Gut immune system has the challenge of responding

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The gut immune system has the challenge of responding to pathogens while remaining, relatively unresponsive to food antigens and the commensal microflora. Intestinal epithelium (400 m2) is the site of most antibody production in the body and the largest collection of T cells. Mucosal immune responses involve the gut-associated lymphoid tissue (GALT). Lymphocytes are fond at three sites within the mucosa. They exist in organized lymphoid aggregates (Peyer's patches) beneath the epithelium of the terminal small intestine. Lymphocytes can also be found within the epithelial cell layer (intraepithelial lymphocytes). Finally lymphocytes exist scattered, with other immunocompetent cells, within the lamina propria (fig. 1)

Oganisation and strusture of gut-associated lymphoid tissue (GALT).

GALT is divided into two functional compartments: Peyer's patches, where interaction occurs between luminal antigen and the immune system, and the diffusely distributed intraepithelial and lamina propria lymphocytes.

Peyer's patches have the anatomic appearance of secondary lymphoid organs. Peyer's patches are covered by specialised epithelium (follicle-associated epithelium). Some of these epithelial cells have surfaces which are wrinkled or folded. These microfold are M cells and their role is to sample and actively transport particulate antigens from the lumen into the 'dome' area, where priming of both T and B lymphocytes occurs. Within Peyer's patches are specialized T cells that induce immature IgM- bearing B lymphocytes to switch isotype to IgA. Primed B lympoblasts, committed mainly to producing IgA class antibody, migrate from Peyer's patches, via the lymphatics and mesenteric lymph nodes, to the thoracic duct and hence into the circulation. These cells return preferentially to the lamina propria a process called 'homing'. Once back in the gut, they mature into IgA plasma cells and are responsible for local and secretory immune defences. The number of IgA- producing cells in the lamina propria far exceeds the numbers producing IgM, IgG, or IgE. The IgA coating the epithelium is specially adapted for its function. IgA plasma cells produce monomeric IgA, which is converted into a dimer by a smaller 'joining' peptide (J chain), also produced y the plasma cells. Secretory component is a 70-KDa fragment of the polymeric immunoglobulin receptor that is synthesized by epithelial cells and is essential for transport of secretory IgA into the lumen of the gut. The polymeric Ig receptor occurs. As a result, the IGA dimer is released into the gut attached to the proteolytic fragments of the receptor, now called secretory component stabilises the secretory IgA molecule and protects it from proteolytic attack enzymes in the gut. Secretory IGA neutralises viruses, bacteria and toxins, prevents the adherence of pathogenic microorganisms to gut epithelium and so blocks the uptake of antigen into the systemic immune system, a role termed 'immune exclusion'.

Effector site lymphocytes can be subclassified into lamina propria lymphocytes (LPLs) and intraepithelial lymphocytes (IELs). LPLs have a unique phenotype-these cells are terminally differentiated effector T cells that have pathways of stimulation that are different from peripheral blood T cells.

Additional to LPLs, large number of natural killer cells, mast cells,macrophages and plasma cells can also be found in Lamina propria. T and B lymphocytes both exist in Lamina propria, but T cells predominate in a ratio of about four to one. These T cells do not proliferate well after stimulation of the T-cell receptor, yet produce large amounts of the cytokines interleukin 2 (IL-2), IL-4, interferon-γ (IFN-γ) and tumour necrosis factor-α (TNFα). The IELs also constritute a unique population of lymphocytes in the body, More than 80% of IELs are CD8+. Some IELs are cytotoxic and some have natural killer cell activity, fuctions important in the control of enterovirus infection. IELs also seem to have a role in controlling epithelial cell barrier function.

2. a) Discuss septic (endotoxin) shock and toxic shock, indicating their similarities and differences

b) Discuss the phagocytosis of bacterial cells and their killing.

Phagocytosis (cell eating) is the main mechanism of killing extracellular bacteria.

It consists of four stages: attraction (chemotaxis), attachment, engulfment and killing.

Phagocytosis begins when phagocytes move to the site where they are needed. This directed migration is called chemotaxis, and is the result of chemical attractions is known as chemotaxis agents. Chemotactic agents produced by various cells of the human body referred as chemokines. Chimotactic agents are produced during the complement cascade and inflammation. When phagocytes 'sense' the presence of chemotactic agents, they move along a concentration gradient. This means they move from areas of low concentrations of chemotactic agents to the area of low concentrations. The area of highest concentration is the site where the chemotactic agents are being produced or released. For example the site of inflammation. Thus, the phagocytes are attracted to where they are needed. Different types of chemotactic agents attract different types of leukocytes. Some attract monocytes, other neutrophils, and still other eosinophils.

The next step in phagocytosis is attachment of the phagocyte to bacterial cell to be ingested. Phagocytes can only 'eat' objects to which they can attach. (Opsonisation is the process by which phagocytosis is helped by the deposition of opsonins such as antibodies or certain complement fragments onto the surface of bacterial.) Opsonization is sometimes necessary to enable phagocytes to attach to encapsulated bacteria. Than the bacteria becomes coated with opsonins. Because the phagocyte possesses surface molecules (receptors) for complement fragments and antibodies, the phagocyte can now attach to the bacterial.

The following step is engulfment or (ingestion). The phagocyte then surrounds the bacterial with pseudopodia, which fuse together, and the bacterial is ingested. Phagocytosis is a type endocytosis (a general term outside the cell). Within the cytoplasm of the phagocyte, the bacterial is contined within a membrane-bound vesicle called phagsome.

The phagosome next fuses with a nearby lysosome to form a digestive vascular (phagolysosome), within which killing and digestion occur. Lysosomes are membrane bound vesicles containing digestive enzymes. Digestive enzymes found within lysosomes indude enzyme myeloperoxidase. Following lysosome fusion, myeloperoxidase is release, which, in the present of hydrogen peroxide and chloride ion, produces a potent microbicidal agent called hypochorous acid.

The killing pathways of phagocytic cells can be oxygen dependent and oxygen independent. One oxygen-dependent pathway involves the reduction of oxygen to suproxide anion. This is molecular oxygen to which a single unpaired electron has been added). This then interacts with numerous other molecules to give rise to a series of free radicals and other toxic derivatives, which can kill bacteria and fungi. In neutrophils the oxidative burst may also act indirectly, by promoting the flux of K+ ions into the phagosome and activating microbicidal proteases.

A second oxygen dependent pathway involves the creation of nitric oxide from the guanidine nitrogen of L-arginine. This in turn leads to further toxic substances such as the peroxynitrites, which result from interaction of nitric oxide with the products of the oxygen reduction pathway.

Oxygen-independent killing mechanisms may be more important than previously thought. Many organism can be killed by cells from patients with myeloperoxidase acids. Some of this killed anaerobically,so other mechanisms must exist.