamma). The IL-2 activates other CD4+T helper cells and perpetuates the response while IFN-y is important in transforming macrophages into epitheloid cells and multinucleated giant cells. The cytokines have been implicated not only in the formation but also in the maintenance of granuloma. Macrophage inhibitory factor helps to localize activated macrophages and epithelioid cells.