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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‘
• Transgenic technology has allowed the study of
tolerance to authentic self antigens
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.
T cell development involves positive and negative selection and lineage
commitment
T cells are positively selected for 'usefulness' (MHC restriction)
T cell selection is compartmentalized in the thymus
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
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
A VARIETY OF MECHANISMS MAINTAIN
TOLERANCE IN PERIPHERAL LYMPHOID ORGANS
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
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).
CD28 signaling enhances cell survival and enhances CD40L expression
CTLA-4 pathway inhibits IL-2 synthesis and cell proliferation.
CTLA-4 has a higher avidity (100 ×) for CD80 and CD86 than CD28
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.
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
TOLERANCE IS
ALSO IMPOSED
ON B CELLS.
However, anergy in
an autoreactive B
cell can be
overcome
Tolerance can be induced
articially in vivo by
antibodies to co-receptor
and co-stimulatory
molecules
Blocking both B7
molecules with a soluble
form of CTLA-4 (CTLA4-Ig). In combination with
an antibody to the ligand
for CD40 (CD154) allow
long-term skin allograft
survival in mice
Soluble or oral antigens induce tolerance
• tolerance of spleen B cells requires much
more time and higher doses of antigen than
T cells
Chap 20 Autoimmunity and autoimmune
disease-breakdown of self tolerance
Trai-Ming Yeh, Ph.D.
Department of Medical Laboratory Science
and Biotechnology
College of Medicine
National Cheng Kung University
• 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.
organ-specific diseaseHashimoto's thyroiditis
systemic autoimmune diseasesSLE
GENETIC FACTORS PLAY
A ROLE IN THE
DEVELOPMENT OF
AUTOIMMUNITY
Certain HLA haplotypes
predispose to autoimmunity
Molecular mimicry by cross-reactive microbial
antigens can stimulate autoreactive B and T cells
B cells can be stimulated if the cross-reacting antigen bears a
'foreign' carrier epitope to which the T cells have not been tolerized
Cytokine dysregulation, inappropriate MHC expression, and failure
of suppression may induce autoimmunity
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
NZB/NZW
mice treatment
with anti-CD4
Autoantibodies against TSH receptor can
give rise to a wide spectrum of clinical
thyroid dysfunction
A variety of other diseases are associated
with autoantibodies against receptor
• antibodies to acetylcholine receptor in
myathenia gravis
Autoantibodies have diagnostic
and prognostic value
• Antinuclear antibody (ANA)
• IFA staining against a variety of Ag within
Hep2 cell nucleus
• screening tool for SLE
Anti-mitochondrial antibodies
(AMA)
• used in diagnosing primary biliary cirrhosis
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.)
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.
Immunocomplex in synovial tissue of RA
Rheumatoid factor: Antibodies
against IgG Fc
• Due to deficiency of terminal galactose of
IgG (agalacto IgG)
MANY AUTOIMMUNE DISEASES CAN
BE TREATED SUCCESSFULLY
• anti-TNFα monoclonal antibody plus
methotrexate for RA patients
Reversal of compromised regulatory T
cell function in RA by anti-TNF therapy
Anti-CD20 (B cell depletion) in SLE
resistant to immunosuppressive drugs
Some less well-established approaches
to treatment may become practicable