2. Immunological Disease of the Gastrointestinal Tract
Dr. Niknam
Samaneh Zoghi
Jan 2016

3. Importance of GI Immunology
The gastrointestinal tract:
Largest mass of immune cells
Exposed to dietary and microbial antigens
Employs strategies for immune tolerance

4. Immune system in GI secreted IgA
epithelial-produced antimicrobial peptides,
A physical barrier (the tight junction)
A specialized epithelial cell
A dendritic cell network (induction of inflammatory and regulatory(suppressive) responses)

5. GI diseases Despite these adaptations, the GI uniquely susceptible to:
chronic immune-mediated inflammation
These conditions arise from:
Genetically determined antigen responsiveness
Defects in the adaptive and innate immune systems

6. GI mucosa Importance of GI mucosa Structure of GI mucosa
Immune system in GI mucosa
Immune response in GI
Immunological disease of GI

7. Diarrheal Diseases
3.1 million
Acute
Respiratory
Diseases
4.4 million
Tuberculosis:
3.1 million
Hepatitis B
1.1 million
HIV/AIDS: > 1 million
Measles: > 1 million
Malaria: 2.1 million
Roundworm and
Hookworm: 165,000
Neonatal Tetanus: 500,000
Whooping Cough: 388,000

9. The Gut is Bombarded by Foreign Antigens
cell
cel
cell

10. Types of Mucosal Surfaces
small and large intestine
Type I
upper female reproductive tract
Mucosal Surfaces
respiratory tract
Mouth
Type II
Vagina

11. Structure of Mucosal Tissues
لومن
لایه اپی تلیال
لایه مخاطی
لامینا پروپریا
لایه زیرمخاط
لایه عضلانی
لایه همبند

12. Innate immune system in mucosa
Defensins
AMPs
Tight junction

14. Mucosal Associated Lymphoid Tissue (MALT)
Gut Associated Lymphoid Tissue
(GALT)

15. MALT structure

16. M cells

18. Effector site Inductive site B cell Activated Helper T cell IgA
Plasma cell

19. IgA transport Poly-Ig receptor With bound IgA J chain IgA producing
Plasma cell
Endocytosed
Complex of IgA
And poly Ig
receptor
Dimeric IgA

20. IgA structure and function
Inhibiting pathogen adherence
Neutralizing viruses, enzymes, and toxins

21. Immunological Disease of the Gastrointestinal Tract

22. Celiac disease

23. Celiac disease gluten enteropathy
Most prevalent immune-mediated disease of the human GI
Chronic inflammation due to activation of gluten-specific T cells  specific autoantibody formation
Small intestinal villous atrophy,
Malabsorption
پرز

25. Immune pathophysiology Celiac disease
Gluten peptides APC expressing specific HLA molecules in the lamina propria of the gut (primarily the small intestine)
Activated T cells  pro-inflammatory cytokines IFNg, IL-18, TNF-α, IL-21
Can induce B-cell maturation to plasma cells producing antibodies to gluten peptides as well as tissue transglutaminase;

26. Treatment
The goals of gluten-free diet treatment are relief of symptoms, reversal of malabsorption, and restoration of villi
Few cases need corticostroids and immunosuppressive drugs (poly clonal IEL)
Novel therapies that modify gluten to non-immunogenic forms or that induce tolerance to gluten in persons at risk for or suffering from celiac disease

27. IBD
Heterogeneous group of chronic inflammation in large and small intestine
Weak regulation of immune response toward commensal bacteria
Main types:
Crohn’s disease  occurs every region of GI and in transmural  (full-thickness) involvement
Ulcerative colitis  only in colon mucosa

28. یک گروه هتروژن از اختلالات التهابی مزمن بدلیل تنظیم ضعیف پاسخ ها علیه باکتری های کومنسال. دو نوع اصلی آن بیماری کرون و کولیت اولسراتیو است.

30. Crohn’s disease

31. Crohn’s disease (terminal ileitis)
A chronic idiopathic inflammation of the gut
Transmural involvement of the bowel wall (mucosa, muscle layer and serosa)
bowel obstruction from fibrous strictures
bowel wall perforation leading to abscesses and fistulae
Treatment  corticosteroids and immunosupressants and more recently with antibodies targeting TNF-α

32. Immune pathophysiology
Dysregulated Th1 and Th17 cytokine pathways mediate disease in animal models  IL-12 and IL-23 role
Defects in innate immunity
Defective defensin production  incresead the invading of commensal bacteria into epithelium
Several gene mutations and many genetic loci are associated with disease risk, including NOD2 and ATG16L1

33. Immune pathophysiology
IL-12
Th1
IL-23
Th17

34. Treatment
The colitis could be blocked or reversed by treating animals with anti-IL-12 antibodies
Blockade of IFNg activity also prevented development of gut inflammation
Production of IL-12, IL-23, IFN-g, and IL-17 are significantly elevated
targeting both IL-12 and IL-23, IL-23 alone, and IL-17

35. Treatment
Crohn’s disease is a chronic, relapsing inflammation of the bowel and up to 80% of patients will require surgical treatment at some point.

36. Gastrointestinal Complications of Primary Immunodeficiencies
Some of PIDs has GI complications
Most frequently CVID and CGD

37. CVID
Heterogeneous set of disorders ; hypogammaglobulinemia, reduced numbers of peripheral blood isotype-switched memory B cells, loss of plasma cells & recurrent sinopulnonary infections
At least 2 of 3 Ig classes is decreased (IgG & IgM or IgA)
Genetic defects: ICOS, TACI, CD19, CD20, CD81, CD21; accounts for 15% of CVID
Inflammatory, autoimmune disorders & some malignancies are frequent in CVID

38. IVIg treats the sinopulmonary infections
But no other complications such as autoimmune disease and GI symptoms, including intestinal infections
CVID enteropathy is often confused with celiac disease due to similar villous damage on biopsy but additional features

39. CVID GI complications Infectious complications
Giadia, Salmonella, Campylobacter jejuni, Cryptosporidium, Clostridium difficile
Immune-mediated and autoimmune
Idiopathic enteropathy (villus atrophy, increased IEL, lymphoid hyperplasia, vit B12 deficiency (pernicious anemia)
Neoplastic complications
Intestinal lymphoma and gastric adenocarcinoma

40. Treatment CVID enteropathy has no established therapy
Use of short courses of oral steroids or conventional immunosuppression may relieve the malabsorption and diarrhea temporarily

41. Quiz
Which of the following T cells are involed in the pathogenesis of Crohn’s disease?
More than one answer may be correct
A)TH1
B)TH2
C)TH17
D)TH22