Immunology 1 IMMUNOLOGY Sherko A Omer MB ChB, MSc., PhD

Immunology 2 THE MUCOSAL IMMUNE SYSYEM An immune system characterised by:  Lymphoid tissues associated with mucosal surfaces (MALT).  Mucosa-related immunoglobulin (IgA).  Mucosal-oriented cell traffic system (cells initially induced in mucosal follicles to migrate to diffuse mucosal lymphoid tissues under epithelium.  T regulatory cells.

Immunology 3 THE MUCOSAL IMMUNE SYSYEM MALT, the lymphoid tissues of the intestinal tract (GALT), genitourinary tract, tracheobronchial tree (BALT), and mammary glands. Unencapsulated lymphoid tissues. Contain predominating B lymphocytes.

Immunology 4 THE MUCOSAL IMMUNE SYSYEM MALT

Immunology 5 THE MUCOSAL IMMUNE SYSYEM The outer mucosal epithelial layer contains so-called intraepithelial lymphocytes (IELs) mainly T cells with  TCRs. Lamina propria contains large numbers of B cells, plasma cells, activated T H cells, and macrophages in loose clusters. The submucosal layer contains Peyer’s patches, nodules of 30–40 lymphoid follicles that develop into secondary follicles with germinal centres.

Immunology 6 THE MUCOSAL IMMUNE SYSYEM Antigen transport from mucosal surfaces is carried out by specialized cells (M cells).  M cells are located in so-called inductive sites—small regions of a mucous membrane that lie over organized lymphoid follicles.  M cells are flattened epithelial cells lacking the microvilli as the rest of the mucous epithelium.  M cells have a deep invagination, or pocket, in the basolateral plasma membrane; this pocket is filled with a cluster of B cells, T cells, and macrophages.

Immunology 7 THE MUCOSAL IMMUNE SYSYEM Luminal antigens are endocytosed into vesicles that are transported from the luminal membrane to the underlying pocket membrane. The vesicles then fuse with the pocket membrane, delivering the potentially response-activating antigens to the clusters of lymphocytes contained within the pocket..

Immunology 8 THE MUCOSAL IMMUNE SYSYEM Antigens transported across the mucous membrane by M cells can activate B cells within these lymphoid follicles. Activated B cells differentiate into plasma cells, which leave the follicles and secrete the IgA class of antibodies. These antibodies then are transported across the epithelial cells and released as secretory IgA in to the lumen, where they can interact with antigens.

Immunology 9 THE MUCOSAL IMMUNE SYSYEM

Immunology 10 THE MUCOSAL IMMUNE SYSYEM Immunoglobulins rather than IgA are produced in mucosal tissues, but usually not passed into the lumen

Immunology 11 THE MUCOSAL IMMUNE SYSYEM Secretory IgA serves an important effector function at mucous membrane surfaces. Secretory IgA has may features:  Because it is polymeric, secretory IgA can cross-link large antigens with multiple epitopes.  Secretory component makes IgA less* susceptible to proteolysis and more mucophilic.  Binding of secretory IgA to bacterial and viral surface antigens prevents attachment of the pathogens to the mucosal cells, thus inhibiting viral infection and bacterial colonization.

Immunology 12 THE MUCOSAL IMMUNE SYSYEM  Complexes of secretory IgA and antigen are easily entrapped in mucus and then eliminated by the ciliated epithelial cells of the respiratory tract or by peristalsis of the gut.  Secretory IgA has been shown to provide an important line of defense against bacteria such as Salmonella, Vibrio cholerae, and Neisseria gonorrhoeae and viruses such as polio, influenza, and reovirus.  Breast milk contains secretory IgA and many other molecules that help protect the newborn against infection during the first month of life.

Immunology 13 THE MUCOSAL IMMUNE SYSYEM  Clearance of mucosal antigens via hepatic clearance system, circulating IgA will bind to antigens and transported by blood to liver where it is joined to SC and secreted with bile.

Immunology 14 THE MUCOSAL IMMUNE SYSYEM Antigen-sensitized cells from the gut-associated lymphoid tissue (GALT), or from the peribronchial lymphoid tissues, enter the general circulation via the draining lymphatic vessels. Their systemic recirculation results in their migration towards the remaining secretory-associated lymphoid tissues including the gastro-intestinal tract, the airways, the urinary tract, and the mammary glands, the salivary glands, and the cervical glands of the uterus.

Immunology 15 THE MUCOSAL IMMUNE SYSYEM

Immunology 16 THE MUCOSAL IMMUNE SYSYEM Mucosal Tolerance, a process by which mucosal immune system normally prevent immune response to food and intestinal bacteria while responding to potential pathogens A proposed framework for this type of suppression is as follows: The ingested antigen ( usually a protein) is transported to submucosal accessory cells in the Peyer’s patches where it is processed and presented to T regs (both of CD4+ and CD8+) phenotypes, including special subpopulations of  CD4+ and  CD8+ T cells).

Immunology 17 THE MUCOSAL IMMUNE SYSYEM After proliferation and differentiation these cells become functionally suppressor cells. The suppressor effect is mediated by secretion of IL-10, and IL-4 after re exposure to the tolerizing antigen. The activated T regs enter the circulation and are attracted to areas of ongoing reactivity. In the peripheral lymphoid tissues they may downregulate immune responses to the tolerizing antigen.

Immunology 18 THE MUCOSAL IMMUNE SYSYEM Breast Feeding The lactating breast is an important component of mucosal traffic loop and ensures that mucosal Immunoglobulins and cells are available to protect the neonate during a critical period of immunological incompetence. The colostrum contain large amount of IgA and this level will be reduced in the next days. IgA is synthesized from IgA B cells in breast tissue, these cells have been migrated to breast from gastrointestinal tract or from respiratory tract lymphoid cells.

Immunology 19 THE MUCOSAL IMMUNE SYSYEM The colostrum and breast milk contain a variety of antibodies which protect the newborn. Colostrum is important in establishment of normal flora and preventing uptake of certain macromolecules which may play role in prevention of allergic diseases. Beast milk contains significant numbers of cells and when ingested it result in the transfer of as many as 10 8 cells daily, cell such as macrophages, granulocytes, B and T cells.

Immunology 20 THE MUCOSAL IMMUNE SYSYEM Macrophages delivered via lactation contain ingested IgA so act as a vehicle for delivery of IgA. Small amount of T cells can transfer immune reactivity as they may enter the circulation of the new born?.