SBMS 108 Clinical Immunology
Mucosal Immunity and Transfer of Immunity
The Mucosal Immune System
The mucosal immune system is designed both to protect the wet surfaces of the body against microorganisms and to minimise the risk of allergic reactions to food allergens. In particular we will be looking at:1) The secretory immune system which prevents infectious organisms from adhering to the wet surfaces of the body 2) The T cells which concentrate in the gut wall and especially those with the gamma delta TCR 3) How interactions between the mucosal and the systemic immune systems may produce tolerance.
Preventing allergies
• Three mechanisms for inducing tolerance are well known. These are 1. Deletion of the clone(s) of cells reacting with a certain allergen 2. Inactivation of clones of cells (anergy) 3. Suppression of the response by immunosuppressive cytokines especially TGFbeta. This is especially important in the mucosal immune system
Transfer of Immunoglobulins across Epithelia
• Polymeric IgA and, to a lesser extent IgM, is transferred across the wet surfaces of the body and, in some species, across liver into bile • IgG is transferred from mother to child. The site of transfer varies between species • In both cases specific receptors are responsible for the transfer
The first line of defence
1) A good way for bacteria and viruses to invade the body is to stick onto the surface and work their way in by destroying surface cells. Obviously the body does not want this to happen so it protects itself by:-
a) Sampling what is outside and producing an immune response b) Preventing adhesion
The Dry Surfaces of the Body
2) The outside of the body includes both dry surfaces (skin) and wet surfaces such as the GI, respiratory and UG tracts
3)The wet surfaces of the body are obviously more “bug friendly” than the dry surfaces. This applies especially to the thin epithelia of the GI and respiratory tracts
4) The skin and other stratified epithelia are patrolled by antigen presenting cells (Langehans cells) and lymphocytes of all classes. Both circulate between the epithelial layer and lymph nodes.
The Wet Surfaces of the Body
Adhesion of bacteria and other lower organisims is made difficult by:1) A mechanical barrier. The wet surfaces of the body are protected by a barrier of mucus which makes a barrier between the bacteria and the actual cell surfaces 2) Specific defences. Microorganisms must adhere to cells if they are not to be carried out of the body. IgA class antibodies coat the microorganism so preventing adhesion
IgA
• IgA, like all other immunoglobulins, is made by plasma cells. In the case of IgA these are found in large number in the subepithelium of gut and respiratory tree and, to a lesser extent, in the urino-genital tract. Large numbers of IgA lymphocytes colonise the mammary glands late in pregnancy • IgA normally exists as a polymer of between 2-4 IgA monomers. As in IgM they are joined by Jchain. • Polymeric IgA is passed across the epithelia layer into, for example the lumen of the gut
IgA (Continued)
• IgA molecules do not cause inflammation because they are not recognised by phagocyte nor do they fix complement • It is believed that IgA molecules function by coating potentially infectious material preventing it from adhering to the walls of the vessel • IgA deficiency in children is a not-uncommon condition. There are few clinical signs or associations apart from some increase in atopy However certain bacteria (eg Neisseria gonorrheae) have evolved a specific IgA protease, so clearly they have found the system a limit to growth
MALTS
GI Immunity
Pictures of a Peyer’s Patch
Transport of IgA across the epithelium
Sampling the Outside of the Body
Sampling is carried out by the O-MALT (organised mucous-associated lymphoid tissue). This is found in the tonsils NALT), bronchi (BALT) or intestine (GALT) and may be present either as single lymphoid follicles embedded in the wall of the tissue or as aggregated follicles such as Peyer's patches in the intestine.a specialised epithelium sometimes called a lymphoepithelium which lacks goblet cells but has M-cells
MALT -Continued
• The M-cells form a basket into which penetrate B and T cells. The B-cells are mainly "naive" and the T cells helper. Just below the M-cell is an area rich in macrophages and antigen presenting cells. The whole assembly suggests differentiation in a protected environment. In the Peyer's patch, at least, this area of differentiation overlies an area rich in what appear to be IgA memory cells • M-cells are armed with a series of "take up" devices. Receptor mediated endocytosis and fluid phase endocytosis have both been observed and the M-cell also appears capable of phagocytosis
Unwelcome Guests
• Both viruses and bacteria have "learnt to exploit" the uptake. Specific binding has been detected with reovirus, poliovirus, mouse mammary tumour virus and there are indication that it may play a role in uptake of HIV, especially from the rectum. Salmonella, Yersinia and Shigella are among bacterial classes which have learnt to exploit this route • A few chemicals may also invade the Peyer’s patch, examples include partially degraded carageenan but nuisance dusts such as coal dust have also been found • MORE WELCOME is that Peyer’s patches have been used as a route for Vaccines
Locked Out
• The presence of an uptake system means that there has been considerable interest in using these to take up vaccines. Three favoured routes are 1. Oral administration is well accepted but by the time the vaccine has reached the Peyer’s patches it will have been subject to attack by digestive enzymes 2. Humans unlike rats have little organised BALT and mucus of the respiratory ladder will bind particles more than 1 micron in diameter 3. There has hence been quite a lot of interest in nasal vaccines
Movement of IgA Plasma Cells and Transfer of IgA
Activated IgA plasma cells do not remain in the OMALT but head off to populate the subepithelia of the wet surface of the body and associated glands. Secreted IgA binds to its receptor (secretory component) on the basal surface of the epithelial cells and is transported across the cells by endocytosis and released at the far side by proteolysis. The secretory component helps anchor the IgA in the mucous layer
GI Immunity in germ free rats
Structure of the human placenta
Transfer of Immunity from Mother to Child
• At birth a child’s own immune will have responded to few if any pathogens. Something must be done to provide immunity, that something is to transfer IgG from mother to baby. • In humans the process is similar to transfer of IgA. In the human placenta fingerlike projections covered with a cell type called the syncytial trophoblast and containing capillaries dip into enlarged blood vessels on the maternal side of circulation. Maternal IgG binds to a receptor on the trophoblast and is transferred to the babies side of the circulation
Transfer in other species
• This is very complex because the structure of the placenta differs markedly from one species of animal to another. • In ruminants no significant transfer occurs before birth. IgG is secreted into the first milk (colostrum) and is transferred across the intestinal epithelial cell • In rabbits (if my memory is right) transfer occurs across the yolk sack vessels • In rats and mice most transfer occurs in milk but there may be some across the placenta
Mucosal T Cells
• If a section of gut is examined under the microscope we see small, mononucleate , cells inserted between the enterocytes. • Until recently these have been dismissed as curiosities but firstly it was found that the cells form a discrete subset. Over half have gamma and delta cains for the T cell receptor rather than the more usual alpha and beta. More recently it has been suggested that mucosal T cells are the primary target for HIV
Gamma-Delta T cells
• The name refers to the T-cell receptor peptides, the vast (95%) of T cells having alpha-beta chains • Contrary to what you may see in older textbooks they probably have as much diversity as alpha-beta cells though there are differences in generation of diversity • It would appear that gamma-deta cells do not require antigen to be presented by MHC • They are concentrated in the gut and in the lung but are found in many other locations. However there are very few present in the blood or in lymph nodes • At least some seem not need thymic processing
And their role (and the problems they cause)
• Their role is not fully understood but it is suggested that because of their ability to recognise antigen without the need for processing that they allow an immediate if weaker response to material penetrating the intestinal wall • It is claimed that the presence of gamma delta T cells in the lung is symptomatic for allergic lung disease and that atopy may be associated with malfunction of these cells. • It has also been suggested that gamma delta T cells have a role in immune surveillance against cancer
Modulation of the Immune Response by Oral Antigens
• It has long been known that oral administration of an antigen can remarkably reduce a later response following parenteral administration • There appear to be two ways in which this is achieved a) At high doses of antigen there may be deletion or anergy of the Th1 (promote Tc and IgG2a responses) and Th2 (promote IgG/IgE responses) cells b) At low doses there would seem to be active suppression mediated by regulatory (Tr) cells
Tr Cells
• As you will have seen earlier CD4+ CD25+ T-regulatory cells play a number of roles in the body and are, in particular, responsible for inducing anergy in auto-reactive T cells which have evaded negative selection • The active suppression is partly associated with a subset of Tr cells which secrete TGF-beta. These cells are found in large numbers in the Peyer’s patches. They act as helper cells for an IgA response in addition to suppressing cell mediated, IgG and IgE responses. • Immunosuppression is also found with other groups of T cells which share the antigenic combination CD4+CD45RBlow. These cells form IL10 which like TGF beta is immunosuppressive to T cells and antigen presenting cells. Mice in which the TGF beta receptor on T cells is blocked or where the CD10 gene is deleted develop autoimmune disease
References
• IgA Macpherson et al (2001) Microbes and infection 3, 1021-1035 • Kraehenbuhl Trends Immunol 22 (2002) 646 • Fagarsan and Honjo Current Opinion in Imminology 16 (2004) 277-283 • gamma,delta T cells:- Refs cited by Ferranini et al Trends Immunol 23 (2002) 14 Neurath, M. et al. Trends in Immunology 22 (2001) 21 Roncarolo, M-G and Levings, M.K. Current Opinions in Immunology 12 (2000) 676 Mucosal immunity Simecka (1998) Advanced drug delivery systems 34, 235-259 NALT Davis (2001) Advanced drug delivery system 51, 21-42 CD4+CD25+ cells Fahervari and Sakaguchi Current Opinion in Immunology 16 (2004) 203-208