chap 19 immunological tolerance - a state of unresponsiveness for a particular antigen
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Chap 19 Immunological tolerance - a state of unresponsiveness for a particular antigen. Trai-Ming Yeh, Ph.D. Department of Medical Laboratory Science and Biotechnology College of Medicine National Cheng Kung University. Self tolerance. neonatal tolerance=' immune deviation ‘ - PowerPoint PPT PresentationTRANSCRIPT
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Chap 19 Immunological tolerance-a state of unresponsiveness for a
particular antigen
Trai-Ming Yeh, Ph.D.Department of Medical Laboratory Science
and BiotechnologyCollege of Medicine
National Cheng Kung University
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Self tolerance• neonatal tolerance='immune deviation‘• Transgenic technology has allowed the study of
tolerance to authentic self antigens
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Ways in which self-reactive lymphocytes may be prevented from responding to
self antigen • in tissues sequestered from the circulation • in a privileged site• self-reactive cells may be deleted at certain
stages of development;• self-reactive cells may be rendered anergic
and unable to respond;• a state of tolerance to self antigens can also
be maintained by immune regulation.
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T cell development involves positive and negative selection and lineage commitment
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T cells are positively selected for 'usefulness' (MHC restriction)
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T cell selection is compartmentalized in the thymus
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Medullary thymic epithelial cells can express antigens whose expression was previously thought to be limited to specific organs
Aire (autoimmune regulaotry) defect causes autoimmune polyendocrinopathy syndrome type 1 (APS-1) in humans
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T cell development includes a series of checkpoints
• β selection checkpoint - only cells with a rearranged β chain mature from DN to DP cells - this process is not dependent on MHC proteins;
• α selection checkpoint - cells expressing an αβ complex must interact with MHC molecules to survive;
• lineage commitment checkpoint - cells are instructed to repress expression of either CD4 or CD8 and to develop into SP cells;
• negative selection checkpoint - cells that interact strongly with MHC molecules and antigen in the thymus are deleted
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A VARIETY OF MECHANISMS MAINTAIN TOLERANCE IN PERIPHERAL LYMPHOID
ORGANS
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T cell death can be induced by persistent activation or neglect
activation-induced cell death (AICD); and programmed cell death (PCD)
Fas is the most important death receptor
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The Fas pathway is required for peripheral tolerance autoimmune lymphoproliferative syndrome (ALPS), mutations in the Fas gene (ALPS type 1a) or the Fas ligand gene (ALPS type 1b).
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CD28 signaling enhances cell survival and enhances CD40L expressionCTLA-4 pathway inhibits IL-2 synthesis and cell proliferation.CTLA-4 has a higher avidity (100 ×) for CD80 and CD86 than CD28
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Dendritic cells contribute to peripheral tolerance
immature dendritic cells presenting antigen activate T cells, but the outcome is different, resulting in apoptosis, anergy, or the generation of regulatory T cells.
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Regulatory T cells suppress the activation of other T cells and play a crucial role in controlling autoimmune responses
FoxP3 gene were found in the affected members of families with the IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) syndrome
The ligands for TLRs and cytokines override suppression in potentially overwhelming infection
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TOLERANCE IS ALSO IMPOSED ON B CELLS. However, anergy in an autoreactive B cell can be overcome
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Tolerance can be induced articially in vivo by antibodies to co-receptor and co-stimulatory moleculesBlocking both B7 molecules with a soluble form of CTLA-4 (CTLA-4-Ig). In combination with an antibody to the ligand for CD40 (CD154) allow long-term skin allograft survival in mice
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Soluble or oral antigens induce tolerance• tolerance of spleen B cells requires much
more time and higher doses of antigen than T cells
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Chap 20 Autoimmunity and autoimmune disease-breakdown of self tolerance
Trai-Ming Yeh, Ph.D.Department of Medical Laboratory Science
and BiotechnologyCollege of Medicine
National Cheng Kung University
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• Autoimmunity is associated with disease.• Genetic factors play a role in the development of
autoimmune diseases. • Self-reactive B and T cells persist even in normal
subjects. • Controls on the development of autoimmunity can
be bypassed. • In most diseases associated with autoimmunity,
the autoimmune process produces the lesions. • Treatment of autoimmune disease has a variety of
aims.
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organ-specific disease-Hashimoto's thyroiditissystemic autoimmune diseases- SLE
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GENETIC FACTORS PLAY A ROLE IN THE DEVELOPMENT OF AUTOIMMUNITY
Certain HLA haplotypes predispose to autoimmunity
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Molecular mimicry by cross-reactive microbial antigens can stimulate autoreactive B and T cells
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B cells can be stimulated if the cross-reacting antigen bears a 'foreign' carrier epitope to which the T cells have not been tolerized
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Cytokine dysregulation, inappropriate MHC expression, and failure of suppression may induce autoimmunity
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The pathogenic role of autoimmunity can be demonstrated in experimental models
• Experimental autoimmune diseases (strain dependent)
• Induced by antigen immunization vs. spontaneous.
• NOD murine model of IDDM• NZB/NZW model of SLE
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NZB/NZW mice treatment with anti-CD4
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Autoantibodies against TSH receptor can give rise to a wide spectrum of clinical
thyroid dysfunction
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A variety of other diseases are associated with autoantibodies against receptor• antibodies to acetylcholine receptor in
myathenia gravis
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Autoantibodies have diagnostic and prognostic value
• Antinuclear antibody (ANA)• IFA staining against a variety of Ag within
Hep2 cell nucleus• screening tool for SLE
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Anti-mitochondrial antibodies (AMA)
• used in diagnosing primary biliary cirrhosis
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Anti-parietal cell antibodies(APCA) • Specific fluorescence is seen in stomach parietal
cells. Cytoplasm and lumenal border of kidney tubules are negative. (AMA will stain parietal cells and kidney tubules.)
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Antibodies to the glomerular capillary basement membrane cause Goodpasture's syndrome
• kidney biopsy specimen from a patient with antiglomerular basement membrane nephritis showing a linear deposition of immunoglobulin G along the glomerular basement membrane.
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Immunocomplex in synovial tissue of RA
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Rheumatoid factor: Antibodies against IgG Fc
• Due to deficiency of terminal galactose of IgG (agalacto IgG)
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MANY AUTOIMMUNE DISEASES CAN BE TREATED SUCCESSFULLY
• anti-TNFα monoclonal antibody plus methotrexate for RA patients
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Reversal of compromised regulatory T cell function in RA by anti-TNF therapy
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Anti-CD20 (B cell depletion) in SLE resistant to immunosuppressive drugs
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Some less well-established approaches to treatment may become practicable