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Molecular mechanisms of immune tolerance

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Immunotolerance Christoph Mueller christoph.mueller_at_pathology.unibe.ch Molecular mechanisms of immune tolerance Central tolerance induction in the B cell and T cell ... – PowerPoint PPT presentation

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Title: Molecular mechanisms of immune tolerance


1
Immunotolerance Christoph Mueller christoph.muel
ler_at_pathology.unibe.ch
  • Molecular mechanisms of immune tolerance
  • Central tolerance induction in the B cell and T
    cell compartment
  • Immune tolerance in the periphery
  • Immunopathology vs. Autoimmunity
  • Immune Tolerance vs. Immune Privilege vs. Immune
    Ignorance

2
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Selection of T cells in the Thymus based on the
affinity of their TCR for MHC peptide
Number of T cells
Negative Selection
Positive Selection
No Selection
No or very low
Intermediate
High
Affinity of TCR for MHC peptide
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AutoImmune RegulatorAIRE
8
Central and peripheral Tolerance in B cells
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Peripheral naive CD4 T cell precursor cells
(THp) can differentiate into three subsets of
effector T cells (TH1, TH2 and TH-17) and several
subsets of Treg cells, including induced Treg
cells (iTreg), Tr1 cells and TH3 cells. Naturally
occurring Treg cells (nTreg) are generated from
CD4 thymic T cell precursors. The
differentiation of these subsets is governed by
selective cytokines and transcription factors,
and each subset accomplishes specialized
functions.
11
Rregulatory T cell subsets
Natural regulatory T cells express the
cell-surface marker CD25 and the transcriptional
repressor FOXP3 (forkhead box P3). These cells
mature and migrate from the thymus and constitute
510 of peripheral T cells in normal mice. Other
populations of antigen-specific regulatory T
cells can be induced from naive CD4CD25- or
CD8CD25- T cells in the periphery under the
influence of semi-mature dendritic cells,
interleukin-10 (IL-10), transforming growth
factor- (TGF-) and possibly interferon- (IFN-).
The inducible populations of regulatory T cells
include distinct subtypes of CD4 T cell T
regulatory 1 (TR1) cells, which secrete high
levels of IL-10, no IL-4 and no or low levels of
IFN- and T helper 3 (TH3) cells, which secrete
high levels of TGF-. Although CD8 T cells are
normally associated with cytotoxic T-lymphocyte
function and IFN- production, these cells or a
subtype of these cells can secrete IL-10 and have
been called CD8 regulatory T cells.
12
Postulated mechanisms of autoimmunity
Various genetic loci may confer susceptibility to
autoimmunity in part by influencing The
maintenance of self-tolerance. Environmental
triggers, such as infections and other stimuli
promote the influx of lymphocytes into the
tissues and the activation of self-reactive T
cells
13
Role of infections in the development of
autoimmunity
14
Examples of Diseases caused by cell and tissue
specific antibodies
15
Examples of T cell-mediated Immunological diseases
16
Examples of Gene Mutations that Result in (an
Enhanced Risk for) Autoimmunity
  • Table 18-6

17
Autoimmune general principles and observations
  • Autoimmunity results from a failure or breakdown
    of the mechanisms normally responsible for
    maintaining self-tolerance in B cells, T cells,
    or both.
  • The major factors that contribute to the
    development of autoimmunity are genetic
    susceptibility and environmental triggers, such
    as infections.
  • Autoimmune diseases may be either systemic or
    organ specific.
  • Various effector mechanisms are responsible for
    tissue injury in different autoimmune diseases.
  • Epitope spreading Autoimmune reactions initiated
    against one self antigen that injure tissues may
    result in the release and alterations of other
    tissue antigens, activation of lymphocytes
    specific for these other antigens, and
    exacerbation of the disease.

18
Autoimmune disease vs. Immunopathology Crohns
disease
19
Inflammatory Bowel Diseases (IBD) Ulcerative
colitis Crohns disease
Crohns disease
Ulcerative colitis
  • Continuous inflammation of the colonic mucosa
  • Hyperemic, edematous mucosa, often associated
    with crypt abscesses
  • Incidence 2-3 new cases per 100'000 persons per
    year
  • Entire gastrointestinal tract may be affected
  • Discontinuous, transmural, granulomatous
    inflammation
  • Incidence 4-5 new cases per 100'000 persons per
    year

CM 4/2007
20
Inflammatory Bowel Diseases Incidence
rates (based on prospective studies)
Stockholm (Sweden) CD 4.9 per 100000 UC 2.2
per 100000 IBD 7.4 per 100000 Gut. 2003
521432-1434
Wisconsin (USA) CD 4.56 per 100000 UC 2.14
per 100000 IBD 7.05 per 100000 J. Pediatr.
2003 143 525-531
21
Mutant mice that spontaneously develop colitis
  • TCR-a-/-
  • TCR-b-/-
  • MHC class II-/-
  • TGF- b -/-
  • IL-2-/-
  • IL-10-/-
  • Smad3-/-
  • GFAP- targeted
  • enteric glia cell
  • depletion
  • N-cadherin
  • dominant
  • negative mutant
  • cathepsin D-/-
  • Gai2-/-
  • NF-kB p55-/-
  • TNF DARE
  • trefoil factor -/-

22
Etiology of Inflammatory Bowel Disease
Psychosocial Factors
Bacterial / Viral Infections

Vascular factors
Immunological Factors
Environ- mental Factors
Genetic Predisposition
Nutrition
23
Etiopathogenesis of Inflammatory Bowel Diseases
  • Induction and perpetuation of IBD is generally
    considered to depend on

- aberrant local immune responses to luminal
antigens - in genetically predisposed
individuals.
24
  • Genetic loci identified in inflammatory
  • bowel disease linkage studies
  • Locus name Chromosomal region Disease type
    Genetic association
  • IBD1 Chromosome 16q CD only NOD2/CARD15
  • IBD2 Chromosome 12q UCgtCD Not established
  • IBD3 Chromosome 6p CD and UC HLA, TNF or
    IRF4?
  • IBD4 Chromosome 14q CD Not established
  • IBD5 Chromosome 5q CD UC (?) OCTN1/SLC22A4,
    OCTN2/SLC22A5
  • IBD6 Chromosome 19 CDgtUC Not established
  • IBD7 Chromosome 1p CD and UC IL23R
  • IBD8 Chromosome 16p CD and UC Not established
  • IBD9 Chromosome 3p CD and UC Not established

25
Inflammatory Bowel Diseases (IBD) Ulcerative
colitis Crohns disease
Crohns disease
Ulcerative colitis
  • Continuous inflammation of the colonic mucosa
  • Hyperemic, edematous mucosa, often associated
    with crypt abscesses
  • Incidence 2-3 new cases per 100'000 persons per
    year
  • Entire gastrointestinal tract may be affected
  • Discontinuous, transmural, granulomatous
    inflammation
  • Incidence 4-5 new cases per 100'000 persons per
    year

CM 4/2007
26
  • Generalized pathway of the mucosal inflammation
    underlying inflammatory bowel disease (IBD) and
    potential points of therapeutic intervention.

27
  • Immune Tolerance
  • vs.
  • Immune Privilege
  • vs.
  • Immune Ignorance

28
Maintaining immune homeostasis To respond, or
not to to respond....
Nature Reviews Immunology 8, 74-80, 2008
29
  • Immune Tolerance
  • Central tolerance mechanisms
  • - Peripheral tolerance mechanisms

30
  • Immune Privilege
  • vs.
  • Immune Ignorance

31
Immune privilege
  • Organs with limited access to effector cells of
    the adaptive (and innate) immune system (passive)
  • and/or
  • Organs with enhanced immunoregulatory properties
    that generally prevent the induction of effector
    immune functions (active)

32
Nature Reviews Immunology 8, 74-80, 2008
33
Nature Reviews Immunology 8, 74-80, 2008
34
  • Immune Ignorance

35
Immune ignorance by the adaptive immune system
outside the GALT of antigens, taken-up in the
intestinal mucosa
Functional anatomy of induction of immune
responses by intestinal antigens. Abundant
protein antigens and live commensal bacteria are
present in the intestine. Antigenic peptides can
pass into the bloodstream through one of the
tributaries of the hepatic portal vein or are
taken up by DCs in the subepithelial region of
the Peyer's patches and carried to the MLNs via
the afferent lymphatics. Although it is possible
for circulating peptides to tolerize T cells in
the liver or peripheral lymph nodes, presentation
in the MLNs is the dominant tolerogenic pathway.
Commensal bacteria are also sampled by intestinal
DCs and induce IgA responses in the Peyer's
patches although very small numbers of
commensals can be carried to MLN by DC, systemic
tolerance to these organisms is not induced.
Because the commensal laden DCs do not penetrate
further than the MLN, the systemic immune system
is protected from unwanted priming reactions from
live bacteria.
Macpherson Smith J Exp Med. 203(3) 49750
2006
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