Dendritic Cells and Gut Immunity

Mucosal Immunology

• Mucosal immunity is a crucial component of the body's defense against pathogens.
• Pathogens commonly enter the body through mucosal surfaces.
• Local immunity, involving IgA and IgG, and cellular immunity are important defense mechanisms at these sites.
• Mucosal immunity can sometimes provide sterilizing immunity (like against influenza).
• It is vital for dealing with pathogens that circumvent later immune responses.

Learning Objectives

• Understand the normal function of the mucosa and associated immune tissue.
• Comprehend how mucosal immunity responds to food antigens, commensals, and pathogens in the digestive tract.

What's Special About Mucosal Immunity

• Most pathogens enter the body through mucosal surfaces.
• Local immune responses (IgA/IgG and cellular immunity) act as a primary defense against pathogens.
• Mucosal immunity can induce sterilizing immunity in some cases (influenza).
• It's especially important for pathogens that evade subsequent immune responses.

Physiological Barriers

• Tight junctions within the mucosa's structure are a significant barrier.
• Epithelial cells turnover rapidly, originating from stem cells.
• Mucus and glycocalyx coat the surfaces.
• Ciliated surfaces facilitate movement of material.
• Optimal pH levels are present.
• Physiological microflora also contributes to defense.

Mucosal Immune System (MALT)

• Protects mucous-coated surfaces (GI, GU, respiratory tracts).
• Comprises significant immune tissue (approximately 75% of lymphocytes).
• Mucosa is permeable, thus susceptible to infection.
• Most pathogens gain entry through mucous membranes.
• Contact with non-pathogenic molecules (like food proteins and commensal bacteria) is also common.
• Mucosal immunity must differentiate between pathogens and innocuous entities.

Mucosal Immune System (MALT) - Examples

• GALT (gut-associated lymphoid tissue)
• NALT (nose-associated lymphoid tissue)
• BALT (bronchus-associated lymphoid tissue)
• Mucosal systems in the eyes, breast, and urogenital areas

Organisation of MALT

• Focuses on intestinal mucosa.
• Immune cells (lymphocytes, macrophages, DCs) are found throughout in organized tissues (GALT) or dispersed throughout the mucosal epithelium and underlying connective tissues.
• Organized tissues (GALT and mesenteric lymph nodes) are important for immune responses.
• Scattered cells are also involved in local immune responses.

Gut-associated Lymphoid Tissue (GALT)

• Intestinal lymphocytes are located in organized tissues where immune responses develop and in the gut where they carry out effector functions.
• Scattered lymphoid cells are present in the epithelium.
• Organized lymphoid tissues include intestinal lumen, lamina propria lymphocytes, and intraepithelial lymphocytes, as well as Peyer's patches, subepithelial domes, isolated lymphoid follicles.

Antigen Uptake in the Intestine

• M cells absorb particles from the gut lumen through endocytosis and phagocytosis.
• Particles are transported through the cells (transcytosis).
• Dendritic cells (DCs) are recruited to the epithelium.
• M cell basal borders form pockets encompassing DCs and lymphocytes.
• DCs migrate to T cell areas when they absorb antigens, and present to T cells.
• Then B cell activation occurs and class switching to IgA.

Effector Cells in the Intestine

• Large numbers of effector T cells and plasma cells reside within the intestinal tissues.
• Unusual for non-lymphoid tissues.
• CD8+ T cells are predominant in the epithelium.
• CD4+ T cells, plasma cells, DCs, macrophages, mast cells, and eosinophils are located within the lamina propria.
• A healthy gut exhibits a similar structure to a chronic inflammatory state, but this is a normal phenomenon.
• Effector and regulatory T cells need to balance one another.

CD4+ T Cells in Lamina Propria

• Effector CD4+ T cells are scattered in the lamina propria.
• Include Th1 (antibacterial responses), Th2 (anti-parasitic responses), and Th17 cells (ileum and colon, recruiting neutrophils)
• Induced regulatory T cells (Treg cells) are CD25+ and suppress inflammation, expressing TGFβ and IL-10

CD4+ T cells in Lamina Propria

• Induced regulatory T cells (Tregs) are present, expressing TGFβ and IL-10, which are immunosuppressive.
• Th1, Th2, and Th17 cells are balanced by these Tregs. This state is termed physiological inflammation.

Induction of Immune Responses

• Gut is exposed to pathogens, non-pathogenic bacteria and other innocuous substances.
• Mucosal immune system differentiates between harmful (pathogenic) and harmless.
• Commensal organisms are present in various locations (mouth, esophagus, stomach to cervix).

Response to Food Antigens

• Oral tolerance generates tolerance toward food antigens.
• Both mucosal and systemic immune systems are affected (oral tolerance).
• Oral tolerance is a state of immunosuppression in the oral mucosa, preventing reactions to harmless antigens.
• It prevents unnecessary immune responses to commensal bacteria and food.

Mechanisms of Oral Tolerance

• Anergy and deletion of antigen-specific T cells.
• Generation of antigen-specific Treg cells via activation of naïve T cells in mesenteric lymph nodes by immature DCs.
• unclear how this leads to systemic tolerance.

Response to Commensals

• Gut commensal bacteria perform essential functions (metabolism, cofactor synthesis).
• Commensals are important for immune development.
• They don't produce virulence factors, so they don't invades the epithelium.
• However, they are cleared rapidly by phagocytes, therefore do not cause infections.
• Commensals are recognized by the immune system but don't induce immune tolerance.
• Inflammation in the gut is limited.
• commensal-specific Th1 and Th17 effector cells are produced but usually do not initiate inflammatory responses. DCs produce IL-23 to drive Th17 differentiation. Th17 cells generate IL-22, which promotes antimicrobial peptides. Commensal bacteria stimulate cytokine and chemokine production by inhibiting NFκB activity. Microorganisms are controlled in the gut via tight junctions, mucin production, IgA and defensins.

Response to Pathogens

• Pathogens are recognized by TLRs and NODs on cell surfaces or within intracellular vesicles.
• Intracellular pathogens trigger inflammasome formation and destruction in autophagosomes.
• Invasive microorganisms penetrate the epithelium to activate dendritic cells.
• TLRs, NOD1, NOD2 activate NFκB, stimulating inflammatory cytokines, chemokines, and other mediators.
• These molecules recruit and activate neutrophils, macrophages, and dendritic cells.
• Pathogens in the cytoplasm form autophagosomes, then are destroyed inside lysosomes.
• Activated dendritic cells expressing co-stimulatory ligands promote differentiation of CD4 into Th1, Th17, and Th2 cells.

Effect of Antibiotics on Commensal Bacteria

• Antibiotics can kill commensal bacteria.
• Clostridium difficile can colonize and produce toxins.
• Toxins cause tissue damage, leading to inflammation.

Summary

• Mucosal lining acts as a physical barrier to pathogens and damage.
• Specialized immune cells detect and respond to threats.
• System learns to tolerate harmless food antigens.
• Maintains symbiotic relationship with beneficial bacteria, preventing overgrowth.
• Pathogen-associated molecules initiate immune responses via pattern recognition receptors (PRRs), activating immune cells, which promotes inflammation and recruits cells to eliminate the pathogen.