slide1 n.
Download
Skip this Video
Loading SlideShow in 5 Seconds..
Molecular mechanisms of immune tolerance Central tolerance induction in the B cell and T cell compartment Immune toleran PowerPoint Presentation
Download Presentation
Molecular mechanisms of immune tolerance Central tolerance induction in the B cell and T cell compartment Immune toleran

Loading in 2 Seconds...

play fullscreen
1 / 35

Molecular mechanisms of immune tolerance Central tolerance induction in the B cell and T cell compartment Immune toleran - PowerPoint PPT Presentation


  • 790 Views
  • Uploaded on

Immunotolerance 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

loader
I am the owner, or an agent authorized to act on behalf of the owner, of the copyrighted work described.
capcha
Download Presentation

PowerPoint Slideshow about 'Molecular mechanisms of immune tolerance Central tolerance induction in the B cell and T cell compartment Immune toleran' - gene


Download Now An Image/Link below is provided (as is) to download presentation

Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author.While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server.


- - - - - - - - - - - - - - - - - - - - - - - - - - E N D - - - - - - - - - - - - - - - - - - - - - - - - - -
Presentation Transcript
slide1

Immunotolerance

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
slide3

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

slide10

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.

slide11

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 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.

postulated mechanisms of autoimmunity
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

autoimmune general principles and observations
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.
slide19

Inflammatory Bowel Diseases (IBD)

Ulcerative colitis Crohn’s disease

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 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

slide20

Inflammatory Bowel Diseases: Incidence rates

(based on prospective studies)

Stockholm (Sweden):

CD: 4.9 per 100’000

UC: 2.2 per 100’000

IBD: 7.4 per 100’000

Gut. 2003; 52:1432-1434

Wisconsin (USA):

CD: 4.56 per 100’000

UC: 2.14 per 100’000

IBD: 7.05 per 100’000

J. Pediatr. 2003; 143: 525-531

mutant mice that spontaneously develop colitis
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 -/-
etiology of inflammatory bowel disease

Psychosocial

Factors

Etiology of Inflammatory Bowel Disease

Bacterial / Viral

Infections

Vascular

factors

Immunological

Factors

Environ-

mental

Factors

Genetic

Predisposition

Nutrition

etiopathogenesis of inflammatory bowel diseases

Etiopathogenesis of Inflammatory Bowel Diseases

- aberrant local immune responses to luminal antigens

- in genetically predisposed individuals.

Induction and perpetuation of IBD is generally considered to depend on:

slide24

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 UC>CD 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 CD>UC 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

slide25

Inflammatory Bowel Diseases (IBD)

Ulcerative colitis Crohn’s disease

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 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

slide26

Generalized pathway of the mucosal inflammation underlying inflammatory bowel disease (IBD) and potential points of therapeutic intervention.

slide27

Immune Tolerance

vs.

Immune Privilege

vs.

Immune Ignorance

slide28

Maintaining immune homeostasis: To respond, or not to to respond....

Nature Reviews Immunology 8, 74-80, 2008

slide29

Immune Tolerance:

  • Central tolerance mechanisms

- Peripheral tolerance mechanisms

slide30

Immune Privilege

vs.

Immune Ignorance

immune privilege
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)

slide35

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): 497–50; 2006