Intestinal Immune Response

With the surface area of a tennis court, the GI tract represents the largest lymphoid organ of the body.

The GI tract is continuously challenged by bacterial antigens and foreign molecules from dietary protein.

80% of immunoglobulins are in the GI tract.

The GI tract is rich in lymphocytes

Factors Involved in Immune Response

NON IMMUNOLOGICAL FACTORS – provide protection by physical and chemical means.

MUCUS – a viscous hostile environment, prevents penetration, traps microorganisms, and provides a binding matrix for secreted Ab’s (IgA). Also CILIA, TIGHT JUNCTIONS, CELL RENEWAL, PERISTALSIS, and SECRETIONS function, with the epithelium, to physically form an impermeable barrier from environmental antigens. Chemicals LYSOZYME, SPERMINE, BILE SALTS, and GASTRIC ACID also help to provide protection.

ORAL TOLERANCE – animals that receive their primary exposure to a foreign protein orally are unable to respond in a subsequent challenge to the same protein administered by any route. Tolerance gained in GI tract has systemic effects. Lymphocytes are "taught" not to respond. Possibly due to clonal deletion, clonal anergy, or suppressor cells (for T-cells). Oral tolerance is necessary to prevent excessive response to normal flora and food antigens.

primary encounter with luminal antigen occurs in lymphoid follicles via APCs to resident T and B cells

PEYER’S PATCH – a repository for lymphocytes. Peyer’s Patches in the small intestine, Lymphoid follicles in the colon. Organized similar to a lymph node. In the germinal center B cells are educated by CD4+ helper T cells. Surrounding the germinal center the T cells are presented antigen by macrophages or dendritic cells in the context of MHC class II surface proteins. Educated lymphocytes leave the follicle are drain into the mesenteric lymph nodes, then onto the thoracic duct Þ blood stream. >90% of these cells recognize mucosal addressin in the gut and "home" to the intestinal mucosa. [addressins are tissue specific receptors (members of the integrin or selectin gene families) that cause the lymphocyte to extravasate through the vessel wall and enter a tissue.]

THE M CELL – a flattened cell that forms a dome over the lymphoid follicles. It is assumed that they are important in trapping Ag’s. The M cell lacks Ag processing capabilities (no lysosomes) and is believed to transport the unprocessed antigens to mucosal APC ‘s (antigen presenting cells) by pinocytosis and endosomal transport.

PLASMA CELLS the IgA factory. As B cells mature, they differentiate into plasma cells whose sole function is to synthesize vast amounts of Ag-specific immunoglobulins. The lamina propria is heavily populated with IgA secreting plasma cells that have homed to the mucosa.

IgA – IgA is a dimeric protein joined by a J chain. There are two forms of IgA; form 2 can dimerize and is secreted in the gut, form 1 is a monomer and is systemic. IgA is well suited for secretion into the gut because it is resistant to proteases, does not activate compliment, and is capable of interfering with bacterial attachment by adhering to the mucin layer coating the luminal side of the epithelium.

IgA SECRETION – IgA is synthesized in the lamina propria on the basolateral side of the epithelium. Polymeric IgA containing a J chain binds with high affinity to the polymer immunoglobulin receptor (pIgR). This complex is internalized into a coated endocytic vesicle. Avoiding lysosomes, the vesicle crosses to the apical side of the cell and fuses with the apical membrane. The complex is proteolytically cleaved, releasing into the lumen the complex of IgA, the J chain, and part of the pIgR known as the secretory chain (SC).

INTRAEPITHELIAL LYMPHOCYTES – (IEL), both thymus dependent and thymus independent effector T cells which are present as 1 in every 7 epithelial cells in the small intestine (less in the colon). Not well characterized but predominantly CD8+ and CD3+ suggesting they perform an immunosurveillance activity in the epithelium. Resemble NK cells. Granular with cytolytic activity. g and d T cell receptor expressed. Assumed they migrate to luminal surface and are shed with adjacent epithelial cells.

LAMINA PROPRIA T CELLS – are different from systemic memory cells, homing receptors for lymph nodes are downregulated while expression of activation/memory markers is increased (Ý CD44, Ý IL-2). It is assumed that these distinctions are responsible for oral tolerance and intestinal physiological inflammation. Serve both a regulatory and effector function.

EPITHELIAL CELLS – in addition to being a physical barrier, epithelial cells produce cytokines and co-stimulatory molecules when contacting Ag, can present Ag via MHC class II, and express adhesion molecules (ICAM, VCAM). May activate lamina propria and intraepithelial lymphocytes.

NERVES- neuropeptide receptors present on lymphocytes. Mucosal immune response can be modified by neuropeptides.

	Lymphocyte proliferation	IgA production	IgA production	IgA production
Neuropeptides		spleen	Mesenteric node	Peyer’s patch
VIP	ß	Ý	Ý	ß
Somatostatin	ß	ß	ß	ß
Substance P	Ý	Ý	Ý	Ý