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

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

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)

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

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

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

The Gut is Bombarded by Foreign Antigens cell cel cell

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

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

Innate immune system in mucosa Defensins AMPs Tight junction

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

MALT structure

M cells

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

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

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

Immunological Disease of the Gastrointestinal Tract

Celiac disease

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

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;

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

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

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.

Crohn’s disease

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

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

Immune pathophysiology IL-12 Th1 IL-23 Th17

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

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.

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

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

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

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

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

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