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Return to Type I Diabetes and
       Overview of Immune
             Response
              M1 – Immunology Sequence



Winter 2009
One of the first pathologies observed is infiltration of the
pancreatic islets with leukocytes (inflammation—insulitis) and
subsequent destruction of the beta cells in the islets. Since the
beta cells produce insulin, loss of the beta cells results in loss
of insulin production.

By the time a patient presents with the symptoms of diabetes,
more than 90% of the beta cells have been destroyed.
Normal pancreas                   Insulin-dependent diabetic
pancreas




     Garland Publishing, Inc. 2000
Is the pattern of lymphocyte infiltration consistent with
an ongoing infection?
Is the pattern of lymphocyte infiltration consistent with
an ongoing infection?

       No, no neutrophils. (But could be a viral infection.)

       Neutrophils go to the site of an infection, because
inflammatory mediators upregulate receptors on endothelial
cells.
On Tuesday, Dr. Pietropaolo discussed that the beta cells of the
pancreas are destroyed by an immunological mechanism in
Type I diabetes. Dr. Fantone, discussed four types of
immunopathology.

Which of the four types of immunopathology might be active in
Type I diabetes?
What is the effector function
  (pathology) associated with
pancreatic beta cell destruction?

   Summary: Type I Reaction
•  Antibody: IgE
•  Effector Cells: Mast Cell &
   Eosinophil
•  Complement: No
•  Reaction: Minutes
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-lymphocytes
•  Complement: No
•  Reaction: 48-72 hours (skin test)
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
                         Y
    Tissue section of pancreatic islet
Source Undetermined
Source Undetermined
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?
If antibody mediated the destruction of the beta cells,
would B lymphocytes necessarily infiltrate the pancreas? No, B
cells act at a distance, by secreting antibodies.

       What type of leukocytes would more likely to be found?

       Neutrophils. A lack of neutrophils, antibody, or
complement deposition in the pancreas argues that antibodies
(including those binding to insulin) are not very important in the
disease.
Are these anti-self antibodies the primary cause
of islet cell destruction?

     Probably not.

     If antibodies were the cause, the histopathology
would be characterized by the presence of
immunoglobulin, complement, and neutrophils.

What are other candidates for the destruction?

     CD4+ T cells + macrophages

     CD8+ T cell cytotoxicity
What does the lymphocyte infiltration of the pancreatic
islets indicate about the pathology of Type I diabetes?
Since the infiltration is mostly lymphocytes, the
pathology is not Types I, II, or III (mast cells,
eosinophils, neutrophils would be expected).

      However, the lymphocyte infiltration is consistent
with a Type IV reaction.
To understand the lymphocyte infiltration better, what more
detailed histological test would you like to perform?
To understand the lymphocyte infiltration better, what more
detailed histological test would you like to perform?

        To distinguish between DTH and cytotoxicity by CD8+
cells, look for macrophages, and also do immunofluorescence
with anti-CD4 and anti-CD8 antibodies conjugated with
fluorescein.
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.)
Normal pancreas                    Insulin-dependent diabetic pancreas




   Garland Publishing, Inc. 2000
HLA Type and Insulin Dependent Diabetes

            Population         Type I Diabetics

DR3/DR4        2.5%                  39%
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.
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.
Differentiation of T helper cells
   Antigen                  Proliferation                    Characteristic      Major functions
 recognition                                                  Cytokines
                                                                             Cell-mediated Immunity
                                                 Th1
                                                                                      DTH
                              IL- 12                                IFN-γ
                                                                             Macrophage activation
                              IFN-γ

APC            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
CTL induces programmed cell death
                  (apoptosis) in target cells.




                                                                                                                  Fig 6.24




Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
Cytokines: AT&T of the immune response

• The major means for inflammatory cell activation
• Two-way communication between innate and acquired
immune response
• Two-way communication between cells of the acquired
immune response
Have immunologists defined the autoantigen that is
recognized by the CD4+ T cell, leads to an immune response,
and ultimately to Type I diabetes?
Have immunologists defined the autoantigen
that is recognized by the CD4+ T cell, leads to an
immune response, and ultimately to Type I diabetes?
     No, it is not defined. However, it is almost surely
an antigen expressed by a pancreatic beta cell.
      There remains a small chance that the anti-
insulin and anti-GAD antibodies are the cause of the
Type I diabetes. Alternatively, pancreatic beta cells
might be damaged via some other type of pathology,
releasing insulin and GAD antigens so that APCs can
take them up and present them to Th and B cells. In
this scenario, anti-self antibodies would be a result of
Type 1 diabetes. Current thinking favors the latter
scenario.
An immune response to a pathogen is fundamentally the
same as an immune response to a self antigen of the islet
cell.

Review of immune responses to two types of pathogens—
extracellular (usually bacteria) and intracellular (viruses and
some bacteria).
Return to the BIG PICTURE, without concerning ourselves
with all of the details.
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
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
Activated APC
                                                                     Naive
                                                                     T cells
 Ig production
                                                                                         Activated
                                                APC
                                                                                      Effector T cells
Killing microbes



                                                                               Help
                                                        MHC   Peptide




                                                                      TCR
                                  APC                                       T cell

                                                      Costimulatory
                                                        molecule



  University of Michigan Department of Microbiology and Immunology
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
HLA class II                                              HLA class I




Human MHC genes are highly polymorphic.
Each individual express only two of these
alleles by co-dominance.
                                                                                       Fig 3. 20
   Parham. The Immune System. Garland Publishing/Elsevier Science Ltd. 1997
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
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
Where do the anti-virus or anti-bacteria cell T cells and B cells
come from in the first place?

They arise from random, antigen-independent differentiation.

T cells and B cells derive from the bone marrow.
orange arrow: CACAGTG
                                                               blue arrow: GGTTTTTGT




Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
The T cell receptor resembles a membrane-
      bound Fab fragment of antibody.

                                                                                     TCR

BCR




                      •  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
Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
A. Specificity of recognition by cells and molecules—each
antigen is distinguished from (almost) all other antigens.

B. Diversity of recognition--The immune response can
recognize ten million or more different antigens.
A simple view of the thymic selection


                                                  CD4+CD8+
                                                    TCR+

          Strength of signal
weak                                                                         strong



Too weak or                                 Poor recognition         Good binding to
No binding                                 of peptide-MHC or            activating
to 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
Tolerance--Depending on how an antigen is encountered,
the immune system can become non-responsive to that
antigen. Individuals are (usually) tolerant to self antigens.
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
For extracellular pathogens, once CD4+ T cells are activated,
they will help B cells to become activated, differentiate, and
produce antibodies. The antibodies eliminate the pathogen by
neutralization, by opsinization for macrophages or neutrophils,
by complement mediated lysis, and so on.
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
For intracellular pathogens, once CD4+ T cells are activated,
they may help CD8+ T cells to divide, differentiate, and
become cytotoxic. Alternatively, the CD4+ T cells may
produce large amounts of interferon-γ, and activate
macrophages. Both cytotoxic CD8+ T cells and activated
macrophages eliminate the intracellular pathogen by killing
the cell in which it resides. Many intracellular bacteria grow
only in macrophages, and activated macrophages kill bacteria
growing in them better than do macrophages not exposed to
interferon-γ, etc.
Transplantation reactions are mediated by T cells
recognizing allogeneic MHC molecules
Summary
1.  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.
Additional Source Information
                  for more information see: http://open.umich.edu/wiki/CitationPolicy


Slide 5: Garland Publishing, Inc. 2000
Slide 14: Source Undetermined
Slide 15: Source Undetermined
Slide 24: Garland Publishing, Inc. 2000
Slide 28: University of Michigan Department of Microbiology and Immunology
Slide 29: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
Slide 34: Image Sources Undetermined
Slide 36: University of Michigan Department of Microbiology and Immunology
Slide 37: Current Biology Ltd./Garland Publishing, Inc, Current Biology Ltd./Garland Publishing, Inc
Slide 38: Parham. The Immune System. Garland Publishing/Elsevier Science Ltd. 1997
Slide 40: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
Slide 42: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
Slide 43: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
Slide 44: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
Slide 46: University of Michigan Department of Microbiology and Immunology
Slide 48: Image Sources Undetermined
Slide 50: Image Sources Undetermined

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

  • 1. Attribution: University of Michigan Medical School, Department of Microbiology and Immunology License: Unless otherwise noted, this material is made available under the terms of the Creative Commons Attribution–Noncommercial–Share Alike 3.0 License: 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. Citation Key for more information see: http://open.umich.edu/wiki/CitationPolicy Use + 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 License Make 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. Return to Type I Diabetes and Overview of Immune Response M1 – Immunology Sequence Winter 2009
  • 4. One of the first pathologies observed is infiltration of the pancreatic islets with leukocytes (inflammation—insulitis) and subsequent destruction of the beta cells in the islets. Since the beta cells produce insulin, loss of the beta cells results in loss of insulin production. By the time a patient presents with the symptoms of diabetes, more than 90% of the beta cells have been destroyed.
  • 5. Normal pancreas Insulin-dependent diabetic pancreas Garland Publishing, Inc. 2000
  • 6. Is the pattern of lymphocyte infiltration consistent with an ongoing infection?
  • 7. Is the pattern of lymphocyte infiltration consistent with an ongoing infection? No, no neutrophils. (But could be a viral infection.) Neutrophils go to the site of an infection, because inflammatory mediators upregulate receptors on endothelial cells.
  • 8. On Tuesday, Dr. Pietropaolo discussed that the beta cells of the pancreas are destroyed by an immunological mechanism in Type I diabetes. Dr. Fantone, discussed four types of immunopathology. Which of the four types of immunopathology might be active in Type I diabetes?
  • 9. What is the effector function (pathology) associated with pancreatic beta cell destruction? Summary: Type I Reaction •  Antibody: IgE •  Effector Cells: Mast Cell & Eosinophil •  Complement: No •  Reaction: Minutes
  • 10. Summary: Type II/III Reaction •  Antibody: IgM & IgG •  Effector Cells: Phagocytic •  Complement: Yes •  Reaction: 6-24 hours
  • 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. Are anti-self antibodies the primary cause of islet cell destruction (Type II/III immunopathology)?
  • 13. Test for anti-self antibodies on islet cells YFl Anti-human IgG Anti-islet antibody Y Tissue section of pancreatic islet
  • 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. If antibody mediated the destruction of the beta cells, would B lymphocytes necessarily infiltrate the pancreas? No, B cells act at a distance, by secreting antibodies. What type of leukocytes would more likely to be found? Neutrophils. A lack of neutrophils, antibody, or complement deposition in the pancreas argues that antibodies (including those binding to insulin) are not very important in the disease.
  • 18. Are these anti-self antibodies the primary cause of islet cell destruction? Probably not. If antibodies were the cause, the histopathology would be characterized by the presence of immunoglobulin, complement, and neutrophils. What are other candidates for the destruction? CD4+ T cells + macrophages CD8+ T cell cytotoxicity
  • 19. What does the lymphocyte infiltration of the pancreatic islets indicate about the pathology of Type I diabetes?
  • 20. Since the infiltration is mostly lymphocytes, the pathology is not Types I, II, or III (mast cells, eosinophils, neutrophils would be expected). However, the lymphocyte infiltration is consistent with a Type IV reaction.
  • 21. To understand the lymphocyte infiltration better, what more detailed histological test would you like to perform?
  • 22. To understand the lymphocyte infiltration better, what more detailed histological test would you like to perform? To distinguish between DTH and cytotoxicity by CD8+ cells, look for macrophages, and also do immunofluorescence with anti-CD4 and anti-CD8 antibodies conjugated with fluorescein.
  • 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. Normal pancreas Insulin-dependent diabetic pancreas Garland Publishing, Inc. 2000
  • 25. HLA Type and Insulin Dependent Diabetes Population Type I Diabetics DR3/DR4 2.5% 39%
  • 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. 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. Differentiation of T helper cells Antigen Proliferation Characteristic Major functions recognition Cytokines Cell-mediated Immunity Th1 DTH IL- 12 IFN-γ Macrophage activation IFN-γ APC 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. CTL induces programmed cell death (apoptosis) in target cells. Fig 6.24 Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
  • 30. Cytokines: AT&T of the immune response • The major means for inflammatory cell activation • Two-way communication between innate and acquired immune response • Two-way communication between cells of the acquired immune response
  • 31. Have immunologists defined the autoantigen that is recognized by the CD4+ T cell, leads to an immune response, and ultimately to Type I diabetes?
  • 32. Have immunologists defined the autoantigen that is recognized by the CD4+ T cell, leads to an immune response, and ultimately to Type I diabetes? No, it is not defined. However, it is almost surely an antigen expressed by a pancreatic beta cell. There remains a small chance that the anti- insulin and anti-GAD antibodies are the cause of the Type I diabetes. Alternatively, pancreatic beta cells might be damaged via some other type of pathology, releasing insulin and GAD antigens so that APCs can take them up and present them to Th and B cells. In this scenario, anti-self antibodies would be a result of Type 1 diabetes. Current thinking favors the latter scenario.
  • 33. An immune response to a pathogen is fundamentally the same as an immune response to a self antigen of the islet cell. Review of immune responses to two types of pathogens— extracellular (usually bacteria) and intracellular (viruses and some bacteria). Return to the BIG PICTURE, without concerning ourselves with all of the details.
  • 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. 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. Activated APC Naive T cells Ig production Activated APC Effector T cells Killing microbes Help MHC Peptide TCR APC T cell Costimulatory molecule University of Michigan Department of Microbiology and Immunology
  • 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. HLA class II HLA class I Human MHC genes are highly polymorphic. Each individual express only two of these alleles by co-dominance. Fig 3. 20 Parham. The Immune System. Garland Publishing/Elsevier Science Ltd. 1997
  • 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. 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. Where do the anti-virus or anti-bacteria cell T cells and B cells come from in the first place? They arise from random, antigen-independent differentiation. T cells and B cells derive from the bone marrow.
  • 42. orange arrow: CACAGTG blue arrow: GGTTTTTGT Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
  • 43. The T cell receptor resembles a membrane- bound Fab fragment of antibody. TCR BCR •  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. Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997
  • 45. A. Specificity of recognition by cells and molecules—each antigen is distinguished from (almost) all other antigens. B. Diversity of recognition--The immune response can recognize ten million or more different antigens.
  • 46. A simple view of the thymic selection CD4+CD8+ TCR+ Strength of signal weak strong Too weak or Poor recognition Good binding to No binding of peptide-MHC or activating to 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. Tolerance--Depending on how an antigen is encountered, the immune system can become non-responsive to that antigen. Individuals are (usually) tolerant to self antigens.
  • 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. For extracellular pathogens, once CD4+ T cells are activated, they will help B cells to become activated, differentiate, and produce antibodies. The antibodies eliminate the pathogen by neutralization, by opsinization for macrophages or neutrophils, by complement mediated lysis, and so on.
  • 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. For intracellular pathogens, once CD4+ T cells are activated, they may help CD8+ T cells to divide, differentiate, and become cytotoxic. Alternatively, the CD4+ T cells may produce large amounts of interferon-γ, and activate macrophages. Both cytotoxic CD8+ T cells and activated macrophages eliminate the intracellular pathogen by killing the cell in which it resides. Many intracellular bacteria grow only in macrophages, and activated macrophages kill bacteria growing in them better than do macrophages not exposed to interferon-γ, etc.
  • 52. Transplantation reactions are mediated by T cells recognizing allogeneic MHC molecules
  • 53. Summary 1.  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. Additional Source Information for more information see: http://open.umich.edu/wiki/CitationPolicy Slide 5: Garland Publishing, Inc. 2000 Slide 14: Source Undetermined Slide 15: Source Undetermined Slide 24: Garland Publishing, Inc. 2000 Slide 28: University of Michigan Department of Microbiology and Immunology Slide 29: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997 Slide 34: Image Sources Undetermined Slide 36: University of Michigan Department of Microbiology and Immunology Slide 37: Current Biology Ltd./Garland Publishing, Inc, Current Biology Ltd./Garland Publishing, Inc Slide 38: Parham. The Immune System. Garland Publishing/Elsevier Science Ltd. 1997 Slide 40: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997 Slide 42: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997 Slide 43: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997 Slide 44: Janeway. Immunobiology: The Immune System in Health and Disease. Current Biology Ltd./Garland Publishing, Inc. 1997 Slide 46: University of Michigan Department of Microbiology and Immunology Slide 48: Image Sources Undetermined Slide 50: Image Sources Undetermined