Mucosal Immune System functions

Gastrointestinal Mucosal Immune System

• The mucosal immune system protects the internal surfaces of the body, encompassing the GI tract, respiratory tract, urogenital tract, and exocrine glands associated with these organs.
• The immune system's role is critical due to the constant exposure to antigens like food and microorganisms in the gut.
• The gut is a major site of contact for foreign antigens.
• Gastrointestinal diseases affect over 2 million people annually.
• Effective mucosal vaccines are lacking.

Outline of the Gastrointestinal Mucosal Immune System

• Introduction to the topic
• Gut-associated lymphoid tissues (GALT)
• Effector sites within the gut
• Antigen entry into gut sites
• Mucosal immune responses
• The human gut flora
• Oral tolerance

Gut-Associated Lymphoid Tissues (GALT)

• Peyer's patches
• Lymphoid follicles within the intestine
• Appendix
• Tonsils
• Adenoids
• Mesenteric lymph nodes

Features of the Mucosal Immune System

• Intimate interactions between mucosal epithelia and lymphoid tissues
• Separate compartments of diffuse lymphoid tissue, organized such as Peyer's patches, isolated lymphoid follicles, and tonsils
• Specialized antigen-uptake mechanisms, including M cells in Peyer's patches, adenoids, and tonsils
• Activated/memory T cells are predominant, even in the absence of infection.
• Nonspecifically activated (natural) effector/regulatory T cells.
• Active downregulation of immune responses to harmless antigens (e.g., food).
• Inhibitory macrophages and tolerance-inducing dendritic cells.

Organization of the Mucosal Immune System

• Mucosal tissues of the human body are comprehensively showcased, with detailed depictions of various mucosal sites.
• Mucosal sites are exposed to a broad range of antigens, including food.

Microfold Cells (M Cells)

• Route by which antigens enter Peyer's patches.
• Isolated lymphoid follicles in the small and large intestine contain mainly B cells.
• Similar isolated follicles are present in bronchus-associated lymphoid tissues (BALT) and nasal-associated lymphoid tissues (NALT).
• Fetal development of intestinal lymphoid tissues is controlled by specific cytokines.

Epithelium of Peyer's Patches (PP)

• Peyer's patches are covered by specialized cells, called M cells, characterized by unique membrane ruffles/microvilli.

Why Understanding Gut Immunity is Crucial

• The gut is a critical site of contact for exogenous antigens.
• Gastrointestinal diseases are significant health concerns.
• The need for effective mucosal vaccines.

Multiple Factors Protecting Against GI Pathogens

• Saliva
• Stomach acid and enzymes
• Bile
• Water and electrolyte secretion
• Mucosal products (mucus, defensins)
• Epithelial barrier
• Peristalsis
• Bacterial flora

Diseases of the Intestinal Immune System

• Caused by failure to establish or maintain oral tolerance

Effector Sites in the Gut

• Effector sites in the epithelium and lamina propria

Effector Sites: Epithelium and Lamina Propria

• The mucosal immune system is composed of the epithelium and lamina propria.
• The lamina propria contains a diverse array of immune cells.
• The epithelium principally contains CD8 T cells.

Intraepithelial Lymphocytes (IELs)

• IELs (intraepithelial lymphocytes) are mostly (90%) CD8 T cells.
• IELs are situated within the epithelial lining of the gut.
• These cells are restricted in their V regions and display limited specificities.
• Two types of IELs exist: conventional CD8 αβ and CD8αα

Antigen Entry into Mucosal Sites

• M cells in follicle-associated epithelium continuously take up molecules and particles from the gut lumen through endocytosis and phagocytosis
• Released into the extracellular space.
• Dendritic cells (DCs) then uptake the transported materials.
• Antigen presentation occurs to T lymphocytes

M Cells and Antigen Uptake

• M cells are responsible for antigen uptake via endocytosis and phagocytosis.
• Transported antigen is released at the basal surface
• Dendritic cells subsequently bind and take up the antigen
• M cells are non-APC (Antigen Presenting Cells)

Dendritic Cells and Antigen Uptake

• Dendritic cells extend processes across the epithelial layer, capturing antigens from the gut lumen.
• DCs are abundant in the wall of the intestine, mostly in the lamina propria.
• They acquire antigens even across intact epithelial barriers without M cell assistance.
• DCs then transport the antigens to T cell areas of mesenteric lymph nodes.

Mucosal Immune Responses

• Epithelial cells interact with pathogens via intracellular Toll-like receptors (TLRs) and Nod-like receptors (NLRs).
• TLRs and NODs initiate immediate immune responses against invasion or tissue damage.
• Activation of receptors triggers NF-κB activation, leading to cytokine production and cell survival.
• Promoters for inflammatory mediators are activated by NF-κB

IgA Response

• Effective immunization against enteric pathogens is associated with IgA response.
• Most IgA originates from the GI tract/Peyer’s Patches.

Functions of IEL (Conventional T Cells)

• CD8αβ T cells safeguard against viral infections and infected mucosal epithelial cells.

Role of Commensal Bacteria in Tolerance and Immunity

• Commensal bacteria stimulate the epithelium to produce cytokines and other factors that prevent dendritic cell maturation.
• Immature dendritic cells can induce T regulatory cells.
• Mature T cells support the development of T helpers

The Human Gut Flora

• Rapidly colonizes the gut after birth.
• Comprises >1014 organisms.
• Weighs ~1-2 kg.

• 400 species.

• Individual microbiota is unique.
• Symbiotic relationship with the host.
• Probiotic administration is used by individuals at times.

Pathogen Exploitation of Mucosal Immunity: Salmonella

• Salmonella enter gut lumen.
• Salmonella invade the epithelial cells.
• Salmonella can infect dendritic cells.
• Salmonella can penetrate via M cells, epithelial cells, or with the help of dendritic cells.

Our Gut Flora Helps Prevent Colonization by Pathogens

• An imbalance in gut flora can allow pathogens like Clostridium difficile to cause mucosal injury.

Immune Responses in the Gut

• Immune responses initiate with infection by foreign antigens.
• APC activation leads to T-cell activation.
• Inflammation helps eradicate pathogens.

Initiation of Gut Responses

• M cells located between enterocytes and subepithelial lymphocytes/dendritic cells take up antigens via endocytosis
• Released antigens are then taken up by nearby antigen-presenting dendritic cells.

Oral Tolerance

• Prevents an immune response to normal flora and food antigens.
• Causes poor or absent immune responses to many orally administered antigens.

Breakdown of Oral Tolerance

• Celiac disease results from IFNγ-producing CD4 T-cells, leading to inflammation in the upper small intestine.

Mechanisms of Oral Tolerance

• Anergy or deletion
• Generation of regulatory T cells of various types.