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Immune tolerance & Autoimmunity
             Dr Ghada Barakat
    lecturer, Med Microbiology & Immunology
Contents



           1   Introduction


           2    Tolerance


           3    Autoimmunity
Tolerance
 Our own bodies produce some 100,000 different
  proteins and one of the longstanding conundrums of
  immunology has been to understand how the
  immune system produces a virtual repertoire
  against pathogens while at the same time avoiding
  reacting to self.
 The strict definition of immunological tolerance
  occurs when an immunocompetent host fails to
  respond to an immunogenic challenge with a
  specific antigen.
Tolerance
Tolerance

 Definition:
   Immunological non-reactivity to an antigen.
   Resulting from a previous exposure.


 The most important form is non-reactivity to self Ag

 When an antigen induces tolerance, it is tolerogen.
Tolerance & autoimmunity
Tolerance

                         Immune response                       Tolerance
Physical form of Ag      Large,aggregated, complex      Soluble, smaller, less complex


Route of Ag                      SC or IM                         Oral or IV

Dose of Ag                     Optimal dose              Very large (sometimes very
                                                                     small)

Age of responding        Older and immunologically        Newborn, immunologicall
   animal                           mature                        immature



Differentiation state   Fully differentiated; memory   Relatively undifferen: B, T cells
    of cells                         T and B
Tolerance, mechanism
 B cell tolerance
     • Deletion
     • Anergy
     • receptor editing
 T cell tolerance
     • Deletion
     • Ignorance
 Loss of Ts cells
 Anti-idiotype antibody
Tolerance & autoimmunity
Tolerance, T cell tolerance
 Thymus
   • Positive selection: cells that are able to recognize
     and bind to self MHC or to peptide + MHC molecules
     are selected to grow
   • Negative selection: cells that recognize and
     efficiently bind self peptides are auto-reactive cells
     and undergo apoptotic cell death because they are
     harmful to the host
 Cells that pass both positive and negative selection
  tests “graduate” from thymus ; enter circulation as
  mature T lymphocytes
Mechanism of tolerance

 1- Clonal deletion:
   Auto-reactive T-cells are eliminated in the thymus
    following interaction with self-antigen during their
    differentiation (negative selection).
   Likewise, differentiating early B cells become
    tolerant when they encounter cell-associated or
    soluble self-antigen.
Mechanism of tolerance

 2- Clonal anergy:
   Auto-reactive T cells, when exposed to antigenic
    peptides lose the second signal, become anergic to
    the antigen.

   B cells when exposed to large amounts of soluble
    antigen down regulate their surface IgM and
    become anergic.
Mechanism of tolerance
Ignorance

 It can be shown that there are T cells and B cells
  specific for auto-antigens present in circulation.
 These cells are quite capable of making a
  response but are unaware of the presence of their
  auto-antigen. This arises for 2 reasons.
Ignorance

 The first is that the antigen may simply be present
  in too low concentration. Since all lymphocytes
  have a threshold for receptor occupancy which is
  required to trigger a response then very low
  concentrations of antigen will not be sensed.
Ignorance
 The second possibility is a more interesting one.
  Some antigens are sequestered from the immune
  system in locations which are not freely exposed
  to surveillance.
 These are termed immunologically privileged
  sites. Examples of such sites are the eye, CNS
  and testis.
 Pathologically mediated disruption of these
  privileged sites may expose the sequestered
  antigens leading to an autoimmune response.
Mechanism of tolerance

 4- Receptor editing:
 B cells which encounter large amounts of soluble
  antigen, as they do in the body, and bind to this
  antigen with very low affinity become activated to
  re-express their RAG-1 and RAG-2 genes.
 These genes cause them to undergo DNA
  recombination and change their antigen
  specificity.
Tolerance & autoimmunity
Mechanism of tolerance

 5- Anti-idiotype antibody:
    produced during the process of tolerization. They
     prevent the receptor from combining with antigen
     so inhibit immune response to it.


 6- Suppressor cells:
    Both low and high doses of antigen may induce
     suppressor T cells, which can specifically suppress
     immune responses of both B and T cells.
Tolerance & autoimmunity
Autoimmunity
AUTOIMMUNITY- Definition


 Immune recognition and injury of self tissues
  (autoimmunity) results from a loss of self tolerance.
 Autoimmunity is
    Breakdown of mechanisms responsible for self
     tolerance
    Induction of an immune response against components
     of the self.
Loss of Self Tolerance

 Most self peptides are presented at levels
   too low to engage effector T cells
   those presented at high levels induce clonal
    deletion or anergy.

 Autoimmunity arises most frequently to
   Tissue-specific antigens with only certain MHC
    molecules
   present the peptide at an intermediate level
    recognized by T cells without inducing tolerance.
MHC Association with
                Autoimmune Disease
 The level of presented autoantigenic peptide
   Is determined by residues in MHC molecules
   These molecules govern the affinity of peptide
    binding.

 Autoimmune diseases are associated with
   particular MHC genotypes.
Classification

Table 1. Spectrum of autoimmune diseases, target organs and diagnostic tests
                             Disease                  Organ                    Antibody to                 Diagnostic Test
                     Hashimoto's thyroiditis          Thyroid          Thyroglobulin, thyroid             RIA, Passive, CF,
Organ specific
                                                                            peroxidase                    hemagglutination
                       Primary Myxedema               Thyroid         Cytoplasmic TSH receptor        Immunofluorescence (IF)
                       Pernicious anemia             Red cells         Intrinsic factor, Gastric          B-12 binding to IF
                                                                             parietal cell               immunofluorescence
                        Addison's disease             Adrenal                  Adrenal cells            Immunofluorescence
                         Male infertility             Sperm                    Spermatozoa                Agglutination,
                                                                                                        Immunofluorescence
                   Insulin dependent juvenile        Pancreas         Pancreatic islet beta cells
                            diabetes
                    Insulin resistant diabetic       Systemic              Insulin receptor            Competition for receptor
                       Myasthenia graves              Muscle            Muscle, acetyl choline           Immunofluorescence,
                                                                             receptor                  competition for receptor
                             Vitiligo               Skin Joints                Melanocytes              Immunofluorescence
Non-organ             Rheumatoid arthritis         Skin, kidney,                   IgG                 IgG-latex agglutination
specific                                              joints
                         Systemic lupus             Joints, etc.     DNA, RNA, nucleoproteins       RNA-, DNA-latex agglutination,
                         erythematosus                                                                          IF
Organ-specific Autoimmune
              diseases
 Antigens and autoimmunity restricted to specific
  organs in the body
     Hashimoto’ thyroiditis
     Type I diabetes
     Multiple sclerosis
     Grave’s disease
     Myasthenia gravis
Systemic Autoimmune Disease

 Antigens and autoimmunity are distributed in
  many tissues (systemic)
     Rheumatoid arthritis
     polymyositis
     Scleroderma
     Systemic lupus erythematosus
AUTOIMMUNITY- mechanisms

 Antibodies
 Effector T cells
AUTOIMMUNITY- aetiology
1. Sequestered antigen
     Lymphoid cells may not be exposed to some self
      antigens during their differentiation,
     They may be late-developing antigens or may be
      confined to specialized organs (e.g., testes, brain,
      eye, etc.).

 A release of antigens from these organs
  resulting from
     accidental traumatic injury or
     surgery can
 Result in the stimulation of an immune response
  and initiation of an autoimmune disease.
AUTOIMMUNITY- aetiology
1.    Escape of auto-reactive clones
      The negative selection in the thymus may not be fully
        functional to eliminate self reactive cells.
      Not all self antigens may be represented in the
        thymus
      Certain antigens may not be properly processed and
        presented.
AUTOIMMUNITY- aetiology
1. Cross reactive antigens
     Antigens on certain pathogens may have
      determinants which cross react with self antigens
      and an immune response against these
      determinants may lead to effector cell or
      antibodies against tissue antigens.
     Post streptococcal nephritis and carditis,
      anticardiolipin antibodies during syphilis
     Association between Klebsiella and ankylosing
      spondylitis.
AUTOIMMUNITY- aetiology
 Infectious triggers:
     stimulation of co-stimulatory signals,
      inappropriate MHC II expression, or cytokines
     Molecular mimicry (cross-reaction)
     Release of sequestered antigens
     T cell bypass (pathogen binding to self protein)
     Superantigen activity/polyclonal activation
AUTOIMMUNITY- aetiology


2. loss of suppressor cells.
AUTOIMMUNITY- Diagnosis


 Diagnosis:
    Clinical
    Detection of Ab reactive against soluble antigens
     by ELISA.
    Detection of Ab against tissues and cells by IF.
    In some cases, a biological /biochemical assay
     may be used (e.g., Graves diseases, pernicious
     anemia).
AUTOIMMUNITY- Treatment



 Treatment:
   Anti-inflammatory e.g.corticosteroid
   Immunosuppressive (cyclosporin)
   Anti-idiotype antibodies, antigen peptides,
    anti-IL2 receptor antibodies, anti-CD4
    antibodies, anti-TCR antibodies, etc.

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Tolerance & autoimmunity

  • 1. Immune tolerance & Autoimmunity Dr Ghada Barakat lecturer, Med Microbiology & Immunology
  • 2. Contents 1 Introduction 2 Tolerance 3 Autoimmunity
  • 3. Tolerance  Our own bodies produce some 100,000 different proteins and one of the longstanding conundrums of immunology has been to understand how the immune system produces a virtual repertoire against pathogens while at the same time avoiding reacting to self.  The strict definition of immunological tolerance occurs when an immunocompetent host fails to respond to an immunogenic challenge with a specific antigen.
  • 5. Tolerance  Definition:  Immunological non-reactivity to an antigen.  Resulting from a previous exposure.  The most important form is non-reactivity to self Ag  When an antigen induces tolerance, it is tolerogen.
  • 7. Tolerance Immune response Tolerance Physical form of Ag Large,aggregated, complex Soluble, smaller, less complex Route of Ag SC or IM Oral or IV Dose of Ag Optimal dose Very large (sometimes very small) Age of responding Older and immunologically Newborn, immunologicall animal mature immature Differentiation state Fully differentiated; memory Relatively undifferen: B, T cells of cells T and B
  • 8. Tolerance, mechanism  B cell tolerance • Deletion • Anergy • receptor editing  T cell tolerance • Deletion • Ignorance  Loss of Ts cells  Anti-idiotype antibody
  • 10. Tolerance, T cell tolerance  Thymus • Positive selection: cells that are able to recognize and bind to self MHC or to peptide + MHC molecules are selected to grow • Negative selection: cells that recognize and efficiently bind self peptides are auto-reactive cells and undergo apoptotic cell death because they are harmful to the host  Cells that pass both positive and negative selection tests “graduate” from thymus ; enter circulation as mature T lymphocytes
  • 11. Mechanism of tolerance  1- Clonal deletion:  Auto-reactive T-cells are eliminated in the thymus following interaction with self-antigen during their differentiation (negative selection).  Likewise, differentiating early B cells become tolerant when they encounter cell-associated or soluble self-antigen.
  • 12. Mechanism of tolerance  2- Clonal anergy:  Auto-reactive T cells, when exposed to antigenic peptides lose the second signal, become anergic to the antigen.  B cells when exposed to large amounts of soluble antigen down regulate their surface IgM and become anergic.
  • 14. Ignorance  It can be shown that there are T cells and B cells specific for auto-antigens present in circulation.  These cells are quite capable of making a response but are unaware of the presence of their auto-antigen. This arises for 2 reasons.
  • 15. Ignorance  The first is that the antigen may simply be present in too low concentration. Since all lymphocytes have a threshold for receptor occupancy which is required to trigger a response then very low concentrations of antigen will not be sensed.
  • 16. Ignorance  The second possibility is a more interesting one. Some antigens are sequestered from the immune system in locations which are not freely exposed to surveillance.  These are termed immunologically privileged sites. Examples of such sites are the eye, CNS and testis.  Pathologically mediated disruption of these privileged sites may expose the sequestered antigens leading to an autoimmune response.
  • 17. Mechanism of tolerance  4- Receptor editing:  B cells which encounter large amounts of soluble antigen, as they do in the body, and bind to this antigen with very low affinity become activated to re-express their RAG-1 and RAG-2 genes.  These genes cause them to undergo DNA recombination and change their antigen specificity.
  • 19. Mechanism of tolerance  5- Anti-idiotype antibody:  produced during the process of tolerization. They prevent the receptor from combining with antigen so inhibit immune response to it.  6- Suppressor cells:  Both low and high doses of antigen may induce suppressor T cells, which can specifically suppress immune responses of both B and T cells.
  • 22. AUTOIMMUNITY- Definition  Immune recognition and injury of self tissues (autoimmunity) results from a loss of self tolerance.  Autoimmunity is  Breakdown of mechanisms responsible for self tolerance  Induction of an immune response against components of the self.
  • 23. Loss of Self Tolerance  Most self peptides are presented at levels  too low to engage effector T cells  those presented at high levels induce clonal deletion or anergy.  Autoimmunity arises most frequently to  Tissue-specific antigens with only certain MHC molecules  present the peptide at an intermediate level recognized by T cells without inducing tolerance.
  • 24. MHC Association with Autoimmune Disease  The level of presented autoantigenic peptide  Is determined by residues in MHC molecules  These molecules govern the affinity of peptide binding.  Autoimmune diseases are associated with  particular MHC genotypes.
  • 25. Classification Table 1. Spectrum of autoimmune diseases, target organs and diagnostic tests Disease Organ Antibody to Diagnostic Test Hashimoto's thyroiditis Thyroid Thyroglobulin, thyroid RIA, Passive, CF, Organ specific peroxidase hemagglutination Primary Myxedema Thyroid Cytoplasmic TSH receptor Immunofluorescence (IF) Pernicious anemia Red cells Intrinsic factor, Gastric B-12 binding to IF parietal cell immunofluorescence Addison's disease Adrenal Adrenal cells Immunofluorescence Male infertility Sperm Spermatozoa Agglutination, Immunofluorescence Insulin dependent juvenile Pancreas Pancreatic islet beta cells diabetes Insulin resistant diabetic Systemic Insulin receptor Competition for receptor Myasthenia graves Muscle Muscle, acetyl choline Immunofluorescence, receptor competition for receptor Vitiligo Skin Joints Melanocytes Immunofluorescence Non-organ Rheumatoid arthritis Skin, kidney, IgG IgG-latex agglutination specific joints Systemic lupus Joints, etc. DNA, RNA, nucleoproteins RNA-, DNA-latex agglutination, erythematosus IF
  • 26. Organ-specific Autoimmune diseases  Antigens and autoimmunity restricted to specific organs in the body  Hashimoto’ thyroiditis  Type I diabetes  Multiple sclerosis  Grave’s disease  Myasthenia gravis
  • 27. Systemic Autoimmune Disease  Antigens and autoimmunity are distributed in many tissues (systemic)  Rheumatoid arthritis  polymyositis  Scleroderma  Systemic lupus erythematosus
  • 29. AUTOIMMUNITY- aetiology 1. Sequestered antigen  Lymphoid cells may not be exposed to some self antigens during their differentiation,  They may be late-developing antigens or may be confined to specialized organs (e.g., testes, brain, eye, etc.).  A release of antigens from these organs resulting from  accidental traumatic injury or  surgery can  Result in the stimulation of an immune response and initiation of an autoimmune disease.
  • 30. AUTOIMMUNITY- aetiology 1. Escape of auto-reactive clones  The negative selection in the thymus may not be fully functional to eliminate self reactive cells.  Not all self antigens may be represented in the thymus  Certain antigens may not be properly processed and presented.
  • 31. AUTOIMMUNITY- aetiology 1. Cross reactive antigens  Antigens on certain pathogens may have determinants which cross react with self antigens and an immune response against these determinants may lead to effector cell or antibodies against tissue antigens.  Post streptococcal nephritis and carditis, anticardiolipin antibodies during syphilis  Association between Klebsiella and ankylosing spondylitis.
  • 32. AUTOIMMUNITY- aetiology  Infectious triggers:  stimulation of co-stimulatory signals, inappropriate MHC II expression, or cytokines  Molecular mimicry (cross-reaction)  Release of sequestered antigens  T cell bypass (pathogen binding to self protein)  Superantigen activity/polyclonal activation
  • 33. AUTOIMMUNITY- aetiology 2. loss of suppressor cells.
  • 34. AUTOIMMUNITY- Diagnosis  Diagnosis:  Clinical  Detection of Ab reactive against soluble antigens by ELISA.  Detection of Ab against tissues and cells by IF.  In some cases, a biological /biochemical assay may be used (e.g., Graves diseases, pernicious anemia).
  • 35. AUTOIMMUNITY- Treatment  Treatment:  Anti-inflammatory e.g.corticosteroid  Immunosuppressive (cyclosporin)  Anti-idiotype antibodies, antigen peptides, anti-IL2 receptor antibodies, anti-CD4 antibodies, anti-TCR antibodies, etc.