Gastrointestinal Immunology Quiz

Immunology of the GI Tract

• The GI tract has a large mucosal surface area, approximately equal to a tennis court (300 m²).
• This surface area is covered in moist, nutrient-rich, non-keratinized tissue.
• It is colonized by a diverse bacterial flora.
• The gut's immune system works in balance with the bacteria to prevent infection. There are approximately 400 species of commensal bacteria in the gut, numbering 10¹⁴, which is 10 times the number of cells in the human body.
• The GI lymphoid tissue includes T cells, B cells, and antigen-presenting cells involved in immune induction and function.
• Epithelial layers and mucus secretions help limit uncontrolled bacterial growth.
• High acidity in the stomach also contributes to controlling bacteria.

Learning Objectives

• Understanding the need for mucosal immunity, general characteristics of the GI tract mucosal immune response, and physical mechanisms acting as barriers to infection.

• Description of the lymphoid tissue in the GALT (gut-associated lymphoid tissue), characterizing the architecture of structures like Peyer's patches, and the role of intraepithelial and lamina propria lymphocytes.

• The steps involved in the GI tract's immune response, including IgA transport into the lumen and its role in preventing infection.

• The role of various immune mediators, including γδ T cells, mast cells, cytotoxic T lymphocytes, and mucosal epithelial cells.

• The significance of oral tolerance to typical food proteins, how self-tolerance is achieved, and potential therapeutic uses of tolerance in autoimmune disease.

• Overview of common GI diseases with likely immunologic etiologies, including clinical manifestations and their involvement with the immune system.

Gut-Associated Lymphoid Tissue (GALT)

• GALT includes Peyer's patches, appendix, and lymphoid aggregates located in the appendix, large intestine, and lamina propria.
• It consists of distinct B cell follicles and T cell zones, where immune responses are initiated in the gut.

Peyer's Patches

• Located in the lamina propria near specialized epithelial cells.
• These cells transport small amounts of antigens from the gut lumen.
• This allows the immune system to sample antigens passing through the gut.
• Important for promoting IgA production and CTL responses.

M Cells

• Specialized epithelial cells that interface between the gut lumen and Peyer's patches.
• Transfer antigens via endocytosis or phagocytosis.
• Interact directly with underlying antigen-presenting cells (APCs).
• APCs present antigens to T cells to stimulate immune responses.
• Have micro-folds.

Pathogens and M Cells

• Some pathogens (Salmonella, Yersinia, Listeria, and Shigella) enter through M cells.
• They trigger phagocytosis or macropinocytosis.

Intraepithelial Lymphocytes (IELs)

• Found at a ratio of one IEL for every 4–6 epithelial cells.
• Primarily T cells, with >90% being αβ or γδ types.
• CD8+ IELs have cytotoxic function and cell-mediated immunity against intracellular bacteria and viruses.

Gamma Delta T Cells

• A type of T cell bearing a γδ T cell receptor instead of an αβ receptor.
• A significant percentage of IELs in the GI tract.
• Recognize nonpeptide molecules (like antigens, heat-shock proteins, nucleotides, and phospholipids) presented on MHC class I-like molecules (CD1).

Lamina Propria Immune Cells

• The lamina propria contains a diverse array of immune cells, including: CD4+ T cells (including Tregs), B cells and plasma cells, macrophages, dendritic cells, eosinophils, and mast cells.

Dendritic Cells Activating CD4+ T Cells

• Dendritic cells activate CD4+ T cells, which in turn activate B cells.
• This process involves antigen uptake, antigen presentation to T cells, and T cell activation of B cells.

Mast Cells

• Line epithelia (e.g., lungs, GI tract, skin) exposed to the environment.
• Involved in IgE-mediated defense against parasites.
• Elicit food-induced allergic reactions, including diarrhea, anaphylactic shock.

Peyer's Patch Stimulated B Cells

• B cells activated in Peyer's patches or lymph nodes.
• Drain through mesenteric lymph nodes as plasmablasts, entering the bloodstream.
• Mature plasma cells return to the lamina propria and produce IgA.
• IgA is transported into the gut lumen.

Plasma Cells Producing IgA

• Plasma cells in the lamina propria produce IgA.
• IgA binds to poly-immunoglobulin receptors (pIgR), is transported across the cell, and delivered to the mucosal surface.
• IgA binds to microbes to prevent access to the epithelium and promote clearance.

IgA Facilitating Pathogen Clearance

• Prevents microbial binding to epithelial cells.
• Opsonizes pathogens for phagocytosis by cells like eosinophils.
• Leads to degranulation and anti-parasite immunity.

Mucosal Memory

• Mucosal immune memory is shorter than serum memory.
• Mucosal antibody responses (e.g., to rotavirus, RSV, and rhinoviruses) are typically short-lived (months to years).
• Serum antibody responses may persist for decades (e.g., measles, mumps protections).

Oral Tolerance

• Immunization with antigen via the GI tract can induce systemic unresponsiveness.
• Used to prevent hypersensitivity reactions to ingested food proteins.
• High doses can lead to antigen-specific lymphocyte deletion.
• Low doses can lead to clonal anergy and regulatory T cell suppression.
• Regulatory T cells developed in GALT migrate systemically.
• Human trials are being done for autoimmune diseases (multiple sclerosis, rheumatoid arthritis, type I diabetes, and uveitis).

Selective IgA Deficiency

• Most common immunodeficiency in humans.
• Typically not clinically significant because IgM compensates.
• Associated with a higher risk of autoimmune disease.

Food Hypersensitivities

• Some reactions to food proteins result from IgE-mediated immediate hypersensitivity reactions.
• Symptoms can include nausea, vomiting, abdominal pain, skin rashes, pharyngeal edema, and bronchospasm (potentially fatal anaphylaxis).
• Reactions of some food hypersensitivities causing changes in vascular permeability, massive protein loss, enteropathy, and hypoalbuminemia.

Gluten-Sensitive Enteropathy

• Also known as celiac disease or idiopathic, sprue.
• A disease affecting the small intestine.
• Gluten-sensitive enteropathy is characterized by malabsorption due to villous atrophy.
• Due to hypersensitivity to gliadin (a protein family in wheat gluten).
• Epithelial cell lining (though intact) abnormally functions, which is limited to the small intestine since gliadin isn't broken down.
• Treatment includes a lifelong gluten-free diet, which can lead to increased incidence of lymphoma or carcinoma in untreated cases.

Ulcerative Colitis

• Inflammation is confined to the large intestine.
• Characterized by ulcer formation and loss of mucosal absorptive function.
• Anti-inflammatory or immunosuppressive therapy might not control disease.
• Necessary to perform a total colectomy for some cases.

Crohn's Disease

• Inflammatory and granulomatous lesions can affect various parts of the GI tract (particularly the terminal ileum and ascending colon).
• Characterized by obstructive symptoms, fistula formation, and involvement of other organs (i.e., from bowel to other organs).
• Failure of inflammatory macrophages to die from apoptotic mechanisms can lead to problems.

TNF-α and Crohn's Disease

• TNF-α plays an important role.
• Infliximab (a TNF-α inhibitor) blocks TNF-α activity and can reduce symptoms of disease.
• Treatment requires immunosuppressants.
• Surgery (segmental resection) may be necessary, but disease often recurs.

Immunologic Basis of Inflammatory Bowel Disease (IBD)

• Diffuse lymphocyte infiltrate and, later, granulomatous formation.
• Derangement in mucosal immunoregulation permits the development of immune responses to normally ignored mucosal antigens.

Developing a Mucosal Immune Reaction

• Antigen phagocytosis and its transport into cells (M cells).
• Antigen presentation and activation of CD4+ T cells.
• CD4+ T cell stimulation of B cells.
• B cell traffic to lymph nodes, bloodstream maturation into plasma cells.
• Plasma cells returning to the lamina propria to produce IgA, with subsequent transport to the gut lumen for pathogen neutralization.