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The Body's Defenses Against Infection
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The Body's Defenses Against Infection

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  • 1. The Body’s Defenses Against Infection The Mucosal Immune System
    • The variety of human pathogens is very large
  • 2.  
  • 3.  
  • 4.  
  • 5. The Body’s Defenses Against Infection The Mucosal Immune System
    • The variety of human pathogens is very large
    • The vast majority of human pathogens enter the body at mucosal surfaces
  • 6.  
  • 7.  
  • 8.  
  • 9. The Body’s Defenses Against Infection The Mucosal Immune System
    • The variety of human pathogens is very large
    • The vast majority of human pathogens enter the body at mucosal surfaces
    • Surface area is HUGE – small intestine alone has over 2000 ft 2 of surface area
    • Constant interaction with literally billions of pathogens, potential pathogens and resident “commensal” pathogens (normal flora)
    • Immune system has evolved to create a special version designed to provide protection from infections at these mucosal surfaces and within the spaces encompassed by the mucosal layers (e.g., lumen of the gi tract)
  • 10. The Body’s Defenses Against Infection The Mucosal Immune System
    • Even the entrance into the gi tract (i.e., the mouth) has a complex set of mucosal immune system tissues
  • 11. The Body’s Defenses Against Infection The Mucosal Immune System
    • Even the isotype of antibody (sIgA) is uniquely designed to move into these mucosal areas and resist destruction by the rather harsh proteolytic environment of mucosal areas (e.g., digestive enzymes in the gi tract)
  • 12. The Body’s Defenses Against Infection The Mucosal Immune System
    • and function effectively there in a variety of ways
  • 13. Using the human gi tract as a “model” of mucosal immunity
  • 14. Cells of the Mucosal Immune System
    • Designed to constantly “sample” contents of the intestinal lumen
    • Dendritic cells can literally stretch through epithelial cell junctions and reach into the lumen to bind to pathogens there
  • 15. Cells of the Mucosal Immune System
    • All of the cell types needed for almost any type of immune response (innate and adaptive) are found just below the surface of the gut epithelium
  • 16. Lymphoid tissues of the Mucosal Immune System
    • Peyer’s patches
    • Organization is ideal for sampling and responding to pathogens in the intestinal lumen
  • 17. Lymphoid tissues of the Mucosal Immune System
    • In addition to DCs reaching across the epithelial layer
    • M (microfold) cells endocytose and phagocytize antigens in the gi lumen
    • Dump the antigen fragments into the Peyer’s patch
    • DCs take in the degraded antigens, process & present them to T-cells
    • T-helper cells “help” B-cells
  • 18. Lymphoid tissues of the Mucosal Immune System
    • Stimulated (effector) T-cells and B-cells leave the Peyer’s patch
    • Cells move through a lymphatic system associated with the gi tract
      • Mesenteric lymph nodes
      • Connected by a network of lymphatic vessels
      • Found only in the mesentery
    • Cells eventually enter the blood circulation
  • 19. “ Homing” of these effector lymphocytes
    • Effector lymphocytes generated in the mucosal immune system almost always return to that system
    • Unique set of adhesion molecules
  • 20. Lymphoid tissues of the Mucosal Immune System
    • Return to populate the tissue spaces just below the epithelial cell layer
  • 21. Vaccine route of immunization
    • Polio vaccine – introduced in the 1950s
    • Incredibly successful vaccine
    • Two different versions of the polio vaccine
      • Salk inactivated (“killed” virus”) injected – introduced first
      • Sabin attentuated (weakened virus) given orally
  • 22. Vaccine route of immunization
    • Polio vaccine – introduced in the 1950s
    • Incredibly successful vaccine
    • Two different versions of the polio vaccine
      • Salk inactivated (“killed” virus”) injected – introduced first
      • Sabin attentuated (weakened virus) given orally
  • 23. So, why the introduction of the Sabin vaccine?
    • Salk vaccine was certainly incredibly successful
    • Sabin vaccine – given orally , vaccine virus is deposited on intestinal mucosal surfaces
    • Wild-type polio virus most often infects intestinal mucosal sur face, enters the body (via the intestinal epithelial cells) – can cause serious damage inside the body (lungs, nerves)
    • Sabin establishes a mucosal immunity right at the location where the wild-type polio virus first attempts to infect the body
      • STO P it there before it even can attach to the epithelial cells
      • sIgA may be very important in preventing virus attachment to endothelial cells
      • “ Flumist” is an inhaled, attenuated influenza vaccine
  • 24. So, why was the Salk injected version still so successful?
    • Vaccine stimulated primary and secondary antibody responses inside the body
    • Predominant isotype produced is IgG
    • IgG is also very effective in virus neutralization
  • 25. So, why was the Salk injected version still so successful?
    • And all the other responses than involve IgG antibodies specific for virus
  • 26. Form of polio vaccine may also be important
    • One goal of ideal vaccine is to establish a long-term (lifetime) immunity
    • What does the vaccine need to do?
    • May need to stay in the body indefinitely (“forever”) for this to happen
  • 27. Form of polio vaccine may also be important
    • B-cells eventually are required to encounter antigen to survive
  • 28. Form of polio vaccine may also be important
    • One goal of ideal vaccine is to establish a long-term (lifetime) immunity
    • What does the vaccine need to do?
    • May need to stay in the body indefinitely (“forever”) for this to happen
    • Salk inactivated may not persist as long as Sabin attenuated
    • Why?
    • Sabin attenuated virus vaccine – virus can enter into a cell, replicate but rarely causes any damage to the cell
    • Very infrequently the virus particles will be released from the “infected” cell, but there is not significant damage to the body (i.e., no polio)
    • Maintains presence of virus antigens
    • May be needed to maintain the expanded population of memory B-cells (and T-cells)
  • 29.  
  • 30. Form of polio vaccine may also be important
    • One goal of ideal vaccine is to establish a long-term (lifetime) immunity
    • What does the vaccine need to do?
    • May need to stay in the body indefinitely (“forever”) for this to happen
    • Salk inactivated may not persist as long as Sabin attenuated
    • Why?
    • Sabin attenuated virus vaccine – virus can enter into a cell, replicate but rarely causes any damage to the cell
    • Very infrequently the virus particles will be released from the “infected” cell, but there is not significant damage to the body (i.e., no polio)
    • May be needed to maintains the expanded population of memory B-cells (and T-cells)
    • How long? – “lifetime”? (not sure yet)
    • Salk Inactivated virus not be able to “infect” a cell – no viral replication
    • No persistence of the virus antigens in the body
    • B-cell population may still live for quite a while
    • Does lack of continuous availability of virus antigens eventually lead to apoptosis of all of these virus-specific B-cells (and T-cells)?
  • 31. Vaccine safety is also an issue
    • Can the attenuated Sabin polio virus mutate and regain ability to cause polio?
    • Refer to the first homework assignment question
    • Two different forms of the polio vaccine are available. One is the Salk inactivated (“killed”) vaccine. The other is the Sabin attenuated (“weakened”, but not killed) vaccine. The latter vaccine (Sabin) is considered by many immunologists to be more effective in providing long-term protection from polio. However, in the past few years the US pediatric community recommended that only the Salk vaccine be given to infants (as one of the several vaccines recommended for infants). What was the basis for this recommendation to use a possibly less effective version of the polio vaccine for infants?
    • Why? - Sabin vaccine may have actually caused polio in a (very) few immunized persons
  • 32.
    • “ Outbreaks of VAPP ( vaccine-associated paralytic poliomyelitis ) occurred independently in Belarus (1965–66), Canada (1966–68), Egypt (1983–1993), Hispaniola (2000–2001), Philippines (2001), Madagascar (2001–2002), [ and in Haiti (2002), where political strife and poverty have interfered with vaccination efforts. [ In 2006 an outbreak of vaccine-derived poliovirus occurred in China. [ Cases have been reported from Cambodia (2005–2006), Myanmar (2006–2007), Iran (1995, 2005–2007), Syria, Kuwait and Egypt. [ Since 2005, The World Health Organization has been tracking vaccine-caused polio in northern Nigeria caused by a mutation in live oral polio vaccines”
    • Young infants would be much more at risk for developing polio from the attenuated Sabin vaccine.
    • “ The Centers for Disease Control and Prevention and the American Academy of Pediatrics have announced that only the inactivated polio vaccine (IPV) schedule is recommended for all children, effective January 1, 2000” “ Recommended Childhood Immunization Schedule -- United States, 2000 ”
    • http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4902a4.htm
    • “ Children less than 24 months of age are not eligible for FluMist ”
  • 33. Subclasses of sIgA
    • Two subclasses - sIgA1 and sIgA2
    • Same functions
    • Differ slightly in length of “hinge” region
      • sIgA1 – longer length 26 amino acids
      • sIgA2 – shorter length 13 amino acids
    • Longer sIgA 1 hinge-region is much more susceptible to cleavage by bacterial extracellular proteases
    • Results in production of Fab fragments
    • Fab can still bind to bacterial cell
    • Should still prevent attachment of cell to endothelial surface
  • 34.  
  • 35. Subclasses of sIgA
    • Fab should still prevent attachment of cell to endothelial surface
    • WRONG!!
    • sIgA Fab-coated bacteria can actually bind very strongly to epithelial cell surface
    • Appears to be “receptors” for IgA Fab on epithelial cell surface
  • 36. Subclasses of sIgA
    • Clinical relevance of sIgA subclass
    • Three bacteria that secrete sIgA1-cleaving proteases are
    • Streptococcus pneumoniae
    • Neisseria meningitis
    • Haemophilus influenzae
  • 37.
    • Ratio of sIgA1/sIgA2 differs dramatically with tissues
    • Nasal mucosa has a very high % of sIgA1
    • Nasal infections in children can often lead to serious inner ear infections
    • Many inner ear infections are caused by:
    • Strongly adhering bacteria that cause
      • serious inflammation
    • Guess who?
    • Streptococcus pneumoniae
    • Haemophilus influenzae
    Subclasses of sIgA
  • 38. Intestinal parasitic worms
    • IgE antibodies can play a significant role in eliminating these pathogens – you already know that
  • 39. The “real” purpose of IgE antibodies
    • Thought to be very important in response to parasitic worms in the gi tract
    • IgE antibodies specific for surface epitopes on the parasites
      • Antibodies bind to the surface
    • Eosinophils also have Fc receptors for IgE antibodies
      • Bind to IgE antibodies already bound to parasite
      • Release toxins that can kill the parasite
    • Mast cells bind to IgE antibodies on parasite surface
      • Release histamine
        • Smooth muscle contraction –> expels parasites from gi tract
        • Vasodilation of gi tract endothelial cell layer-> water/fluids flow into gi tract (assist in “washing away” the parasites
  • 40. Intestinal parasitic worms
    • IgE antibodies can play a significant role in eliminating these pathogens – you already know that
    • Some helminths stimulate very strong T-helper cell responses
    • Which T-helper subgroup (TH 1 or TH 2 ) predominates will often determine the outcome of a helminth infestation
  • 41.