{"id":946,"date":"2024-01-31T23:59:58","date_gmt":"2024-02-01T04:59:58","guid":{"rendered":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/?post_type=chapter&p=946"},"modified":"2026-01-25T21:44:05","modified_gmt":"2026-01-26T02:44:05","slug":"innate-non-specific-defenses-of-the-human-body-to-pathogens-normal-flora-phagocytes-complement-proteins-interferons-inflammation-and-fever","status":"web-only","type":"chapter","link":"https:\/\/pressbooks.bccampus.ca\/pathophysiology\/chapter\/innate-non-specific-defenses-of-the-human-body-to-pathogens-normal-flora-phagocytes-complement-proteins-interferons-inflammation-and-fever\/","title":{"raw":"Innate (Non-Specific) Defenses of the Human Body to Pathogens - Normal Flora, Phagocytes, Complement Proteins, Interferons, Inflammation and Fever","rendered":"Innate (Non-Specific) Defenses of the Human Body to Pathogens – Normal Flora, Phagocytes, Complement Proteins, Interferons, Inflammation and Fever"},"content":{"raw":"Innate (Non-Specific) Defenses of the Human Body to Pathogens - Normal Flora, Phagocytes, Complement Proteins, Interferons, Inflammation and Fever<\/strong>\r\n\r\n \r\n\r\nInnate Defenses:\u00a0 Normal Flora<\/strong>\r\n\r\nThe human microbiome consists of all of the micro-organisms that occupy the surface of the skin, eyes, hair, nails, nose, mouth, respiratory and digestive tracts, urethra, and vagina.\u00a0 The microbes in these regions that do not cause disease are often referred to as the normal flora.\u00a0 These micro-organisms are diverse in nature and are a combination of different types of bacteria, viruses, and fungi.\u00a0 Globally, each person can be inhabited by different populations of microbes, which are affected by climate, diet, and other factors.\u00a0 Even within one person, the local environments affect the populations found in each region.\u00a0 For example, the microbiota populations found on the wrists, differs from those found in the armpits, and those found in the intestines.\u00a0 The normal flora microbes are considered commensals,<\/strong> meaning that they co-exist with their host without causing harm.\u00a0 Typically normal flora micro-organisms benefit from the dead skin and secreted products on the surface of our bodies as well as from some of the nutrients we ingest.\u00a0 The relationship between microbiota and the human host is sometimes mutualistic<\/strong> in that both benefit.\u00a0 These beneficial micro-organisms can help prevent pathogenic microbes from being able to establish themselves and cause infection to the host.\u00a0 They do this by both occupying surface area and at at times secreting biochemicals that deter or harm pathogenic microbes.\u00a0 Intestinal microbes can be helpful in breaking down some food molecules as well as producing vitamins that human hosts benefit from.\r\n\r\n \r\n\r\n \r\n\r\nInnate Defenses:\u00a0 Phagocytes<\/strong>\r\n\r\nIn this unit, we will explore the major roles of all types<\/span>\u00a0of white blood cells (WBCs, also known as leukocytes).<\/span>\u00a0 Several types of WBCs are capable of phagocytosis of bacteria and cellular debris.\u00a0 These phagocytes include:\u00a0 neutrophils, monocytes, macrophages, dendritic cells, and eosinophils.\u00a0 The ability to phagocytose and destroy many different types of bacteria provides non-specific defense.\u00a0 Phagocytes are capable of ingesting bacteria or fungal cells and lysing them using either lytic enzymes, Reactive Oxidative Species, or lytic chemicals.\u00a0 The typical mechanism involves the pathogen being phagocytosed in a phagosome which fuses with a lysosome that contains lytic enzymes and chemicals.\r\n\r\nNeutrophils<\/strong> are produced by hemopoietic stem cells in the bone marrow and are the most abundant WBC, making up 70% of the population.\u00a0 Neutrophils circulate the blood stream and often the first to arrive in response to cellular damage.\u00a0 Inactive neutrophils live for 5 hours to 5 days, and activated neutrophils are capable of diapedesis, utilizing chemotaxis and amoeboid movement to consuming 200 bacteria and surviving for 1-2 days.\u00a0 At times neutrophils degranulate releasing toxic chemicals or NETs (Neutrophil Extracellular Traps composed of chromatin fibers and proteases) to destroy microbes in an extracellular fashion.\u00a0 Neutrophils are capable of ingesting 100-200 bacteria and releasing over 50 different toxins.\r\n\r\nMonocytes<\/strong> are immature macrophages that once produced by hemopoietic cells within the bone marrow circulate the blood and mature into either fixed macrophages, free macrophages, or dendritic cells within 1-3 days.\u00a0 Despite being immature, monocytes are capable of phagocytosing bacteria as well as secreting cytokines, and functioning as Antigen Presenting Cells (APCs).\u00a0 \u00a0Macrophages<\/strong> and dendritic cells<\/strong> contain large numbers of cytokines that are capable of inducing inflammation as well as recruiting immune cells (e.g. lymphocytes).\u00a0 Fixed macrophages<\/strong> are phagocytes that have exited the blood stream and utilize amoeboid movement to patrol tissue beds for cellular debris, cancerous cells, and pathogens.\u00a0 Several tissue-specific name have been given to fixed macrophages. For example, fixed macrophages within the brain are termed microglia.<\/strong>\u00a0 Alveolar macrophages in the lungs are sometimes termed dust cells.<\/strong>\u00a0 Macrophages in the liver are also known as stellate<\/strong> macrophages (or Kupffer cells).\u00a0 Macrophages in the vertebrae are referred to as histiocytes <\/strong>and macrophage in the skin are historically called Langerhan cells.\u00a0\u00a0Free macrophages<\/strong> circulate the blood stream, exiting through diapedesis (also known as extravasation, emigration, and transmigration) enter tissue beds to assist with the removal of bacteria, cellular debris, aged and dying neutrophils.\u00a0 Dendritic cells<\/strong> travel the blood stream and are located in tissues that are exposed to microbes (e.g. the skin and mucosa) and migrate to lymph nodes once activated in order to function as Antigen Presenting Cells (APCs) in the stimulation of T and B lymphocytes.\r\n\r\nEosinophils<\/strong> are another type of WBC capable of phagocytosis.\u00a0 Additionally they play roles in allergies and asthma as well as in the destruction of helminths (parasitic worms).\u00a0 \u00a0Eosinophils contain toxin-filled granules that can be released to kill pathogens.\u00a0 Toxins include Reactive Oxidative Species (ROS) as well as cationic (major basic) proteins, elastase (proteolytic) enzymes.\u00a0 Eosinophils circulate the blood stream and contain RNases to destroy viruses.\u00a0 Eosinophils can also release cytokines that regulate the immune system (eg. induce inflammation and activate immune cells).\u00a0 To assist in the healing process, eosinophils release growth factors (e.g. VEGF, vascular endothelial growth factor).\r\n\r\nSteps of Phagocytosis:<\/strong>\r\n
    \r\n \t
  1. Activation<\/strong> \u2013 A phagocyte (e.g. neutrophil, monocyte, macrophage, dendritic cell, eosinophil) is activated by pro-inflammatory cytokines.\u00a0 Activated phagocytes can recognize and adhere to cellular debris and foreign material, such as microbes and produce toxins such as anti-microbial oxidants (Reactive Oxidative Species, ROS).<\/li>\r\n \t
  2. Chemotaxis<\/strong> \u2013 Activated phagocytes follow chemokine trails and increasing concentration levels to the site of infection or injury.<\/span><\/li>\r\n \t
  3. Recognition<\/strong> and <\/span>Adherence<\/strong> \u2013 A phagocyte may not be able to bind to a bacterium, if it has a slime capsule or surface proteins.\u00a0 Opsonins (e.g. antibodies, lectin, complement proteins) that have bound to the bacterium facilitate phagocyte adherence to the bacterium.<\/span><\/li>\r\n \t
  4. Ingestion:<\/strong>\u00a0 Once attached, the phagocyte extends plasma membrane extensions (pseudopods) to surround the bacterium.\u00a0 When these pseudopods encircle the bacterium and meet, they form a vesicle called a phagosome around the bacterium which enables phagocytosis (a form of endocytosis).<\/span><\/li>\r\n \t
  5. Killing<\/strong> and <\/span>Recycling<\/strong> \u2013 Within the phagocyte, the phagosome fuses with a lysosome to create a phagolysosome.\u00a0 The lysosome\u2019s lytic enzymes kill the bacterium and the bacterial components are digested into smaller components in order to be recycled, displayed, or expelled.<\/span><\/li>\r\n \t
  6. Antigen Display<\/strong> \u2013 Within the phagocyte\u2019s endoplasmic reticulum, bacterial antigens are coupled to major histocompatibility complexes (MHC) and sent to the plasma membrane to be displayed on the surface of the phagocyte in order to stimulate recruitment and activation of the immune system cells (T cells and B cells).<\/span><\/li>\r\n \t
  7. Expulsion<\/strong> \u2013 The remaining undigested parts of the bacterium are in the phagolysosome, which fuses with the cell membrane to expel these undigestible parts as waste.<\/span><\/li>\r\n<\/ol>\r\nInnate Defenses:\u00a0 Natural Killer Cells<\/strong>\r\n\r\nNatural Killer (NK) cells<\/strong> are another type of WBC, specifically a lymphocyte which provides non-specific defense using different mechanisms than phagocytosis.\u00a0 All three types of lymphocytes (NK cells, T cells and B cells) arise from hemopoietic cells in the bone marrow.\u00a0 NK cells make up 5-20% of lymphocytes and circulate the bloodstream.\u00a0 NK cells are termed cytotoxic as they are able to kill other cells.\u00a0 Specifically, NK cells are able to recognize and destroy most damaged cells, abnormal cells, cancerous cells, virally- or bacterially-infected cells and extracellular pathogenic cells (bacteria, fungi, and protozoa).\u00a0 NK cells contain small granules of perforin<\/strong> and granzymes<\/strong> (protease proteins) that can be degranulated<\/strong> (exocytosed) when in close proximity to abnormal\/damaged\/cancerous\/infected cells or pathogens.\u00a0 NK cells are able to release perforin proteins that form portals in the targeted cells, allowing granzymes to enter and either induce apoptosis<\/strong> or allow the targeted cell to swell with water and lyse.<\/strong>\u00a0 NK cells are strategic, inducing apoptosis of virally-infected cells rather than lysing these cells in order to prevent any newly formed virions from being released, which could result in the infection of surrounding host cells.\u00a0 NK cells can release alpha-defensins<\/strong> as well which target bacterial cell walls for destruction.\u00a0 In the presence of infected or cancerous cells, NK cells release pro-inflammatory cytokines<\/strong> that aid in the activation of other WBCs (e.g. macrophages and neutrophils).\u00a0 In addition to providing innate defense, both NK cells and macrophages are responsible for recycling<\/strong> senescent cells (cells that have stopped replicating and are at risk of DNA damage often due to age).\r\n\r\n*Note: Defensins<\/strong> are a large family of anti-microbial peptides that disrupt bacterial or fungal structure or metabolism.\r\n\r\n**Note:\u00a0 Cancerous cells or pathogens that evade the NK cells can spread through tissue, blood or lymph to potentially create damage in multiple locations in the body.\r\n\r\n \r\n\r\nInnate Defenses:\u00a0 Complement System<\/strong>\r\n\r\nThe complement system is comprised of over 30 complement proteins produced by the liver, that circulate the blood.\u00a0 The complement proteins become active during infections and play a crucial role in the immune response.\u00a0 There are three complement pathways:\u00a0 Classical, Lectin, and Alternative.\r\n\r\nThe Classical Pathway<\/strong> is triggered by the presence of antibodies that have formed complexes with antigens on the surface of a pathogen (e.g. bacterial cell walls).\u00a0 This stimulates a cascade of complement protein activation, including C1, C2, C3, etc.\u00a0 Initially, C1 must bind to two antibodies to start the cascade.\u00a0 In each case of complement protein activation (Classical, Lectin and Alternative), there are 3 common outcomes.\u00a0 Firstly,\u00a0 C3b attaches to the bacterial cell wall and acts as an opsonin, enhancing phagocytosis.\u00a0 Secondly, the C3b proteins stimulate the formation of C5-9 into Membrane Attack Complexes (MAC), which create portals or pores in the bacterial cell leading to the entrance of water, cellular swelling and eventual rupture.\u00a0 \u00a0Thirdly, the activation complement proteins attract white blood cells for further defense and induce mast cells and basophils to release pro-inflammatory cytokines (e.g. histamine, prostaglandin, bradykinin, and leukotriene).\r\n\r\nThe Lectin Pathway<\/strong> utilizes Mannose-Binding Lectin (MBL), which is a protein produced by the liver that circulates the bloodstream.\u00a0 The Lectin Pathway is initiated by MBL binding to pathogen surfaces that contain mannose.\u00a0 Mannose is a sticky sugar (carbohydrate) used by some bacteria as part of their slimy capsule for adhesion.\u00a0 Mannose is also present on the surface of other pathogens:\u00a0 yeast, viruses, and protozoa.\u00a0 \u00a0Once MBL is bound to the pathogen's surface, a similar cascade of complement protein activation occurs, leading to C3b attachment to the pathogen cell wall or membrane.\u00a0 This results in functions similar to the Classical Pathway: opsonization, enhancing phagocytosis, inducing MAC pore formation, and promotion inflammation and recruitment of WBCs.\r\n\r\n*Some examples of pathogens that have been shown to be bound by MBL are:\u00a0 bacteria (e.g. Salmonella<\/em> and Streptococci)<\/em>,\u00a0 yeast (e.g. Candida albicans<\/em> which causes oral thrush and vaginal yeast infections), viruses (e.g. HIV, SARS CoV-2, and influenza A), and protozoa (Leishmania<\/em>, spread by sand flies).\r\n\r\nThe Alternative Pathway<\/strong> is independent of antibodies and lectin.\u00a0 The complement proteins upon recognizing the presence of a pathogen (e.g. bacteria, protozoa, fungi, or virally-infected cells) initiate the cascade themselves.\u00a0 Various proteins such as Properdin, Factor B, and Factor D contribute to complement activation and binding to the pathogen.\u00a0 In a similar manner to the Classical and Lectin Pathways, C3b attachment results in opsonization, enhancing phagocytosis, inducing MAC pore formation, and promotion inflammation and recruitment of WBCs.\r\n\r\n \r\n\r\nInnate Defenses:\u00a0 Interferons<\/strong>\r\n\r\nInterferons (IFNs)<\/strong> are a type of cytokines (signalling glycoproteins).\u00a0 Interferons are released by almost all cell types during any type of infection (viral, bacterial, fungal, protozoa).\u00a0 The name interferon is derived from their main function of interfering with viral replication.\u00a0 There are over 20 different IFN genes.\u00a0 Some IFNs act as anti-viral proteins (AVPs) blocking viral replication.\u00a0 Some IFNs act as endogenous pyrogens<\/strong> (inducing fever).\u00a0 The presence of interferons can also cause muscle pain, body aches, and flu-like symptoms.\u00a0 Type I interferons are produced by virally-infected cells and stimulate the expression of anti-viral proteins (AVPs) in neighbouring cells that will inhibit the viral replication of its RNA\/DNA.\u00a0 During an infection, alpha IFNs activate NK cells and macrophages,\u00a0 Gamma-interferons are released by NK cells, cytotoxic T cells (CD8 T lymphocytes) and helper T cells (CD4 T lymphocytes) and stimulate macrophage activity. Beta-interferons are produced by fibroblasts and are considered anti-inflammatory and are released in preparation for healing.\r\n\r\n \r\n\r\nCytokines:<\/strong>\u00a0 are a family of signalling glycoproteins that are produced by macrophages, B cells, T cells, mast cells, fibroblasts, endothelial cells, and stromal (connective tissue) cells.\u00a0 Some cytokines have a role in innate (non-specific defense) and some cytokines have a role in specifc defense and immune responses.\u00a0 There are four categories of cytokines that this unit will discuss.\r\n
      \r\n \t
    1. Interferons:<\/strong> as mentioned in the previous section, these cytokines have many subtypes and fulfill various roles. Interferons can be secreted by host cells, infected cells, NK cells, T cells, and fibroblasts.\u00a0 Interferons are released by cells in response to pathogens (viruses, bacteria, protozoa, fungi) and tumors. There are Type I, Type II, Type II interferons, and within the Type 1 category, there are alpha, beta and gamma interferons.\u00a0 The main roles of interferons are to interfere with viral replication, activate NK cell and macrophages during infection, act as endogenous pyrogens and slow down inflammation after infection in preparation for healing.<\/li>\r\n \t
    2. Chemokines: <\/strong>are responsible for inducing chemotaxis and recruitment of WBCs.<\/li>\r\n \t
    3. Lymphokines:<\/strong> are produced by T lymphocytes (T cells) to: a) attract macrophages and b) stimulate B lymphocytes (B cells)<\/li>\r\n \t
    4. Interleukins:<\/strong> as the name suggested are cytokines produced by leukocytes for signaling and activating each other.\u00a0 Specifically interleukins are produced by Helper T cells to: a) activate macrophages and stimulate fever (act as endogenous pyrogens); b) stimulate T & B cell differentiation; c) stimulate hemopoietic cells to proliferate producing more WBCs.<\/li>\r\n<\/ol>\r\n \r\n\r\nInnate Defenses:\u00a0 Inflammation<\/strong>\r\n\r\nInflammation<\/strong> is a protective response that is stimulated by any type of irritant or damage to cells. Possible causes of cellular damage or irritation include: cuts, blunt trauma, burns, infections, sprains, chemicals, ischemia, excess heat or cold, and foreign objects (e.g. thorns).\u00a0 Inflammation is an important innate response as it facilitates the removal of harmful irritants and pathogens and sets the stage for healing.\r\n\r\nTypically inflammation will occur when damaged cells release cytokines which trigger mast cell<\/strong> activation.\u00a0 Once activated, mast cells degranulate releasing pro-inflammatory cytokines such as histamine, bradykinin,<\/strong> and prostaglandin,<\/strong> all three of which cause vasodilation<\/strong> of local blood vessels resulting in increased blood flow to the area.\u00a0 These specific types of prostaglandins, bradykinin, and histamine also increase the permeability of local capillaries, resulting in plasma fluid leaking into the damaged tissue bed.\u00a0 This leaked plasma fluid (called exudate)<\/strong> contains plasma proteins such as fibrinogen as well as platelets.\u00a0 Platelets, fibrin, and clotting will form any necesary platelet plugs to seal any broken blood vessels.\u00a0 Additionally platelets and fibrin serve to contain the infected or damaged area.\u00a0 Platelets are even capable of coating or encircling bacteria, facilitating phagocytosis by neutrophils.\u00a0 At the same time, blood vessels are vasodilated which slows blood flow in this region which may be an asset for WBC diapedesis<\/strong> (movement of WBCs from inside the blood vessel to outside the blood vessel).\u00a0 \u00a0Additionally, blood vessel wall endothelial cells express factors that facilitate the stages of diapedesis<\/strong> (emigration) of WBCs into the tissue bed.\u00a0 Specifically, endothelial cells express receptors that stimulate WBC rolling and adhesion and then will express enzymes to loosen junctions between neighbouring endothelial cells to facilitate transmigration (WBC exiting blood vessel to enter tissue bed).\r\n\r\nThere are many chemokines<\/strong> are secreted by several cell types including endothelial cells and mast cells to induce chemotaxis of WBCs.\u00a0 In fact, it has been found that there are various contributors (cells, pro-inflammatory cytokines, and chemokines) to the inflammatory response, which serves to increase the movement and recruitment of neutrophils, monocytes, macrophages, dendritic<\/strong> cells, eosinophils<\/strong> and basophils.<\/strong>\u00a0 Not only do WBCs contribute to removal of pathogens and cellular debris, they also secrete growth factors to stimulate healing.\r\n\r\nIt is often state that there are two phases of inflammation: vascular<\/strong> and cellular.<\/strong>\u00a0 In the vascular phase,\u00a0 vasodilation and increased capillary permeability are occuring within local blood vessels.\u00a0 In the cellular phase, emigration of the WBCs is occurring.\r\n\r\nLocal Effects of Inflammation:<\/strong>\r\n\r\nThere are 5 possible signs of inflammation<\/strong>, some of which are viewable from the surface when the injury affects the skin or underlying connective tissue.\u00a0 These 5 signs are: redness, warmth, swelling, pain,<\/strong> and sometimes loss of function<\/strong>.\u00a0 The increased blood flow (hyperemia) causes both redness and warmth as blood temperature (37C) is often slightly warmer than surface tissues of the body.\u00a0 The increased capillary permeability allows for leaked plasma fluid (exudate) leaking into interstitial spaces causes the swelling, which can be called edema when the amount of leaked fluid is substantial.\u00a0 Several chemicals can trigger nociceptors<\/strong> (pain sensory neuron receptors).\u00a0 For example, chemicals released by damaged cells, chemicals released from mast cells and basophils (e.g. histamine, prostaglandins, leukotriene and bradykinin).\u00a0 Leaked blood and extracellular ATP can trigger nociceptors as can pressure building up from exudate.\u00a0 Interestingly, it has been found that histamine stimulates a particular type of nociceptor which gives rise to an itching sensation.\r\n\r\nThere are four types of exudate: serous, fibrinous, purulent<\/strong> and hemorrhagic.<\/strong>\u00a0 Serous exudate is watery, containing some proteins and WBCs.\u00a0 Small burn blisters that haven't be punctured, typically contain serous exudate.\u00a0 \u00a0Fibrinous exudate found in severe injuries and infections is thick, sticky, contains fibrin and is associated with an increase of scar tissue formation.\u00a0 Purulent exudate is often thick, yellow-green, containing WBCs and micro-organisms occurring in bacterially-infected abscesses and acne.\u00a0 Hemorrhagic exudate contains blood from damaged blood vessels.\u00a0 At times the swelling during inflammation results in loss of function.\u00a0 For example, loss of mobility in joints can occur due to swelling or pain, and within the lungs, exudate can reduce gas exchange in lungs due to fluid accumulation within the alveoli or interstial spaces.\r\n\r\nSystemic Effects of Inflammation:<\/strong>\r\n\r\nThere are several systemic effects that arise during the inflammatory response:\u00a0 mild fever, malaise, fatigue, headache, and loss of appetite.\u00a0 \u00a0At times decreased mental function can occur particularly in the elderly.\r\n\r\n \r\n\r\n*Note:\u00a0 Problems can arise when too little inflammation occurs.\u00a0 In some immunosuppressive<\/strong> diseases, too little inflammation can result in prolonged irritation, damage, infection of tissues and greater amounts of tissue damage which could be permanent depending on the location.\r\n\r\n**Note:\u00a0 Unfortunately, too much inflammation can also be a problem.\u00a0 Chronic health issues such as atherosclerosis, osteoarthritis, autoimmune<\/strong> diseases, allergies,<\/strong> and asthma<\/strong> stimulate prolonged inflammatory responses resulting in too much WBC activity which leads to cyclical deteriorative bouts of tissue healing and destruction.\u00a0 It has been found that the cytokine leukotriene plays a role in prolonged inflammation.\u00a0 Leukotriene, as the name suggests is produced by many types of leukocytes including mast cells, basophils, neutrophils, monocytes, and eosinophils. Leukotriene is a vasodilator, it increases capillary permeability, and within cases of asthma has been found to be a potent bronchoconstrictor.\r\n\r\n***Note:\u00a0 The cytokines involved in inflammation, Histamine<\/strong> (a nitrogenous compound), Bradykinin<\/strong> peptides (activated through enzymatic cleavage of its kinogen precursor), and the lipids Prostaglandin <\/strong>and Leukotrienes<\/strong> are referred to as vasoactive<\/strong> compounds as they all induce a change in blood vessel diameter (the prefix, vaso- referring to blood vessel).\u00a0 They also play a strong role in causing bronchoconstriction, bronchiole\/intestinal mucus production and chemotaxis of WBCs.\u00a0 Mucus is helpful in immobilizing pathogens and cellular debris and within the respiratory tract and bronchioles, cilia assist in clearing (or sweeping) this mucus towards the esophagus entrance to be swallowed in what is referred to as the mucociliary escalator .\u00a0 \u00a0In addition to mast cells and basophils, macrophages also release pro-inflammatory prostaglandins.\u00a0 Activated platelets also secrete platelet activating cytokines and pro-inflammatory prostaglandins.\r\n\r\n****Note:\u00a0 During healing of a wound, in addition to the surrounding tissue cells (mesenchymal cells, endothelial cells, fibroblasts, epithelial cells), the following activated WBCs (macrophages, T-lymphocytes) have been found to secrete growth factors<\/strong> (EGF, TGF-alpha, PDGF, FGF-1, FGF-2, PDGF, TGF-alpha, TGF-beta) to stimulate healing.\r\n\r\n \r\n\r\nInnate Defenses:\u00a0 Fever<\/strong>\r\n\r\nThe rise in body temperature above 37.2\u00b0C is termed a fever and can occur when pyrogens are released in response to cellular damage or irritation.\u00a0 As with inflammation, fever can be caused by any type of cellular damage or irritation (e.g. cuts, blunt trauma, burns, infections, sprains, chemicals, ischemia, excess heat or cold, and even heart attacks, strokes and some degenerative disease).\u00a0 Low-grade fever (38-39\u00b0C) is an important innate response as it accelerates WBC activity, inhibits pathogen metabolism and replication rates, and speeds up healing.\r\n\r\nChemicals that stimulate the thermoregulation center in the hypothalamus to increase body temperature are termed pyrogens.\u00a0 Endogenous pyrogens (e.g. interferons and interleukins) are those produced by the body whereas exogenous pyrogens are foreign components (e.g. LPS, Lipopolysaccharides of bacterial cell walls).\r\n\r\nThere are four stages of fever:\r\n
        \r\n \t
      1. Prodromal<\/strong> - in this stage you're just starting to not feel well and pyrogens are beginning to circulate..<\/li>\r\n \t
      2. Chills<\/strong> - when the pyrogens stimulate the hypothalamus thermoregulatory center to reset the thermostat to a higher temperature (e.g. 39\u00b0F), and your body is not yet at 39\u00b0F, you feel cold and have the chills (even though you are likely 37\u00b0C or even warmer). During this stage your body is increasing it's temperature by: shivering, and through behavioural changes (e.g. putting on a sweater or climbing under blankets).\u00a0 When you are shivering you may notice that the erector pili muscles in your skin that hold your hair follicles are contracting giving the appearance of goose bumps, and also generating heat (through muscle contraction).\u00a0 You may also notice that your skin becomes paler as cutaneous blood vessels vasoconstrict in order to reduce loss of heat through radiation from your body.\u00a0 Other autonomic responses are occurring that also generate heat including an increased heart rate and increased basal metabolic rate.<\/li>\r\n \t
      3. Flush<\/strong> - in this stage you have a fever (your temperature is above 37.2F) and you will stay in this stage as long as pyrogens are still stimulating your hypothalamus.<\/li>\r\n \t
      4. Defervescence<\/strong> (Sweating) - when the infection or injury has been resolved, the number of pyrogens circulating will diminish and the hypothalamus thermoregulatory center will reset to 37\u00b0F.\u00a0 During this stage your body will need to cool off in order to be 37\u00b0F and will therefore do the following in order to increase heat loss:\u00a0 a) vasodilate cutaneous blood vessels to allow more heat to radiate from the body; b) sweat; c) reduce BMR and heart rate; d) feel tired and reduce movement and muscle contractions; and e) remove extra clothing (e.g. sweaters) and blankets.<\/li>\r\n<\/ol>\r\n*Note:\u00a0 High, spiking fever (40\u00b0C or above) can be dangerous as it can induce febrile seizures, which put the brain at risk for neural damage.\u00a0 High temperature is also exhibited in those suffering from heat stroke, and the inability to thermoregulate to cool oneself.\r\n\r\n**Blunted or absent febrile response to an infection can occur in the elderly or immunosuppressed and this may delay diagnosis and treatment.\r\n\r\n***Fever of Unknown Origin, FUO are thought to be caused by inflammatory responses to undetectable cellular damage (possibly due to infections, trauma, cancer, heart attacks, blood clots, inflammatory diseases, or drug reactions, etc.)\r\n\r\n****Systemic Inflammatory Response Syndrome can be fatal and is associated with an enormous release of inflammatory cytokines causing systemic vasodilation, capillary permeability which results in hypotension and cirulatory shock.\u00a0 Most freuqent causes include sepsis.\r\n\r\n[h5p id=\"114\"]\r\n\r\n \r\n\r\nSummary:\u00a0 <\/strong>Normal Innate Defenses of the Body:<\/strong>\r\n
          \r\n \t
        • Innate (non-specific) Defenses:<\/span><\/strong>\r\n
            \r\n \t
          • Mechanical\/Physical<\/strong>\u00a0- skin, hair, mucus, sebum, urination, cilia, cell shedding<\/span><\/li>\r\n \t
          • Biochemical<\/strong> - <\/span>sweat, tears & saliva (lysozymes), bile, stomach pH, cerumen, mucus, vaginal secretions, prostatic and testicular secretions,<\/li>\r\n \t
          • Normal Flora<\/span><\/strong><\/li>\r\n \t
          • \r\n
            Phagocytes:<\/strong> (WBCs such as monocytes, fixed and free macrophages, microglia, neutrophils, eosinophils, dendritic cells) capable of diapedesis\/emigration\/transmigration.<\/div><\/li>\r\n \t
          • Complement System<\/strong> (Classical Pathway with antibody, Lectin Pathway, and Alternative Pathway) - involving 30+ complement plasma protein cascade of activation - resulting in opsonization, MAC (Membrane Attack Complexes), stimulation of mast cells & basophils<\/li>\r\n \t
          • Cytokine family:<\/strong>\u00a0 Glycoproteins produced by WBCs, fibroblasts, endothelial cells, stromal (connect tissue) cells\r\n
              \r\n \t
            • \r\n
              Interferons:<\/strong> (chemical messages that stimulate defense)<\/div>\r\n
                \r\n \t
              • Alpha Interferons<\/strong> - produced by virally infected host cells to attract & stimulate NK cells and stimulate AVP production in neighbouring cells.<\/li>\r\n \t
              • Beta Interferons<\/strong> - produced by fibroblasts to slow inflammation, and promote healing<\/li>\r\n \t
              • Gamma Interferons<\/strong> - produced by T\u00a0 & NK cells to stimulate macrophage activity<\/li>\r\n<\/ul>\r\n<\/li>\r\n \t
              • \r\n
                Chemokines:<\/strong> induce chemotaxis<\/div><\/li>\r\n \t
              • \r\n
                Lymphokines:<\/strong> produced by T lymphocytes to: 1) attract macrophages & 2) stimulate B lymphocytes to produce antibodies<\/div><\/li>\r\n \t
              • \r\n
                Interleukins:<\/strong> produced by helper T cells to:<\/div>\r\n
                1. activate macrophages and stimulate fever (act as endogenous pyrogens)<\/div>\r\n
                2. stimulate T & B cell differentiation<\/div>\r\n
                3. Stimulate hemopoietic cells to proliferate \u2192 producing more WBCs<\/div><\/li>\r\n \t
              • \r\n
                Natural Killer cells (NK Lymphocytes) - type of WBC (White Blood Cell\/Leukocyte)<\/div><\/li>\r\n<\/ul>\r\n<\/li>\r\n \t
              • Inflammatory Response<\/strong><\/li>\r\n \t
              • Fever<\/strong> - speeds up WBC activity and repairs, inhibits pathogen activity<\/li>\r\n<\/ul>\r\n<\/li>\r\n<\/ul>\r\nThink About Questions:<\/strong>\r\n\r\nWhy is inflammation considered a non-specific defense?\u00a0 What are other non-specific defenses of the human body?<\/strong>\r\n\r\nWhy does inflammation occur any time that there is an injury or disease?<\/strong>\r\n\r\nDid you know that biologists sometimes call the digestive system an external tube that penetrates the body?\u00a0 Name one feature of the digestive system that prevents ingested microbes from causing an infection.\u00a0<\/strong>\r\n\r\nWhy does taking an antacid put you more at risk for stomach infections?<\/strong>\r\n\r\nImagine you have a papercut - list the innate factors of your body that will help eliminate the bacteria that enter that cut.\u00a0<\/strong>\r\n\r\nOn a neutrophil, define the following: pseudopod, phagosome, lysosome, granule<\/strong>\r\n\r\nHow does a NK cells kill bacteria?<\/strong>\r\n\r\nWhat is properdin?<\/strong>\r\n\r\nWhat is an interferon?<\/strong>\r\n\r\nWhat is a respiratory burst?<\/strong>\r\n\r\nDid you know that some diseases are caused by auto-antibodies?\u00a0 And some are caused by auto-complement proteins?\u00a0 https:\/\/www.thelancet.com\/journals\/lancet\/article\/PIIS0140-6736(23)01524-6\/fulltext","rendered":"

                Innate (Non-Specific) Defenses of the Human Body to Pathogens – Normal Flora, Phagocytes, Complement Proteins, Interferons, Inflammation and Fever<\/strong><\/p>\n

                 <\/p>\n

                Innate Defenses:\u00a0 Normal Flora<\/strong><\/p>\n

                The human microbiome consists of all of the micro-organisms that occupy the surface of the skin, eyes, hair, nails, nose, mouth, respiratory and digestive tracts, urethra, and vagina.\u00a0 The microbes in these regions that do not cause disease are often referred to as the normal flora.\u00a0 These micro-organisms are diverse in nature and are a combination of different types of bacteria, viruses, and fungi.\u00a0 Globally, each person can be inhabited by different populations of microbes, which are affected by climate, diet, and other factors.\u00a0 Even within one person, the local environments affect the populations found in each region.\u00a0 For example, the microbiota populations found on the wrists, differs from those found in the armpits, and those found in the intestines.\u00a0 The normal flora microbes are considered commensals,<\/strong> meaning that they co-exist with their host without causing harm.\u00a0 Typically normal flora micro-organisms benefit from the dead skin and secreted products on the surface of our bodies as well as from some of the nutrients we ingest.\u00a0 The relationship between microbiota and the human host is sometimes mutualistic<\/strong> in that both benefit.\u00a0 These beneficial micro-organisms can help prevent pathogenic microbes from being able to establish themselves and cause infection to the host.\u00a0 They do this by both occupying surface area and at at times secreting biochemicals that deter or harm pathogenic microbes.\u00a0 Intestinal microbes can be helpful in breaking down some food molecules as well as producing vitamins that human hosts benefit from.<\/p>\n

                 <\/p>\n

                 <\/p>\n

                Innate Defenses:\u00a0 Phagocytes<\/strong><\/p>\n

                In this unit, we will explore the major roles of all types<\/span>\u00a0of white blood cells (WBCs, also known as leukocytes).<\/span>\u00a0 Several types of WBCs are capable of phagocytosis of bacteria and cellular debris.\u00a0 These phagocytes include:\u00a0 neutrophils, monocytes, macrophages, dendritic cells, and eosinophils.\u00a0 The ability to phagocytose and destroy many different types of bacteria provides non-specific defense.\u00a0 Phagocytes are capable of ingesting bacteria or fungal cells and lysing them using either lytic enzymes, Reactive Oxidative Species, or lytic chemicals.\u00a0 The typical mechanism involves the pathogen being phagocytosed in a phagosome which fuses with a lysosome that contains lytic enzymes and chemicals.<\/p>\n

                Neutrophils<\/strong> are produced by hemopoietic stem cells in the bone marrow and are the most abundant WBC, making up 70% of the population.\u00a0 Neutrophils circulate the blood stream and often the first to arrive in response to cellular damage.\u00a0 Inactive neutrophils live for 5 hours to 5 days, and activated neutrophils are capable of diapedesis, utilizing chemotaxis and amoeboid movement to consuming 200 bacteria and surviving for 1-2 days.\u00a0 At times neutrophils degranulate releasing toxic chemicals or NETs (Neutrophil Extracellular Traps composed of chromatin fibers and proteases) to destroy microbes in an extracellular fashion.\u00a0 Neutrophils are capable of ingesting 100-200 bacteria and releasing over 50 different toxins.<\/p>\n

                Monocytes<\/strong> are immature macrophages that once produced by hemopoietic cells within the bone marrow circulate the blood and mature into either fixed macrophages, free macrophages, or dendritic cells within 1-3 days.\u00a0 Despite being immature, monocytes are capable of phagocytosing bacteria as well as secreting cytokines, and functioning as Antigen Presenting Cells (APCs).\u00a0 \u00a0Macrophages<\/strong> and dendritic cells<\/strong> contain large numbers of cytokines that are capable of inducing inflammation as well as recruiting immune cells (e.g. lymphocytes).\u00a0 Fixed macrophages<\/strong> are phagocytes that have exited the blood stream and utilize amoeboid movement to patrol tissue beds for cellular debris, cancerous cells, and pathogens.\u00a0 Several tissue-specific name have been given to fixed macrophages. For example, fixed macrophages within the brain are termed microglia.<\/strong>\u00a0 Alveolar macrophages in the lungs are sometimes termed dust cells.<\/strong>\u00a0 Macrophages in the liver are also known as stellate<\/strong> macrophages (or Kupffer cells).\u00a0 Macrophages in the vertebrae are referred to as histiocytes <\/strong>and macrophage in the skin are historically called Langerhan cells.\u00a0\u00a0Free macrophages<\/strong> circulate the blood stream, exiting through diapedesis (also known as extravasation, emigration, and transmigration) enter tissue beds to assist with the removal of bacteria, cellular debris, aged and dying neutrophils.\u00a0 Dendritic cells<\/strong> travel the blood stream and are located in tissues that are exposed to microbes (e.g. the skin and mucosa) and migrate to lymph nodes once activated in order to function as Antigen Presenting Cells (APCs) in the stimulation of T and B lymphocytes.<\/p>\n

                Eosinophils<\/strong> are another type of WBC capable of phagocytosis.\u00a0 Additionally they play roles in allergies and asthma as well as in the destruction of helminths (parasitic worms).\u00a0 \u00a0Eosinophils contain toxin-filled granules that can be released to kill pathogens.\u00a0 Toxins include Reactive Oxidative Species (ROS) as well as cationic (major basic) proteins, elastase (proteolytic) enzymes.\u00a0 Eosinophils circulate the blood stream and contain RNases to destroy viruses.\u00a0 Eosinophils can also release cytokines that regulate the immune system (eg. induce inflammation and activate immune cells).\u00a0 To assist in the healing process, eosinophils release growth factors (e.g. VEGF, vascular endothelial growth factor).<\/p>\n

                Steps of Phagocytosis:<\/strong><\/p>\n

                  \n
                1. Activation<\/strong> \u2013 A phagocyte (e.g. neutrophil, monocyte, macrophage, dendritic cell, eosinophil) is activated by pro-inflammatory cytokines.\u00a0 Activated phagocytes can recognize and adhere to cellular debris and foreign material, such as microbes and produce toxins such as anti-microbial oxidants (Reactive Oxidative Species, ROS).<\/li>\n
                2. Chemotaxis<\/strong> \u2013 Activated phagocytes follow chemokine trails and increasing concentration levels to the site of infection or injury.<\/span><\/li>\n
                3. Recognition<\/strong> and <\/span>Adherence<\/strong> \u2013 A phagocyte may not be able to bind to a bacterium, if it has a slime capsule or surface proteins.\u00a0 Opsonins (e.g. antibodies, lectin, complement proteins) that have bound to the bacterium facilitate phagocyte adherence to the bacterium.<\/span><\/li>\n
                4. Ingestion:<\/strong>\u00a0 Once attached, the phagocyte extends plasma membrane extensions (pseudopods) to surround the bacterium.\u00a0 When these pseudopods encircle the bacterium and meet, they form a vesicle called a phagosome around the bacterium which enables phagocytosis (a form of endocytosis).<\/span><\/li>\n
                5. Killing<\/strong> and <\/span>Recycling<\/strong> \u2013 Within the phagocyte, the phagosome fuses with a lysosome to create a phagolysosome.\u00a0 The lysosome\u2019s lytic enzymes kill the bacterium and the bacterial components are digested into smaller components in order to be recycled, displayed, or expelled.<\/span><\/li>\n
                6. Antigen Display<\/strong> \u2013 Within the phagocyte\u2019s endoplasmic reticulum, bacterial antigens are coupled to major histocompatibility complexes (MHC) and sent to the plasma membrane to be displayed on the surface of the phagocyte in order to stimulate recruitment and activation of the immune system cells (T cells and B cells).<\/span><\/li>\n
                7. Expulsion<\/strong> \u2013 The remaining undigested parts of the bacterium are in the phagolysosome, which fuses with the cell membrane to expel these undigestible parts as waste.<\/span><\/li>\n<\/ol>\n

                  Innate Defenses:\u00a0 Natural Killer Cells<\/strong><\/p>\n

                  Natural Killer (NK) cells<\/strong> are another type of WBC, specifically a lymphocyte which provides non-specific defense using different mechanisms than phagocytosis.\u00a0 All three types of lymphocytes (NK cells, T cells and B cells) arise from hemopoietic cells in the bone marrow.\u00a0 NK cells make up 5-20% of lymphocytes and circulate the bloodstream.\u00a0 NK cells are termed cytotoxic as they are able to kill other cells.\u00a0 Specifically, NK cells are able to recognize and destroy most damaged cells, abnormal cells, cancerous cells, virally- or bacterially-infected cells and extracellular pathogenic cells (bacteria, fungi, and protozoa).\u00a0 NK cells contain small granules of perforin<\/strong> and granzymes<\/strong> (protease proteins) that can be degranulated<\/strong> (exocytosed) when in close proximity to abnormal\/damaged\/cancerous\/infected cells or pathogens.\u00a0 NK cells are able to release perforin proteins that form portals in the targeted cells, allowing granzymes to enter and either induce apoptosis<\/strong> or allow the targeted cell to swell with water and lyse.<\/strong>\u00a0 NK cells are strategic, inducing apoptosis of virally-infected cells rather than lysing these cells in order to prevent any newly formed virions from being released, which could result in the infection of surrounding host cells.\u00a0 NK cells can release alpha-defensins<\/strong> as well which target bacterial cell walls for destruction.\u00a0 In the presence of infected or cancerous cells, NK cells release pro-inflammatory cytokines<\/strong> that aid in the activation of other WBCs (e.g. macrophages and neutrophils).\u00a0 In addition to providing innate defense, both NK cells and macrophages are responsible for recycling<\/strong> senescent cells (cells that have stopped replicating and are at risk of DNA damage often due to age).<\/p>\n

                  *Note: Defensins<\/strong> are a large family of anti-microbial peptides that disrupt bacterial or fungal structure or metabolism.<\/p>\n

                  **Note:\u00a0 Cancerous cells or pathogens that evade the NK cells can spread through tissue, blood or lymph to potentially create damage in multiple locations in the body.<\/p>\n

                   <\/p>\n

                  Innate Defenses:\u00a0 Complement System<\/strong><\/p>\n

                  The complement system is comprised of over 30 complement proteins produced by the liver, that circulate the blood.\u00a0 The complement proteins become active during infections and play a crucial role in the immune response.\u00a0 There are three complement pathways:\u00a0 Classical, Lectin, and Alternative.<\/p>\n

                  The Classical Pathway<\/strong> is triggered by the presence of antibodies that have formed complexes with antigens on the surface of a pathogen (e.g. bacterial cell walls).\u00a0 This stimulates a cascade of complement protein activation, including C1, C2, C3, etc.\u00a0 Initially, C1 must bind to two antibodies to start the cascade.\u00a0 In each case of complement protein activation (Classical, Lectin and Alternative), there are 3 common outcomes.\u00a0 Firstly,\u00a0 C3b attaches to the bacterial cell wall and acts as an opsonin, enhancing phagocytosis.\u00a0 Secondly, the C3b proteins stimulate the formation of C5-9 into Membrane Attack Complexes (MAC), which create portals or pores in the bacterial cell leading to the entrance of water, cellular swelling and eventual rupture.\u00a0 \u00a0Thirdly, the activation complement proteins attract white blood cells for further defense and induce mast cells and basophils to release pro-inflammatory cytokines (e.g. histamine, prostaglandin, bradykinin, and leukotriene).<\/p>\n

                  The Lectin Pathway<\/strong> utilizes Mannose-Binding Lectin (MBL), which is a protein produced by the liver that circulates the bloodstream.\u00a0 The Lectin Pathway is initiated by MBL binding to pathogen surfaces that contain mannose.\u00a0 Mannose is a sticky sugar (carbohydrate) used by some bacteria as part of their slimy capsule for adhesion.\u00a0 Mannose is also present on the surface of other pathogens:\u00a0 yeast, viruses, and protozoa.\u00a0 \u00a0Once MBL is bound to the pathogen’s surface, a similar cascade of complement protein activation occurs, leading to C3b attachment to the pathogen cell wall or membrane.\u00a0 This results in functions similar to the Classical Pathway: opsonization, enhancing phagocytosis, inducing MAC pore formation, and promotion inflammation and recruitment of WBCs.<\/p>\n

                  *Some examples of pathogens that have been shown to be bound by MBL are:\u00a0 bacteria (e.g. Salmonella<\/em> and Streptococci)<\/em>,\u00a0 yeast (e.g. Candida albicans<\/em> which causes oral thrush and vaginal yeast infections), viruses (e.g. HIV, SARS CoV-2, and influenza A), and protozoa (Leishmania<\/em>, spread by sand flies).<\/p>\n

                  The Alternative Pathway<\/strong> is independent of antibodies and lectin.\u00a0 The complement proteins upon recognizing the presence of a pathogen (e.g. bacteria, protozoa, fungi, or virally-infected cells) initiate the cascade themselves.\u00a0 Various proteins such as Properdin, Factor B, and Factor D contribute to complement activation and binding to the pathogen.\u00a0 In a similar manner to the Classical and Lectin Pathways, C3b attachment results in opsonization, enhancing phagocytosis, inducing MAC pore formation, and promotion inflammation and recruitment of WBCs.<\/p>\n

                   <\/p>\n

                  Innate Defenses:\u00a0 Interferons<\/strong><\/p>\n

                  Interferons (IFNs)<\/strong> are a type of cytokines (signalling glycoproteins).\u00a0 Interferons are released by almost all cell types during any type of infection (viral, bacterial, fungal, protozoa).\u00a0 The name interferon is derived from their main function of interfering with viral replication.\u00a0 There are over 20 different IFN genes.\u00a0 Some IFNs act as anti-viral proteins (AVPs) blocking viral replication.\u00a0 Some IFNs act as endogenous pyrogens<\/strong> (inducing fever).\u00a0 The presence of interferons can also cause muscle pain, body aches, and flu-like symptoms.\u00a0 Type I interferons are produced by virally-infected cells and stimulate the expression of anti-viral proteins (AVPs) in neighbouring cells that will inhibit the viral replication of its RNA\/DNA.\u00a0 During an infection, alpha IFNs activate NK cells and macrophages,\u00a0 Gamma-interferons are released by NK cells, cytotoxic T cells (CD8 T lymphocytes) and helper T cells (CD4 T lymphocytes) and stimulate macrophage activity. Beta-interferons are produced by fibroblasts and are considered anti-inflammatory and are released in preparation for healing.<\/p>\n

                   <\/p>\n

                  Cytokines:<\/strong>\u00a0 are a family of signalling glycoproteins that are produced by macrophages, B cells, T cells, mast cells, fibroblasts, endothelial cells, and stromal (connective tissue) cells.\u00a0 Some cytokines have a role in innate (non-specific defense) and some cytokines have a role in specifc defense and immune responses.\u00a0 There are four categories of cytokines that this unit will discuss.<\/p>\n

                    \n
                  1. Interferons:<\/strong> as mentioned in the previous section, these cytokines have many subtypes and fulfill various roles. Interferons can be secreted by host cells, infected cells, NK cells, T cells, and fibroblasts.\u00a0 Interferons are released by cells in response to pathogens (viruses, bacteria, protozoa, fungi) and tumors. There are Type I, Type II, Type II interferons, and within the Type 1 category, there are alpha, beta and gamma interferons.\u00a0 The main roles of interferons are to interfere with viral replication, activate NK cell and macrophages during infection, act as endogenous pyrogens and slow down inflammation after infection in preparation for healing.<\/li>\n
                  2. Chemokines: <\/strong>are responsible for inducing chemotaxis and recruitment of WBCs.<\/li>\n
                  3. Lymphokines:<\/strong> are produced by T lymphocytes (T cells) to: a) attract macrophages and b) stimulate B lymphocytes (B cells)<\/li>\n
                  4. Interleukins:<\/strong> as the name suggested are cytokines produced by leukocytes for signaling and activating each other.\u00a0 Specifically interleukins are produced by Helper T cells to: a) activate macrophages and stimulate fever (act as endogenous pyrogens); b) stimulate T & B cell differentiation; c) stimulate hemopoietic cells to proliferate producing more WBCs.<\/li>\n<\/ol>\n

                     <\/p>\n

                    Innate Defenses:\u00a0 Inflammation<\/strong><\/p>\n

                    Inflammation<\/strong> is a protective response that is stimulated by any type of irritant or damage to cells. Possible causes of cellular damage or irritation include: cuts, blunt trauma, burns, infections, sprains, chemicals, ischemia, excess heat or cold, and foreign objects (e.g. thorns).\u00a0 Inflammation is an important innate response as it facilitates the removal of harmful irritants and pathogens and sets the stage for healing.<\/p>\n

                    Typically inflammation will occur when damaged cells release cytokines which trigger mast cell<\/strong> activation.\u00a0 Once activated, mast cells degranulate releasing pro-inflammatory cytokines such as histamine, bradykinin,<\/strong> and prostaglandin,<\/strong> all three of which cause vasodilation<\/strong> of local blood vessels resulting in increased blood flow to the area.\u00a0 These specific types of prostaglandins, bradykinin, and histamine also increase the permeability of local capillaries, resulting in plasma fluid leaking into the damaged tissue bed.\u00a0 This leaked plasma fluid (called exudate)<\/strong> contains plasma proteins such as fibrinogen as well as platelets.\u00a0 Platelets, fibrin, and clotting will form any necesary platelet plugs to seal any broken blood vessels.\u00a0 Additionally platelets and fibrin serve to contain the infected or damaged area.\u00a0 Platelets are even capable of coating or encircling bacteria, facilitating phagocytosis by neutrophils.\u00a0 At the same time, blood vessels are vasodilated which slows blood flow in this region which may be an asset for WBC diapedesis<\/strong> (movement of WBCs from inside the blood vessel to outside the blood vessel).\u00a0 \u00a0Additionally, blood vessel wall endothelial cells express factors that facilitate the stages of diapedesis<\/strong> (emigration) of WBCs into the tissue bed.\u00a0 Specifically, endothelial cells express receptors that stimulate WBC rolling and adhesion and then will express enzymes to loosen junctions between neighbouring endothelial cells to facilitate transmigration (WBC exiting blood vessel to enter tissue bed).<\/p>\n

                    There are many chemokines<\/strong> are secreted by several cell types including endothelial cells and mast cells to induce chemotaxis of WBCs.\u00a0 In fact, it has been found that there are various contributors (cells, pro-inflammatory cytokines, and chemokines) to the inflammatory response, which serves to increase the movement and recruitment of neutrophils, monocytes, macrophages, dendritic<\/strong> cells, eosinophils<\/strong> and basophils.<\/strong>\u00a0 Not only do WBCs contribute to removal of pathogens and cellular debris, they also secrete growth factors to stimulate healing.<\/p>\n

                    It is often state that there are two phases of inflammation: vascular<\/strong> and cellular.<\/strong>\u00a0 In the vascular phase,\u00a0 vasodilation and increased capillary permeability are occuring within local blood vessels.\u00a0 In the cellular phase, emigration of the WBCs is occurring.<\/p>\n

                    Local Effects of Inflammation:<\/strong><\/p>\n

                    There are 5 possible signs of inflammation<\/strong>, some of which are viewable from the surface when the injury affects the skin or underlying connective tissue.\u00a0 These 5 signs are: redness, warmth, swelling, pain,<\/strong> and sometimes loss of function<\/strong>.\u00a0 The increased blood flow (hyperemia) causes both redness and warmth as blood temperature (37C) is often slightly warmer than surface tissues of the body.\u00a0 The increased capillary permeability allows for leaked plasma fluid (exudate) leaking into interstitial spaces causes the swelling, which can be called edema when the amount of leaked fluid is substantial.\u00a0 Several chemicals can trigger nociceptors<\/strong> (pain sensory neuron receptors).\u00a0 For example, chemicals released by damaged cells, chemicals released from mast cells and basophils (e.g. histamine, prostaglandins, leukotriene and bradykinin).\u00a0 Leaked blood and extracellular ATP can trigger nociceptors as can pressure building up from exudate.\u00a0 Interestingly, it has been found that histamine stimulates a particular type of nociceptor which gives rise to an itching sensation.<\/p>\n

                    There are four types of exudate: serous, fibrinous, purulent<\/strong> and hemorrhagic.<\/strong>\u00a0 Serous exudate is watery, containing some proteins and WBCs.\u00a0 Small burn blisters that haven’t be punctured, typically contain serous exudate.\u00a0 \u00a0Fibrinous exudate found in severe injuries and infections is thick, sticky, contains fibrin and is associated with an increase of scar tissue formation.\u00a0 Purulent exudate is often thick, yellow-green, containing WBCs and micro-organisms occurring in bacterially-infected abscesses and acne.\u00a0 Hemorrhagic exudate contains blood from damaged blood vessels.\u00a0 At times the swelling during inflammation results in loss of function.\u00a0 For example, loss of mobility in joints can occur due to swelling or pain, and within the lungs, exudate can reduce gas exchange in lungs due to fluid accumulation within the alveoli or interstial spaces.<\/p>\n

                    Systemic Effects of Inflammation:<\/strong><\/p>\n

                    There are several systemic effects that arise during the inflammatory response:\u00a0 mild fever, malaise, fatigue, headache, and loss of appetite.\u00a0 \u00a0At times decreased mental function can occur particularly in the elderly.<\/p>\n

                     <\/p>\n

                    *Note:\u00a0 Problems can arise when too little inflammation occurs.\u00a0 In some immunosuppressive<\/strong> diseases, too little inflammation can result in prolonged irritation, damage, infection of tissues and greater amounts of tissue damage which could be permanent depending on the location.<\/p>\n

                    **Note:\u00a0 Unfortunately, too much inflammation can also be a problem.\u00a0 Chronic health issues such as atherosclerosis, osteoarthritis, autoimmune<\/strong> diseases, allergies,<\/strong> and asthma<\/strong> stimulate prolonged inflammatory responses resulting in too much WBC activity which leads to cyclical deteriorative bouts of tissue healing and destruction.\u00a0 It has been found that the cytokine leukotriene plays a role in prolonged inflammation.\u00a0 Leukotriene, as the name suggests is produced by many types of leukocytes including mast cells, basophils, neutrophils, monocytes, and eosinophils. Leukotriene is a vasodilator, it increases capillary permeability, and within cases of asthma has been found to be a potent bronchoconstrictor.<\/p>\n

                    ***Note:\u00a0 The cytokines involved in inflammation, Histamine<\/strong> (a nitrogenous compound), Bradykinin<\/strong> peptides (activated through enzymatic cleavage of its kinogen precursor), and the lipids Prostaglandin <\/strong>and Leukotrienes<\/strong> are referred to as vasoactive<\/strong> compounds as they all induce a change in blood vessel diameter (the prefix, vaso- referring to blood vessel).\u00a0 They also play a strong role in causing bronchoconstriction, bronchiole\/intestinal mucus production and chemotaxis of WBCs.\u00a0 Mucus is helpful in immobilizing pathogens and cellular debris and within the respiratory tract and bronchioles, cilia assist in clearing (or sweeping) this mucus towards the esophagus entrance to be swallowed in what is referred to as the mucociliary escalator .\u00a0 \u00a0In addition to mast cells and basophils, macrophages also release pro-inflammatory prostaglandins.\u00a0 Activated platelets also secrete platelet activating cytokines and pro-inflammatory prostaglandins.<\/p>\n

                    ****Note:\u00a0 During healing of a wound, in addition to the surrounding tissue cells (mesenchymal cells, endothelial cells, fibroblasts, epithelial cells), the following activated WBCs (macrophages, T-lymphocytes) have been found to secrete growth factors<\/strong> (EGF, TGF-alpha, PDGF, FGF-1, FGF-2, PDGF, TGF-alpha, TGF-beta) to stimulate healing.<\/p>\n

                     <\/p>\n

                    Innate Defenses:\u00a0 Fever<\/strong><\/p>\n

                    The rise in body temperature above 37.2\u00b0C is termed a fever and can occur when pyrogens are released in response to cellular damage or irritation.\u00a0 As with inflammation, fever can be caused by any type of cellular damage or irritation (e.g. cuts, blunt trauma, burns, infections, sprains, chemicals, ischemia, excess heat or cold, and even heart attacks, strokes and some degenerative disease).\u00a0 Low-grade fever (38-39\u00b0C) is an important innate response as it accelerates WBC activity, inhibits pathogen metabolism and replication rates, and speeds up healing.<\/p>\n

                    Chemicals that stimulate the thermoregulation center in the hypothalamus to increase body temperature are termed pyrogens.\u00a0 Endogenous pyrogens (e.g. interferons and interleukins) are those produced by the body whereas exogenous pyrogens are foreign components (e.g. LPS, Lipopolysaccharides of bacterial cell walls).<\/p>\n

                    There are four stages of fever:<\/p>\n

                      \n
                    1. Prodromal<\/strong> – in this stage you’re just starting to not feel well and pyrogens are beginning to circulate..<\/li>\n
                    2. Chills<\/strong> – when the pyrogens stimulate the hypothalamus thermoregulatory center to reset the thermostat to a higher temperature (e.g. 39\u00b0F), and your body is not yet at 39\u00b0F, you feel cold and have the chills (even though you are likely 37\u00b0C or even warmer). During this stage your body is increasing it’s temperature by: shivering, and through behavioural changes (e.g. putting on a sweater or climbing under blankets).\u00a0 When you are shivering you may notice that the erector pili muscles in your skin that hold your hair follicles are contracting giving the appearance of goose bumps, and also generating heat (through muscle contraction).\u00a0 You may also notice that your skin becomes paler as cutaneous blood vessels vasoconstrict in order to reduce loss of heat through radiation from your body.\u00a0 Other autonomic responses are occurring that also generate heat including an increased heart rate and increased basal metabolic rate.<\/li>\n
                    3. Flush<\/strong> – in this stage you have a fever (your temperature is above 37.2F) and you will stay in this stage as long as pyrogens are still stimulating your hypothalamus.<\/li>\n
                    4. Defervescence<\/strong> (Sweating) – when the infection or injury has been resolved, the number of pyrogens circulating will diminish and the hypothalamus thermoregulatory center will reset to 37\u00b0F.\u00a0 During this stage your body will need to cool off in order to be 37\u00b0F and will therefore do the following in order to increase heat loss:\u00a0 a) vasodilate cutaneous blood vessels to allow more heat to radiate from the body; b) sweat; c) reduce BMR and heart rate; d) feel tired and reduce movement and muscle contractions; and e) remove extra clothing (e.g. sweaters) and blankets.<\/li>\n<\/ol>\n

                      *Note:\u00a0 High, spiking fever (40\u00b0C or above) can be dangerous as it can induce febrile seizures, which put the brain at risk for neural damage.\u00a0 High temperature is also exhibited in those suffering from heat stroke, and the inability to thermoregulate to cool oneself.<\/p>\n

                      **Blunted or absent febrile response to an infection can occur in the elderly or immunosuppressed and this may delay diagnosis and treatment.<\/p>\n

                      ***Fever of Unknown Origin, FUO are thought to be caused by inflammatory responses to undetectable cellular damage (possibly due to infections, trauma, cancer, heart attacks, blood clots, inflammatory diseases, or drug reactions, etc.)<\/p>\n

                      ****Systemic Inflammatory Response Syndrome can be fatal and is associated with an enormous release of inflammatory cytokines causing systemic vasodilation, capillary permeability which results in hypotension and cirulatory shock.\u00a0 Most freuqent causes include sepsis.<\/p>\n

                      \n