Christoph Mueller christoph.mueller@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

Selection of T cells in the Thymus based on the affinity of their TCR for MHC + peptide
No or very low Intermediate High
Affinity of TCR for MHC + peptide

A
I
Re

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 (T
R
1) cells, which secrete high levels of IL-10, no IL-4 and no or low levels of IFN-; and T helper 3 (T
H
3) 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

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

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
Crohn‘s disease
• Entire gastrointestinal tract may be affected
• Discontinuous, transmural, granulomatous inflammation
• Incidence: 4-5 new cases per 100'000 persons per year
CM 4/2007

Wisconsin (USA):
CD: 4.56 per 100’000
UC: 2.14 per 100’000
Stockholm (Sweden):
CD: 4.9 per 100’000
UC: 2.2 per 100’000
IBD: 7.05 per 100’000
J. Pediatr. 2003; 143: 525-531
IBD: 7.4 per 100’000
Gut. 2003; 52:1432-1434

• TCRa -/-
• TCRb -/-
• MHC class II -/-
• TGFb -/-
• IL-2 -/-
• IL-10 -/-
• Smad3 -/-
• GFAP- targeted enteric glia cell depletion
• N-cadherin dominant negative mutant
• cathepsin D -/-
• Gai2 -/-
• NFk B p55 -/-
• TNF D ARE
• trefoil factor -/-

Vascular factors
Environmental
Factors
Psychosocial
Factors

Genetic loci identified in inflammatory bowel disease linkage studies
Locus name Chromosomal region Disease type Genetic association
IBD1
IBD2
IBD3
IBD4
IBD5
IBD6
IBD7
IBD8
IBD9
Chromosome 16q
Chromosome 12q
Chromosome 6p
Chromosome 14q
Chromosome 5q
Chromosome 19
Chromosome 1p
Chromosome 16p
Chromosome 3p
CD only
UC>CD
NOD2/CARD15
Not established
CD and UC HLA, TNF or IRF4?
CD Not established
CD; UC (?) OCTN1/SLC22A4,
OCTN2/SLC22A5
CD>UC
CD and UC
CD and UC
CD and UC
Not established
IL23R
Not established
Not established

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
Crohn‘s disease
• Entire gastrointestinal tract may be affected
• Discontinuous, transmural, granulomatous inflammation
• Incidence: 4-5 new cases per 100'000 persons per year
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

• 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

Macpherson & Smith J Exp Med.
203(3): 497
–50; 2006
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.