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

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

AutoImmune Regulator AIRE

Central and peripheral Tolerance in B cells

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.

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 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 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

Inflammatory Bowel Diseases: Incidence rates (based on prospective studies) 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 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

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 Bacterial / Viral Infections Vascular factors Immunological Factors Environ- mental 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 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

Inflammatory Bowel Diseases (IBD) Ulcerative colitis Crohn’s disease 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

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

Immune Tolerance vs. Immune Privilege 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 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