Transcript Immune Tolerance

Immunotolerance
Christoph Mueller
[email protected]
•
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
No or very low
Intermediate
Negative Selection
Positive Selection
No Selection
Number of T cells
Selection of T cells in the Thymus based on
the affinity of their TCR for MHC + peptide
High
Affinity of TCR for MHC + peptide
AutoImmune Regulator
AIRE
Central and peripheral Tolerance in B cells
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 5–10% of peripheral T cells in normal mice. Other
populations of antigen-specific regulatory T cells can be induced from naive
CD4+CD25- or CD8+CD25- T cells in the periphery under the influence of semimature 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.
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
Role of infections in the development of autoimmunity
Examples of Diseases caused by cell and tissue specific
antibodies
Examples of T cell-mediated Immunological
diseases
Examples of Gene Mutations that Result
in (an Enhanced Risk for) Autoimmunity
• Table 18-6
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.
Autoimmune disease vs. Immunopathology: Crohn‘s disease
Inflammatory Bowel Diseases (IBD)
Ulcerative colitis
Crohn’s disease
Ulcerative colitis
• Continuous inflammation of
the colonic mucosa
• Hyperemic, edematous
mucosa, often associated
with crypt abscesses
• Incidence: 2-3 new cases
Crohn‘s disease
• Entire gastrointestinal tract
may be affected
• Discontinuous, transmural,
granulomatous inflammation
• Incidence: 4-5 new cases
per 100'000 persons per
CM 4/2007
Inflammatory Bowel Diseases: Incidence rates
(based on prospective studies)
Wisconsin (USA):
Stockholm (Sweden):
CD:
UC:
4.56 per 100’000
2.14 per 100’000
CD:
UC:
4.9 per 100’000
2.2 per 100’000
IBD:
7.05 per 100’000
IBD:
7.4 per 100’000
J. Pediatr. 2003; 143: 525-531
Gut. 2003; 52:1432-1434
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
• cathepsin D-/• Gai2-/-
• N-cadherin
dominant
negative mutant
• TNF DARE
• NF-kB p55-/• trefoil factor -/-
Etiology of Inflammatory Bowel Disease
Psychosocial
Factors
Vascular
factors
Environmental
Factors
Bacterial / Viral
Infections
Immunological
Factors
Genetic
Predisposition
Nutrition
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.
Genetic loci identified in inflammatory
bowel disease linkage studies
Locus name
Chromosomal region Disease type
IBD1
IBD2
IBD3
IBD4
IBD5
Chromosome 16q
Chromosome 12q
Chromosome 6p
Chromosome 14q
Chromosome 5q
IBD6
IBD7
IBD8
IBD9
Chromosome 19
Chromosome 1p
Chromosome 16p
Chromosome 3p
Genetic association
CD only
NOD2/CARD15
UC>CD
Not established
CD and UC
HLA, TNF or IRF4?
CD
Not established
CD; UC (?)
OCTN1/SLC22A4,
OCTN2/SLC22A5
CD>UC
Not established
CD and UC
IL23R
CD and UC
Not established
CD and UC
Not established
Inflammatory Bowel Diseases (IBD)
Ulcerative colitis
Crohn’s disease
Ulcerative colitis
• Continuous inflammation of
the colonic mucosa
• Hyperemic, edematous
mucosa, often associated
with crypt abscesses
• Incidence: 2-3 new cases
Crohn‘s disease
• Entire gastrointestinal tract
may be affected
• Discontinuous, transmural,
granulomatous inflammation
• Incidence: 4-5 new cases
per 100'000 persons per
CM 4/2007
Generalized pathway of the mucosal inflammation underlying
inflammatory bowel disease (IBD) and potential points of therapeutic
intervention.
Immune Tolerance
vs.
Immune Privilege
vs.
Immune Ignorance
Maintaining immune homeostasis: To respond, or not to to respond....
Nature Reviews Immunology 8, 74-80, 2008
Immune Tolerance:
- Central tolerance mechanisms
- Peripheral tolerance mechanisms
Immune Privilege
vs.
Immune Ignorance
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)
Nature Reviews Immunology 8, 74-80, 2008
Nature Reviews Immunology 8, 74-80, 2008
Immune Ignorance
Immune ignorance by the
adaptive immune system outside
the GALT of antigens, taken-up
in the intestinal mucosa
Macpherson & Smith J Exp Med.
203(3): 497–50; 2006
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.