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• Immunity


  The immune system's capacity to protect individuals from disease by recognizing and eliminating potentially pathogenic agents
• Role of the Immune System

  • Disposes of unneeded components of the body
  • Participates in wound healing
  • Recognizes and eliminates mutant cells that may develop into cancer
  • Rejects tissues and cells that are not identical to "self"
• Immune response


  1. Surveillance

  2. Recognition

  3. Activation

  4. Effector lymphocytes
• Anatomy of the immune system

  • Physical barriers
  • Leukocytes
  • Lymphoid tissues
• Nonspecific (innate) immunity


  Provides the first defenses against pathogens regardless of the type of pathogen
• Specific (adaptive) immunity


  Represents a stronger defense against a specific pathogen(s) that takes longer to develop
• Nonspecific (innate) immunity


  • Physical barriers
  • Inflammation (phagocytosis)
• Specific (adaptive) immunity


  • Cellular immune response
  • Humoral immune response
• Physical barriers


  • Skin and mucous membranes that separate the internal from the external environment
  • Secretions (sebum, lysozymes, digestive enzymes)
  • Ciliated mucosa of the respiratory tract
  • Stomach acid
  • Washing action of tears, saliva, urine
  • Commensals

  
• Leukocytes (white blood cells)


  Cells from lymphoid and myeloid stem cells responsible for producing a wide range of immune responses

  
• Leukocyte types


  • Granulocytes (neutrophils, eosinophils, basophils)
  • Agranulocytes (monocytes, lymphocytes, natural killer cells)

  
• Natural killer cells


  • Kill by a mechanism similar to cytotoxic T cells but do not express receptors specific to antigens
  • Exhibit immediate readiness to respond
  • Recognize and kill mutant cells that may develop into cancer
  • Play role in innate immune response against virus and tumor recognition
• Phagocytes


  • Can engulf foreign particles and microorganisms, removing them from blood and tissues
  • Neutrophils are the most abundant and important in fighting bacterial infections
  • Eosinophils defend against parasites
  • Basophils involved in allergic reactions

  
• Monocytes


  • Phagocytes in the blood that differentiate into macrophages in tissue
  • Arrive after neutrophils and persist longer at site of infection, involved in chronic inflammation

  
• Macrophages


  • Larger and more active than monocytes
  • Persist longer in tissues, involved in chronic infections and inflammation
  • Found in almost all tissues, some localized (fixed) and others migratory
  • Can do antigen presentation and activation of other immune cells
  • Initiate tissue repair, scar formation, and wound healing
• Functions of phagocytes


  • Phagocytosis
  • Production of cytokines
• Nonspecific defences (PAMP)


  Innate immune cells recognize and bind to common chemical structures on pathogens called pathogen-associated molecular patterns (PAMPs), initiating the defence process
• Receptors on phagocytes


  • Macrophage mannose receptors
  • Scavenger receptors
  • CD14
  • Toll-like receptors
  • Mannose-binding lectin
  • Complement receptors (CR3 and CR4)
• Tissue resident macrophages


  • Kupfer cells: resident in the liver
  • Microglial cells: resident in the brain

  
• Phagocytes


  • Macrophages can do antigen presentation and activation of other immune cells (adaptive immune response)
  • They initiate processes of tissue repair, scar formation(liver fibrosis) and play a role in wound healing
• Functions of phagocytes


  • Phagocytosis
  • Production of cytokines
• Nonspecific defences (PAMP)


  • The innate immune response distinguish self antigens from pathogens through common chemical structures on the surface of many pathogens called pathogen-associated molecular patterns (PAMPs)
  • Receptors on cells of the innate immune cells recognize and bind the PAMPs, thereby initiating the defence process
• Receptors on Phagocytes


  • Pathogen Associated Molecular Patterns (PAMPs): sugars (mannose)
  • lipids (lipopolysaccharide, LPS)
  • Toll-like receptors
  • bacterial lipoprotein
  • peptidoglycan
  • flagellin
  • unmethylated DNA
  • Fc receptors
• Phagocytosis


  1. Attachment

  2. Internalization

  3. Degradation

  4. Exocytosis
• Attachment


  • Phagocytes tend to bind to damaged and dead cells with irregular, rough surfaces, but not to healthy cells
  • Phagocytes attach to many types of bacteria through pattern recognition receptors
  • Attachment is sometimes enhanced by opsonins, proteins (including antibodies) that bind tightly to the foreign material and make it easier for the phagocyte to engulf it
• Internalization


  • As soon as the phagocyte has attached to its prey, internalization occurs. In less than 0.01 second, the phagocyte's plasma membrane extends outward around the site of attachment and surrounds the material, enclosing it within a large intracellular vesicle called a phagosome
  • The phagosome moves toward the cell interior and fuses with a lysosome which contains a variety of digestive enzymes, forming (phagolysosome)
• Degradation


  The phagocytosed material is then degraded within the enlarged, enzymatically active organelle, now called a secondary lysosome
• Exocytosis


  The phagocyte uses some of the harmless bacterial debris (amino acids, for example) and eliminates others by exocytosis
• The body's nonspecific defenses

  • Physical barriers
  • Inflammation, a complex series of events causing accumulation of proteins, fluid, and phagocytic cells in an area of tissue that has been injured or invaded by microorganisms
  • Interferons, a family of related proteins that can induce virus resistance to other cells
  • The complement system, a group of plasma proteins that act to lyse foreign cells, especially bacteria
• Recognition of foreign particles or cells by the immune system

  Ligand/Receptor interaction
• Responses


  • Secretion
  • Adherence
  • Chemotaxis
  • Phagocytosis
• Different cells will respond differently to the same ligand
• Acute inflammatory response


  1. Phagocytosis

  2. Complement activation

  3. Mast cell activation

  4. Vasodilation

  5. Vascular permeability

  6. Extravasation
• Cells involved in acute inflammation

  • Phagocytes: neutrophils, monocytes, macrophages, dendritic cells, eosinophils
  • Mast cells
• Molecules involved in acute inflammation

  • Complement: plasma protein cascade
  • Cytokines: eg TNF-α, IL-1, IL-6
• Processes in acute inflammation

  • Phagocytosis
  • Opsonisation
  • Chemotaxis
• Mast cells


  • Localized and resident in tissues (not found in peripheral blood)
  • Contain numerous granules with pre-formed inflammatory mediators such as histamine and platelet activating factor
  • They can release these mediators after the activation of pattern recognition receptors present on the surface of mast cells
  • Histamine increases blood flow and vascular permeability leading to swelling and redness
  • They can also synthesize prostaglandins and leukotrienes hence generating more inflammatory mediators
• Complement system


  • Consists of a large number of soluble molecules that are synthesized in the liver and circulate in the blood
  • It's a proteolytic cascade that results in: Lysis of cells, Opsonization (to facilitate phagocytosis)
• TNF-alpha


  • Is a cytokine that is secreted by mast cells or macrophages
  • It can stimulate the breakdown of tight junctions between the epithelial cells, leading to the formation of gaps and hence increasing permeability, allowing extravasation of cells e.g. neutrophils and causing swelling
  • Cytokines up-regulate the adhesion molecules on the endothelial cells, thereby facilitating the entry of more inflammatory cells to the site of infection
• Phagocytosis of Pathogens and Debris by Nearby Macrophages

  1. Macrophages already present in affected tissues can quickly detect bacteria introduced into a cut by receptors, initiating phagocytosis to engulf the bacteria

  2. Stimulates the macrophages to secrete cytokines which can help in: Synthesis of adhesion molecules by blood vessel endothelial cells, Release of more neutrophils from bone marrow