lecture 3

• Microbiota

  Microorganisms of the mammalian gut harbored from several sources
• Probiotics


  "Good" bacteria that provide health benefits to the host when acquired in adequate amounts
• Probiotics


  • Providing colonization resistance to pathogens
  • Can also indirectly diminish pathogen colonization by stimulating the development of innate and adaptive immunity
  • Regulation of innate immune function and homeostasis
  • Regulation of adaptive immune functions in intestine
  • Regulation of systemic innate and adaptive immune function
• First Line of Defense

  • Tears (and saliva): washes away pathogens, lysozymes, IgA
  • Unbroken skin and mucosal membrane surfaces: forms physical barrier to many microorganisms and normal skin microbiota (normal flora) deter penetration or facilitate elimination of foreign microorganisms from the body
  • Constant motion of the cilia facilitates movement and removal of pathogens
  • Mucus membrane secretions (nose and nasopharynx): trap pathogens and expelled by coughing or sneezing
  • pH of stomach and vagina, secretions produced in the elimination of wastes: physical removes potential pathogen
  • Sebum (oil) from sebaceous glands
  • Lactic acid in sweat
  • Cerumen (earwax): antimicrobial properties
• Natural (innate) immunity


  Common to all living organisms, non-specific mechanism of fighting off invading foreign microorganisms
• Natural (innate) immunity


  • Rapid recognition of microbes
  • No prior exposure required
  • Use of widely expressed non-variant receptors to recognize microbes
  • Receptors to distinguish between non-self and self
• Second Line of Defense

  1. Organism penetrates the skin (first line)

  2. Second line and humoral defense mechanisms activated (phagocytic cells, complement, and acute inflammatory reactions)

  3. Sentinel cells (macrophage and dendritic cells) are activated and send signals to neutrophils - triggered by molecular signatures of the pathogen (patterns) like CW components, viral genomic materials

  4. Immunogenicity is known through pattern recognition receptors and triggers reaction in the body (i.e. inflammation)
• Phagocytosis


  1. Chemotaxis

  2. Adherence

  3. Engulfment

  4. Phagosome formation

  5. Fusion

  6. Digestion and destruction
• Acquired or adaptive immunity

  • Be able to recognize, remember, and respond to a specific stimulus (antigen)
  • Results in elimination of microorganisms and recovery from disease, and the host often acquires memory - be able to respond more rapidly and effective if there is reinfection with the same microorganism
  • Has cellular AND humoral components
• Inflammation


  • A form of second-line normal defense mechanism in the body that is intended to localize and remove an injurious agent
  • A response of vascularized tissues to infections and damaged tissues that brings cells and molecules of host defense from the circulation to the sites where they are needed, in order to eliminate the offending agents
  • The body's nonspecific response to tissue injury, resulting in redness (rubor), swelling (tumor), warmth (calor), pain (dolor), loss of function (functio laesa)
  • Disorders with inflammation usually has -itis at the end (e.g., appendicitis)
• Causes of Inflammation


  • Infection: microbial toxins
  • Tissue necrosis
  • Foreign bodies: (splinters, dirt, sutures) may elicit inflammation by themselves or because they cause traumatic tissue injury or carry microbes
  • Immune reactions (hypersensitivity): induced by cytokines produced by T lymphocytes and other cells of the immune system
• Recognition of Microbes and Damaged Cells

  1. Cellular receptors for microbes: Toll-like receptors (TLRs), express receptors in the plasma membrane (for extracellular microbes), the endosomes (for ingested microbes), and the cytosol (for intracellular microbes)

  2. Sensors of cell damage: inflammasome - a multiprotein cytosolic complex activated by molecules released from cell damage (uric acid, a product of DNA breakdown; ATP, released from damaged mitochondria; reduced intracellular K+ concentrations reflecting loss of ions because of plasma membrane injury; even DNA, which induces the production of the cytokine interleukin1 (IL1))

  3. Other cellular receptors involved in inflammation: many leukocytes express receptors for the Fc tails of antibodies and for complement proteins, that recognize microbes coated with antibodies and complement (opsonization) and promote ingestion and destruction of the microbes as well as inflammation

  4. Circulating proteins: mannose-binding lectin (MBL), recognizes microbial sugars and promotes ingestion of the microbes and the activation of the complement system; collectin, and complement system which reacts against microbes and produces mediators of inflammation
• Inflammatory Reaction


  1. Offending agent, which is located in extravascular tissues, is recognized by host cells and molecules

  2. Leukocytes and plasma proteins are recruited from the circulation to the site where the offending agent is located

  3. Leukocytes and proteins are activated and work together to destroy and eliminate the offending substance

  4. Reaction is controlled and terminated

  5. The damaged tissue is repaired
• Mechanism of (Acute) Inflammation

  1. Injurious agent

  2. Tissue phagocytes in tissues try to eliminate these agents

  3. Cytokines and other mediators of inflammation are released

  4. Mediators act on small blood vessels in the vicinity →promote the efflux of plasma, recruitment of circulating leukocytes to the site

  5. Phagocytosis and elimination
• Blood Vessels in Inflammation

  • Change in vascular flow and caliber: vasodilation (notably due to histamine) in vascular smooth muscle leading to heat and redness (erythema)
  • Increased permeability: outpouring of protein-rich fluid into extravascular tissue
  • Stasis: slow movement of RBC due to loss of fluid and ↑ diameter (↑ viscosity) seen as vascular congestion
  • Neutrophils adhere to endothelium and migrate into the interstitial tissue due expressed increased levels of adhesion molecules (from mediators)
• Vascular Leakage (Increased Permeability)

  1. ↑ permeability of postcapillary venules due to: Contraction of endothelial cells resulting in increased interendothelial spaces - transient immediate response (15-30 mins)

  2. Endothelial injury - endothelial cell necrosis and detachment

  3. Transcytosis: increased transport of fluids and proteins through the endothelial cell
• Leukocyte Recruitment to Inflammation Site

  1. Quickly follows increased blood flow and vascular permeability

  2. Cells (phagocytes): macrophages and neutrophils

  3. Mediated by chemokines
• Chemotaxis


  • The locomotion of leukocytes in the tissues towards the site of injury along a chemical gradient by exogenous/endogenous substances (chemoattractants)
  • Exogenous substance: bacterial products (e.g., N-formylmethionine terminal amino acid and some lipids)
  • Endogenous chemoattractants: cytokines, particularly those of the chemokine family (e.g., IL8); components of the complement system, particularly C5a; arachidonic acid (AA) metabolites, leukotriene B4 (LTB4)
  • Leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension
• Acute Inflammation


  1. Vascular Reaction: Vasodilation is induced by chemical mediators such as histamine, and is the cause of erythema and stasis of blood flow

  2. Increased vascular permeability is induced by histamine, kinins, and other mediators that produce gaps between endothelial cells, by direct or leukocyte-induced endothelial injury, and by increased passage of fluids through the end
• Leukocyte recruitment to sites of injury

  1. Leukocytes move along a chemical gradient towards the site of injury

  2. Exogenous chemoattractants (e.g. bacterial products)

  3. Endogenous chemoattractants (e.g. cytokines, complement components, arachidonic acid metabolites)

  4. Leukocyte moves by extending filopodia that pull the back of the cell in the direction of extension
• Vascular reaction in acute inflammation

  • Vasodilation induced by chemical mediators like histamine, causing erythema and stasis of blood flow
  • Increased vascular permeability induced by histamine, kinins, and other mediators, allowing plasma proteins and leukocytes to enter the site
  • Fluid leak from blood vessels results in edema
• Leukocyte recruitment process


  1. Loose attachment and rolling on endothelium

  2. Firm attachment to endothelium

  3. Migration through interendothelial spaces
• Factors promoting leukocyte recruitment

  • Cytokines promote expression of selectins and integrin ligands on endothelium, increase integrin avidity, and promote directional migration of leukocytes
• Neutrophils predominate in the early inflammatory infiltrate, later replaced by monocytes and macrophages
• Pus


  An exudate consisting of neutrophils, liquefied debris of necrotic cells, and edema fluid; most frequently caused by infection with bacteria that cause liquefactive tissue necrosis
• Abscess


  Localized collection of pus, occurs after substantial tissue destruction, when the inflammatory injury involves tissues incapable of regeneration, or when there is abundant fibrin exudation that cannot be adequately cleared
• Local effects of acute inflammation

  • Redness and warmth (increased blood flow)
  • Swelling or edema (shift of protein and fluid into interstitial space)
  • Pain (increased pressure on nerves, chemical irritation)
  • Loss of function (lack of nutrients, mechanical interference)
• Systemic effects of acute inflammation

  • Fever
  • Malaise (feeling unwell)
  • Fatigue
  • Headache
  • Anorexia (loss of appetite)
• Diagnostic tests for acute inflammation

  • Leukocytosis (increased white blood cells)
  • Elevated C-reactive protein (CRP)
  • Elevated erythrocyte sedimentation rate (ESR)
  • Increased plasma proteins (fibrinogen, prothrombin, α-1 antitrypsin)
  • Elevated cell enzymes (AST/SGOT, ALT/SGPT, CK-MB)
• Chronic inflammation


  • Less swelling and exudate
  • Presence of more lymphocytes, macrophages, and fibroblasts
  • More tissue destruction and more collagen production
• Granuloma


  Small mass of activated macrophages, often with T lymphocytes, sometimes with central necrosis; a cellular attempt to contain an offending agent that is difficult to eradicate
• Types of granulomas


  • Foreign body granuloma
  • Immune granuloma
• Acute inflammation is characterized by more exudation and swelling, while chronic inflammation has less exudation and more tissue destruction and fibrosis
• Tissue repair (healing)


  1. Resolution (minimal tissue damage, cells recover)

  2. Regeneration (damaged cells capable of mitosis, e.g. hepatocytes, epithelial cells)

  3. Replacement by connective tissue (scar or fibrous tissue formation, extensive tissue damage or cells incapable of mitosis)
• Healing by first intention

  Wound is clean, free of foreign material and necrotic tissue, edges held close together, minimal gap (e.g. surgical incisions)
• Healing by second intention

  Large break in tissue, more inflammation, longer healing period, more scar tissue formation (e.g. compound fracture)
• Mechanism of tissue repair

  1. Blood clot forms and seals the area

  2. Inflammation clears foreign materials and cell debris

  3. Granulation tissue formation with nearby epithelial cell mitosis

  4. Collagen production from fibroblasts and connective tissue enters wound

  5. Angiogenesis triggered by fibroblasts and macrophages

  6. Cross-linking and shortening of collagen, scar formation
• Scar tissue is not normal, functional tissue, and does not contain specialized structures like hair follicles or glands
• Factors promoting healing


  • Youth
  • Good nutrition (protein, vitamins A and C)
  • Adequate hemoglobin
  • Effective circulation
  • Clean, undisturbed wound
  • No infection or further trauma
• Factors delaying healing


  • Advanced age, reduced mitosis
  • Poor nutrition, dehydration
  • Anemia
  • Circulatory problems
  • Certain chronic diseases
  • Presence of other disorders (diabetes, cancer)
  • Irritation, bleeding, or excessive mobility
  • Infection, foreign material, or radiation exposure
  • Chemotherapy treatment
  • Prolonged use of glucocorticoids