Attribution: University of Michigan Medical School, Department of Microbiologyand ImmunologyLicense: Unless otherwise note...
Citation Key                          for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Ada...
Return to Type I Diabetes and       Overview of Immune             Response              M1 – Immunology SequenceWinter 2009
One of the first pathologies observed is infiltration of thepancreatic islets with leukocytes (inflammation—insulitis) and...
Normal pancreas                   Insulin-dependent diabeticpancreas     Garland Publishing, Inc. 2000
Is the pattern of lymphocyte infiltration consistent withan ongoing infection?
Is the pattern of lymphocyte infiltration consistent withan ongoing infection?       No, no neutrophils. (But could be a v...
On Tuesday, Dr. Pietropaolo discussed that the beta cells of thepancreas are destroyed by an immunological mechanism inTyp...
What is the effector function  (pathology) associated withpancreatic beta cell destruction?   Summary: Type I Reaction•  A...
Summary: Type II/III Reaction•  Antibody: IgM & IgG•  Effector Cells: Phagocytic•  Complement: Yes•  Reaction: 6-24 hours
Summary: Type IV Reaction•  Antibody: No•  Effector Cells: CD4+ T-   lymphocytes, Monocyte/   Macrophage;   CD8+ T-lymphoc...
Are anti-self antibodies the primary cause of islet cell     destruction (Type II/III immunopathology)?
Test for anti-self antibodies on islet cells                         YFl        Anti-human IgG Anti-islet antibody        ...
Source Undetermined
Source Undetermined
If antibody mediated the destruction of the beta cells,would B lymphocytes necessarily infiltrate the pancreas?What type o...
If antibody mediated the destruction of the beta cells,would B lymphocytes necessarily infiltrate the pancreas? No, Bcells...
Are these anti-self antibodies the primary causeof islet cell destruction?     Probably not.     If antibodies were the ca...
What does the lymphocyte infiltration of the pancreaticislets indicate about the pathology of Type I diabetes?
Since the infiltration is mostly lymphocytes, thepathology is not Types I, II, or III (mast cells,eosinophils, neutrophils...
To understand the lymphocyte infiltration better, what moredetailed histological test would you like to perform?
To understand the lymphocyte infiltration better, what moredetailed histological test would you like to perform?        To...
Test for anti-self antibodies on islet cells                   FlY        Anti-CD4                              Anti-CD8  ...
Normal pancreas                    Insulin-dependent diabetic pancreas   Garland Publishing, Inc. 2000
HLA Type and Insulin Dependent Diabetes            Population         Type I DiabeticsDR3/DR4        2.5%                 ...
One can imagine that Type I diabetes is initiated as  follows:1.  Some physical trauma or infection causes damage to    th...
5.  This CD4+ T cell clones provides help to both B    cell clones and CD8+ T cell clones that recognize    other self epi...
Differentiation of T helper cells   Antigen                  Proliferation                    Characteristic      Major fu...
CTL induces programmed cell death                  (apoptosis) in target cells.                                           ...
Cytokines: AT&T of the immune response• The major means for inflammatory cell activation• Two-way communication between in...
Have immunologists defined the autoantigen that isrecognized by the CD4+ T cell, leads to an immune response,and ultimatel...
Have immunologists defined the autoantigenthat is recognized by the CD4+ T cell, leads to animmune response, and ultimatel...
An immune response to a pathogen is fundamentally thesame as an immune response to a self antigen of the isletcell.Review ...
Simplified overview of an immune response                           Th            help                                B   ...
Differences between innate and adaptive immunity     Innate Immunity            Adaptive Immunity                         ...
Activated APC                                                                     Naive                                   ...
Top                                                                      Side                                             ...
HLA class II                                              HLA class IHuman MHC genes are highly polymorphic.Each individua...
Antigen processing and presentation         to T lymphocytes MHC class I pathway (cytosolic source)     Present antigen to...
Activation of naive T cells requires     two independent signals.                                                         ...
Where do the anti-virus or anti-bacteria cell T cells and B cellscome from in the first place?They arise from random, anti...
orange arrow: CACAGTG                                                               blue arrow: GGTTTTTGTJaneway. Immunobi...
The T cell receptor resembles a membrane-      bound Fab fragment of antibody.                                            ...
Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
A. Specificity of recognition by cells and molecules—eachantigen is distinguished from (almost) all other antigens.B. Dive...
A simple view of the thymic selection                                                  CD4+CD8+                           ...
Tolerance--Depending on how an antigen is encountered,the immune system can become non-responsive to thatantigen. Individu...
Simplified overview of an immune response                           Th            help                                B   ...
For extracellular pathogens, once CD4+ T cells are activated,they will help B cells to become activated, differentiate, an...
Simplified overview of an immune response                           Th            help                                B   ...
For intracellular pathogens, once CD4+ T cells are activated,they may help CD8+ T cells to divide, differentiate, andbecom...
Transplantation reactions are mediated by T cellsrecognizing allogeneic MHC molecules
Summary1.  The immune response is a FANTASTICALLY interesting    inter-relating set of biological effects that result in  ...
Additional Source Information                  for more information see: http://open.umich.edu/wiki/CitationPolicySlide 5:...
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02.18.09: Review: Type 1 Diabetes and Overview of Immune Response

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02.18.09: Review: Type 1 Diabetes and Overview of Immune Response

  1. 1. Attribution: University of Michigan Medical School, Department of Microbiologyand ImmunologyLicense: Unless otherwise noted, this material is made available under the termsof the Creative Commons Attribution–Noncommercial–Share Alike 3.0License: http://creativecommons.org/licenses/by-nc-sa/3.0/ We have reviewed this material in accordance with U.S. Copyright Law and have tried to maximize your ability to use, share, and adapt it. The citation key on the following slide provides information about how you may share and adapt this material. Copyright holders of content included in this material should contact open.michigan@umich.edu with any questions, corrections, or clarification regarding the use of content. For more information about how to cite these materials visit http://open.umich.edu/education/about/terms-of-use. Any medical information in this material is intended to inform and educate and is not a tool for self-diagnosis or a replacement for medical evaluation, advice, diagnosis or treatment by a healthcare professional. Please speak to your physician if you have questions about your medical condition. Viewer discretion is advised: Some medical content is graphic and may not be suitable for all viewers.
  2. 2. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicyUse + Share + Adapt { Content the copyright holder, author, or law permits you to use, share and adapt. } Public Domain – Government: Works that are produced by the U.S. Government. (USC 17 § 105) Public Domain – Expired: Works that are no longer protected due to an expired copyright term. Public Domain – Self Dedicated: Works that a copyright holder has dedicated to the public domain. Creative Commons – Zero Waiver Creative Commons – Attribution License Creative Commons – Attribution Share Alike License Creative Commons – Attribution Noncommercial License Creative Commons – Attribution Noncommercial Share Alike License GNU – Free Documentation LicenseMake Your Own Assessment { Content Open.Michigan believes can be used, shared, and adapted because it is ineligible for copyright. } Public Domain – Ineligible: Works that are ineligible for copyright protection in the U.S. (USC 17 § 102(b)) *laws in your jurisdiction may differ { Content Open.Michigan has used under a Fair Use determination. } Fair Use: Use of works that is determined to be Fair consistent with the U.S. Copyright Act. (USC 17 § 107) *laws in your jurisdiction may differ Our determination DOES NOT mean that all uses of this 3rd-party content are Fair Uses and we DO NOT guarantee that your use of the content is Fair. To use this content you should do your own independent analysis to determine whether or not your use will be Fair.
  3. 3. Return to Type I Diabetes and Overview of Immune Response M1 – Immunology SequenceWinter 2009
  4. 4. One of the first pathologies observed is infiltration of thepancreatic islets with leukocytes (inflammation—insulitis) andsubsequent destruction of the beta cells in the islets. Since thebeta cells produce insulin, loss of the beta cells results in lossof insulin production.By the time a patient presents with the symptoms of diabetes,more than 90% of the beta cells have been destroyed.
  5. 5. Normal pancreas Insulin-dependent diabeticpancreas Garland Publishing, Inc. 2000
  6. 6. Is the pattern of lymphocyte infiltration consistent withan ongoing infection?
  7. 7. Is the pattern of lymphocyte infiltration consistent withan ongoing infection? No, no neutrophils. (But could be a viral infection.) Neutrophils go to the site of an infection, becauseinflammatory mediators upregulate receptors on endothelialcells.
  8. 8. On Tuesday, Dr. Pietropaolo discussed that the beta cells of thepancreas are destroyed by an immunological mechanism inType I diabetes. Dr. Fantone, discussed four types ofimmunopathology.Which of the four types of immunopathology might be active inType I diabetes?
  9. 9. What is the effector function (pathology) associated withpancreatic beta cell destruction? Summary: Type I Reaction•  Antibody: IgE•  Effector Cells: Mast Cell & Eosinophil•  Complement: No•  Reaction: Minutes
  10. 10. Summary: Type II/III Reaction•  Antibody: IgM & IgG•  Effector Cells: Phagocytic•  Complement: Yes•  Reaction: 6-24 hours
  11. 11. Summary: Type IV Reaction•  Antibody: No•  Effector Cells: CD4+ T- lymphocytes, Monocyte/ Macrophage; CD8+ T-lymphocytes•  Complement: No•  Reaction: 48-72 hours (skin test)
  12. 12. Are anti-self antibodies the primary cause of islet cell destruction (Type II/III immunopathology)?
  13. 13. Test for anti-self antibodies on islet cells YFl Anti-human IgG Anti-islet antibody Y Tissue section of pancreatic islet
  14. 14. Source Undetermined
  15. 15. Source Undetermined
  16. 16. If antibody mediated the destruction of the beta cells,would B lymphocytes necessarily infiltrate the pancreas?What type of leukocytes would more likely to be found?
  17. 17. If antibody mediated the destruction of the beta cells,would B lymphocytes necessarily infiltrate the pancreas? No, Bcells act at a distance, by secreting antibodies. What type of leukocytes would more likely to be found? Neutrophils. A lack of neutrophils, antibody, orcomplement deposition in the pancreas argues that antibodies(including those binding to insulin) are not very important in thedisease.
  18. 18. Are these anti-self antibodies the primary causeof islet cell destruction? Probably not. If antibodies were the cause, the histopathologywould be characterized by the presence ofimmunoglobulin, complement, and neutrophils.What are other candidates for the destruction? CD4+ T cells + macrophages CD8+ T cell cytotoxicity
  19. 19. What does the lymphocyte infiltration of the pancreaticislets indicate about the pathology of Type I diabetes?
  20. 20. Since the infiltration is mostly lymphocytes, thepathology is not Types I, II, or III (mast cells,eosinophils, neutrophils would be expected). However, the lymphocyte infiltration is consistentwith a Type IV reaction.
  21. 21. To understand the lymphocyte infiltration better, what moredetailed histological test would you like to perform?
  22. 22. To understand the lymphocyte infiltration better, what moredetailed histological test would you like to perform? To distinguish between DTH and cytotoxicity by CD8+cells, look for macrophages, and also do immunofluorescencewith anti-CD4 and anti-CD8 antibodies conjugated withfluorescein.
  23. 23. Test for anti-self antibodies on islet cells FlY Anti-CD4 Anti-CD8 Anti-CD19 Anti-NK1.1 Tissue section of pancreatic islet (Morphology would define the presence of macrophages or neutrophils.)
  24. 24. Normal pancreas Insulin-dependent diabetic pancreas Garland Publishing, Inc. 2000
  25. 25. HLA Type and Insulin Dependent Diabetes Population Type I DiabeticsDR3/DR4 2.5% 39%
  26. 26. One can imagine that Type I diabetes is initiated as follows:1.  Some physical trauma or infection causes damage to the islets.2.  Inflammatory cells (macrophages, neutrophils) enter the islets, cause further damage (on a micro scale).3. Epitopes on self proteins like insulin or GAD that are not exposed in a healthy islet, are now exposed, and these epitopes are taken up by dendritic cells and macrophages. Those individuals who are DR3/DR4 heterozygotes are more likely to present the critical self peptide on their MHC class II molecules.4.  A CD4+ T cell clone specific for the self peptide:MHC class II complex is activated, begins to divide and differentiate.
  27. 27. 5.  This CD4+ T cell clones provides help to both B cell clones and CD8+ T cell clones that recognize other self epitopes expressed by islet cells. These self epitopes recognized by B cells cannot have been expressed in bone marrow, and the self epitopes expressed by CD8+ T cells cannot have been expressed in the thymus.6.  Cytotoxic CD8+ T cells or antibodies secreted by plasma cells begin to destroy islet cells, leading to Type I diabetes.7.  Alternatively, CD4+ T cells might activate macro- phages, which in turn destroy the islet cells.
  28. 28. Differentiation of T helper cells Antigen Proliferation Characteristic Major functions recognition Cytokines Cell-mediated Immunity Th1 DTH IL- 12 IFN-γ Macrophage activation IFN-γAPC Thp Th0 IL-4 Humoral Immunity Precursor CD4 T cells IL-4 Th2 B-cell help Eosinophil stimulation Activated Mast cell stimulation effector T cells Macrophage deactivation University of Michigan Department of Microbiology and Immunology
  29. 29. CTL induces programmed cell death (apoptosis) in target cells. Fig 6.24Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
  30. 30. Cytokines: AT&T of the immune response• The major means for inflammatory cell activation• Two-way communication between innate and acquiredimmune response• Two-way communication between cells of the acquiredimmune response
  31. 31. Have immunologists defined the autoantigen that isrecognized by the CD4+ T cell, leads to an immune response,and ultimately to Type I diabetes?
  32. 32. Have immunologists defined the autoantigenthat is recognized by the CD4+ T cell, leads to animmune response, and ultimately to Type I diabetes? No, it is not defined. However, it is almost surelyan antigen expressed by a pancreatic beta cell. There remains a small chance that the anti-insulin and anti-GAD antibodies are the cause of theType I diabetes. Alternatively, pancreatic beta cellsmight be damaged via some other type of pathology,releasing insulin and GAD antigens so that APCs cantake them up and present them to Th and B cells. Inthis scenario, anti-self antibodies would be a result ofType 1 diabetes. Current thinking favors the latterscenario.
  33. 33. An immune response to a pathogen is fundamentally thesame as an immune response to a self antigen of the isletcell.Review of immune responses to two types of pathogens—extracellular (usually bacteria) and intracellular (viruses andsome bacteria).Return to the BIG PICTURE, without concerning ourselveswith all of the details.
  34. 34. Simplified overview of an immune response Th help B IgM,IgG,IgA Tc killing Dendritic cell or macrophage Often eliminated by innate immunity: neutrophils or macrophages Clostridium tetani Image Sources Undetermined
  35. 35. Differences between innate and adaptive immunity Innate Immunity Adaptive Immunity Response is antigen-dependent There is immediate There is a lag time between maximal response Exposure and maximal response Not antigen-specific Antigen-specific Exposure results in Exposure results in no immunological memory immunological memory Recognition by antibody and T cell receptors
  36. 36. Activated APC Naive T cells Ig production Activated APC Effector T cellsKilling microbes Help MHC Peptide TCR APC T cell Costimulatory molecule University of Michigan Department of Microbiology and Immunology
  37. 37. Top Side Class I Intracellular Class II Extracellular (and intracellular) Figure 3.8 Current Biology Ltd./Garland Publishing, Inc Current Biology Ltd./Garland Publishing, Inc
  38. 38. HLA class II HLA class IHuman MHC genes are highly polymorphic.Each individual express only two of thesealleles by co-dominance. Fig 3. 20 Parham. The Immune System. Garland Publishing/Elsevier Science Ltd. 1997
  39. 39. Antigen processing and presentation to T lymphocytes MHC class I pathway (cytosolic source) Present antigen to CD8 T cells Virus and intracellular bacteria Mutated tumor antigen MHC class II pathway (endosomal source) Present antigen to CD4 T cells Bacteria
  40. 40. Activation of naive T cells requires two independent signals. CD28 B7 Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997 Fig 6.7
  41. 41. Where do the anti-virus or anti-bacteria cell T cells and B cellscome from in the first place?They arise from random, antigen-independent differentiation.T cells and B cells derive from the bone marrow.
  42. 42. orange arrow: CACAGTG blue arrow: GGTTTTTGTJaneway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
  43. 43. The T cell receptor resembles a membrane- bound Fab fragment of antibody. TCRBCR •  Bivalent •  Monovalent •  Secreted and •  Membrane- membrane-bound • bound form forms Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
  44. 44. Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
  45. 45. A. Specificity of recognition by cells and molecules—eachantigen is distinguished from (almost) all other antigens.B. Diversity of recognition--The immune response canrecognize ten million or more different antigens.
  46. 46. A simple view of the thymic selection CD4+CD8+ TCR+ Strength of signalweak strongToo weak or Poor recognition Good binding toNo binding of peptide-MHC or activatingto self MHC Partial signal to peptide:self-MHC T cells complexes Clonal Death by Survive deletion neglect (apoptosis) University of Michigan Department of Microbiology and Immunology
  47. 47. Tolerance--Depending on how an antigen is encountered,the immune system can become non-responsive to thatantigen. Individuals are (usually) tolerant to self antigens.
  48. 48. Simplified overview of an immune response Th help B IgM,IgG,IgA Tc killing Dendritic cell or macrophage Often eliminated by innate immunity: neutrophils or macrophages Clostridium tetani Image Sources Undetermined
  49. 49. For extracellular pathogens, once CD4+ T cells are activated,they will help B cells to become activated, differentiate, andproduce antibodies. The antibodies eliminate the pathogen byneutralization, by opsinization for macrophages or neutrophils,by complement mediated lysis, and so on.
  50. 50. Simplified overview of an immune response Th help B IgM,IgG,IgA Tc killing Dendritic cell or macrophage Often eliminated by innate immunity: neutrophils or macrophages Clostridium tetani Image Sources Undetermined
  51. 51. For intracellular pathogens, once CD4+ T cells are activated,they may help CD8+ T cells to divide, differentiate, andbecome cytotoxic. Alternatively, the CD4+ T cells mayproduce large amounts of interferon-γ, and activatemacrophages. Both cytotoxic CD8+ T cells and activatedmacrophages eliminate the intracellular pathogen by killingthe cell in which it resides. Many intracellular bacteria growonly in macrophages, and activated macrophages kill bacteriagrowing in them better than do macrophages not exposed tointerferon-γ, etc.
  52. 52. Transplantation reactions are mediated by T cellsrecognizing allogeneic MHC molecules
  53. 53. Summary1.  The immune response is a FANTASTICALLY interesting inter-relating set of biological effects that result in protection against pathogens.2.  At times the immune response goes awry, leading to autoimmune disease and allergies.3.  Its difficult to learn immunology in eight days.
  54. 54. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicySlide 5: Garland Publishing, Inc. 2000Slide 14: Source UndeterminedSlide 15: Source UndeterminedSlide 24: Garland Publishing, Inc. 2000Slide 28: University of Michigan Department of Microbiology and ImmunologySlide 29: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997Slide 34: Image Sources UndeterminedSlide 36: University of Michigan Department of Microbiology and ImmunologySlide 37: Current Biology Ltd./Garland Publishing, Inc, Current Biology Ltd./Garland Publishing, IncSlide 38: Parham. The Immune System. Garland Publishing/Elsevier Science Ltd. 1997Slide 40: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997Slide 42: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997Slide 43: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997Slide 44: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997Slide 46: University of Michigan Department of Microbiology and ImmunologySlide 48: Image Sources UndeterminedSlide 50: Image Sources Undetermined

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