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... of Maryland School of Medicine. GENETICS AND IBD. TH

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... of Maryland School of Medicine. GENETICS AND IBD. THE ABC's. GENETIC ... Genetics of IBD. Familial occurrence (15-20% patients have affected relative) ... – PowerPoint PPT presentation

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Title: ... of Maryland School of Medicine. GENETICS AND IBD. TH


1

GENETICS AND IBD THE ABCs
  • Terez-Shea Donohue
  • Department of Medicine
  • Mucosal Biology Research Center
  • University of Maryland School of Medicine

2
GENETIC SUSCEPTIBILITY
3
Impact of Race and Ethnicity
  • Whites had stronger family history of IBD and
    colorectal cancer.
  • African Americans with CD had higher incidence of
    arthritis.
  • Disease severity similar across all groups.
  • P-anca served as a sensitive maker for Mexican
    Americans as 100 with UC were
    positive compared with 40 in whites

A
Basu, D Am J Gastroenterology 1002254-2261, 2005
4
IBD Antibodies
  • Sensitivity varies among population
  • Positive pANCA with negative ASCA IgA/IgG
    indicates Ulcerative colitis vs Crohns disease
  • pANCA antineutrophil cytoplasmic antibody
  • Positive Crohns patients lack of ileal
    involvement
  • Caucasian patients
  • Ulcerative colitis patients 5984
  • Crohns Disease 10-40
  • controls 10
  • ASCA antisaccharomyces cerevisiae antibody
  • Usually measured with IgA or IgG
  • Increased titers indicated ileal involvement
  • Crohns Disease 50-60

Lawrance IC et al., Am J Gastroenterology
992186-2194, 2004
5
Genetics of IBD
  • Familial occurrence (15-20 patients have
    affected relative)
  • Genetic influence is lower in ulcerative colitis
    than in Crohns disease
  • Human gene testing is looking for markers
  • Genes coded by chromosomes (1,5,6,10,12,16, and
    19)
  • Nucleotide-binding oligomerization domain
  • Nod2 (CARD15) mutations on chromosome 16
  • Nod1 (CARD4)
  • Cytokine cluster region on chromosome 5
  • IBD5 locus on chromosome 5q31
  • OCTN1 and 2 carnitine/organic ion transporter
    thought to be IBD5 susceptibility genes
  • DLG5 on chromosome 10q23, encodes epithelial
    scaffolding protein
  • Correlates between genotype and disease phenotype
    (e.g Nod2 and fibrostentic small intestinal
    disease)

6
A is for AUTOIMMUNE
7
AUTOIMMUNE DISEASES
  • Genetic susceptibility for the host immune system
    to recognize, and potentially misinterpret, an
    environmental antigen presented to the body (eg.,
    within the GI tract).
  • The host must be exposed to the antigen.
  • The antigen must be presented to the mucosal
    immune system following its paracellular passage
    (normally prevented by tight junction competency)
    from the lumen to the submucosa.

8
NOD2 (CARD15)
  • First susceptibility gene for Crohns Disease
    (2002)
  • Strong association for small bowel
  • Phenotype - associated with fibrostenotic small
    intestinal disease
  • Attributable risk
  • Crohns ileitis 30
  • Ulcerative colitis 6
  • Risk by population
  • Causcasian - 19.1-29
  • Ashkenazi Jews 47.4
  • Sephardic Jews 27.45
  • African Americans 2.6
  • Asian (Chinese, Korean, Japanese) - ND

9
Other Genes Involved in Mucosal Function
  • OCTN organic cation transporter gene located on
    5q31, mutations at this loci affect the ability
    of the transporters to pump xenobiotics and amino
    acids
  • DLG5 membrane scaffold protein located on
    10q23, muations impart the ability to maintain
    epithelial polarity
  • Both genes important in epithelial permeability
    and disruption may facilitate exposure to
    bacterial products

10
AUTOIMMUNE DISEASES
  • Genetic susceptibility for the host immune system
    to recognize, and potentially misinterpret, an
    environmental antigen presented to the body (eg.,
    within the GI tract).
  • The host must be exposed to the antigen.
  • The antigen must be presented to the mucosal
    immune system following its paracellular passage
    (normally prevented by tight junction competency)
    from the lumen to the submucosa.

11
(No Transcript)
12
HOST DEFENSE ALERT
13
Stimulation Of Immune Responses In The Normal Host
14
ETIOLOGIC HYPOTHESES
15
AUTOIMMUNE DISEASES
  • Genetic susceptibility for the host immune system
    to recognize, and potentially misinterpret, an
    environmental antigen presented to the body (eg.,
    within the GI tract).
  • The host must be exposed to the antigen.
  • The antigen must be presented to the mucosal
    immune system following its paracellular passage
    (normally prevented by tight junction competency)
    from the lumen to the submucosa.

16
IBD - Defective Mucosal Integrity
  • CD may be considered as a defective immune
    response, no longer only as hyperresponsiveness
    of the mucosal immune system
  • Nod2/ CARD15 expression suggest that macrophages
    and epithelial cells could be the site of a
    primary pathophysiologic defect, and T-cell
    activation might just be a secondary effect
    inducing chronification of the inflammation,
    perhaps as a backup mechanism to a defective
    innate immunity

17
Tight Junction Proteins and IBD
Claudin 2
Claudin 4
Prasad et al., Lab Investigation, 2005
18
B is for BACTERIA
19
Role of Bacteria in the Pathogenesis of Chronic
Immune Mediated Intestinal Inflammation
20
Influence Of Luminal Contents On Reactivation Of
Crohns Disease
21
Regulation Of Experimental Colitis By T Cell
Subsets
22
Role Of Individual Bacteria In The Pathogenesis
Of Experimental Colitis
23
GERMETICS
Convergence of the "germ concept" and the
"genetic concept" of IBD pathophysiology
24
Cytoplasmic Pattern Recognition Receptors Nod1
and Nod2
  • Nod2 - present in macrophages, dendritic and
    Paneth cells, and can be induced in enterocytes.
    Its activation by bacterial muramyl dipeptide
    induces expression of proinflammatory mediators.
  • Nod1 - expressed in intestinal epithelial cells
    and activates proinflammatory cytokine production
    in response to a peptidoglycan motif in
    gram-negative bacteria.

Identification of associations between NOD1 and
NOD2 and IBD indicate that altered recognition of
intracellular bacterial pathogen-associated
molecular patterns (PAMP) may be a key event in
the pathogenesis of the disease.
25
Nod2 and Innate Immunity
  • Transduces signals activating NF?? and initiating
    apoptosis
  • CARD15/NOD2 function and NF?? activation indicate
    that an inflammatory reaction of the intestinal
    mucosa as a response of the innate immune system
    may be necessary for the maintenance of gut
    homeostasis.

26
PANETH CELLS
Kelly P., Clin Exp Immunol. Feb135(2)303-9, 2004
27
Nod2 Functions in Mucosal Defense
  • Nod2 expressed in cytosol of Paneth cells
  • Mutations in Nod2 may confer reduced ability to
    kill gut bacteria.

28
Nod1 and Innate Immunity
  • Nod-1 acts as a cytoplasmic sensor for bacteria
    and their products
  • Important in defense against H. pylori and
    Shigella flexneri
  • Associated with asthma

McGovern D., Human Mol Genetics. March,
141245-1250, 2005
29
Toll Receptors and Their Ligands
Basu AND Fenton, Am J Physiol Lung Cell Mol
Physiol 286 L887-L892, 2004
30
Innate To Adaptive Immunity
Basu AND Fenton, Am J Physiol Lung Cell Mol
Physiol 286 L887-L892, 2004
Rakoff-Nahoum et al., Cell, 118 229-241, 2004.
31
C is forCLINICAL RELEVANCE
32
Potential Clinical Applications Of Genomics In
IBD Patients
33
Hypothetical Regulation Of Clinical Phenotype And
Therapeutic Response In IBD Patients By Genotype
34
BALANCE OF COMMENSAL BACTERIAL COMPONENTS
35
PROBIOTICS
  • A preparation of, or a product containing,
    viable, defined microorganisms in sufficient
    numbers to alter the microflora by implantation
    or colonization in a compartment of the host, and
    exert beneficial effects on host health.
  • Lactobacillus
  • Lactobacillus rhamnosus GG (LGG) (ATCC 53103) is
    now widely used as a probiotic in dairy
    products..
  • Bifidobacterium
  • Immunobiotics therapeutic manipulation of
    microflora
  • Oral LGG adheres and colonizes the human
    intestine Stimulate gut antigen presenting cells
    to promote protection and switch regulatory
    mechanisms

36
BACTERIA
Th1
Th2
Crohns Disease
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37
SUMMARY
  • Autoimmune
  • Bacteria
  • Clinical relevance

38
Gene-Environment Interaction
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