Stopping pathogens at the portal of entry: mucous membrane defence

Fig 1. Mucosal epithelium found within the respiratory tract http://farm4.static.flickr.com/3346/3661529896_fd19543c7f.jpg

Enhancing Oral Vaccine Potency by Targeting Intestinal M Cells.
Azizi A, Kumar A, Diaz-Mitoma F, Mestecky J (2010)

The immune system in the gastrointestinal tract plays a crucial role in the control of infection, as it constitutes the first line of defense against mucosal pathogens. The attractive features of oral immunization have led to the exploration of a variety of oral delivery systems. However, none of these oral delivery systems have been applied to existing commercial vaccines. To overcome this, a new generation of oral vaccine delivery systems that target antigens to gut-associated lymphoid tissue is required. One promising approach is to exploit the potential of microfold (M) cells by mimicking the entry of pathogens into these cells. Targeting specific receptors on the apical surface of M cells might enhance the entry of antigens, initiating the immune response and consequently leading to protection against mucosal pathogens. In this article, we briefly review the challenges associated with current oral vaccine delivery systems and discuss strategies that might potentially target mouse and human intestinal M cells.

Different parts of our bodies are not equally vulnerable to infection and we can consider our immune system to be differentially active across all anatomical sites. One of the biggest sites of pathogen entry is the mucosal epithelium which lines our internal parts including the respiratory, gastrointestinal and urogenital tracts (fig 1.).

These surfaces have been estimated to cover 200x the area that our skin covers and if you think about it, most pathogens will use one of these openings to the outside world to gain entry into our bodies: measles virus via the respiratory tract; HIV through the urogenital tract; and E.coli from the gastrointestinal tract. It is this reason that we expend so much energy and effort in keeping these areas protected from would-be dangerous micro-organisms.

Fig. 2. Dipiction of the mucosal immune system:inductive and effector sites both present with mechanisms of inductive and nuetralisation (SIgA) shown. Notice the MALT complex (M cells, antigen presenting cells and B/T cells). http://www.nature.com/mi/journal/v1/n1/fig_tab/mi20079f1.html

Mucosal immunity is a complex system of anatomical, cellular and molecular 'innate' components: epithelial cells which line the mucosa form very tight layers which prevent bacteria or viruses from penetrating deeper into the body; these cells also secrete a number of antimicrobial compounds and enzymes and can rapidly respond to infection through protein mediated cell-cell signalling establishing intra-cellular protection.

In order to mount an efficient response there is a close association between the mucosal epithelium and lymphoid tissues. This 'mucosa-associated lymphoid tissue' or MALT (examples including nasal-associated lymphoid tissue or NALT and gut-associated ymphoid tissue or GALT) is formed by a close interaction between the epithelial lining (antigen sampling 'M' cells) and underlying immune cell complexes consisting of antigen-presenting cells, T cells and B cells.

These mucosal sites – interestingly – form a collective adaptive unit across the whole body when we consider anti-microbial immunity. This 'common mucosal immune system' is mediated by a network of inductive and effecter sites located within the MALT: inductive sites sensing pathogen activity at one area can generate cellular immune responses which can travel systemically from one site to another (e.g. NALT to GALT) . One of the major players in this immunity is a special type of antibody known as secretory immunoglobulin A (SIgA) which is transported from the underlying immune tissue at effector sites to the surface of the mucosa above and can interact with and bind to pathogens and prevent infection and/or damage being done (see fig2 and fig3).

Interest has stemmed from the thought that if we were able to generate adequate antibody responses at the pathogen site of entry (SIgA at the mucosa) we may able to prevent infection from occurring before it is too late and infection has spread from primary areas to other tissues causing significant disease . Current vaccination strategies have focussed on the development of systemic IgG antibodies without consideration for those found at initial portals of entry and although many have been successful for some diseases, the millions of deaths stemming from pathogen-mucosa related infections warrant further investigation and targeting. The question is which inductive MALT site is best suited for vaccination which in turn depends upon pathogen entry strategy, ease of administration, particular side effects and the relative ability of particular MALTs to develop effecter functions at different mucosal epithelium. To date the most promising of strategies lies with nasal or oral vaccine delivery systems and much research has been carried out in order to improve the efficacy of each.

Fig 3. Cartoon dipicting the general structure of the five basic antibodies in humans: IgA the one concerned with mucosal immunity. http://www.cartage.org.lb/en/themes/sciences/lifescience/generalbiology/physiology/LymphaticSystem/Antibodymediated/AntiBtypes.gif

Novel approaches have been used to target vaccines to those cells responsible for antigenic sampling found across most mucosal surfaces – the M cells. These cells can transport antigenic materials from the epithelial lining to the underlying lymphoid complexes via antigen-presenting cells. These cells however are present in low numbers (1 in 10 million epithelial cells are M cells in the GI tract) with the mucosa hence specific targeting may facilitate higher antigen uptake and greater immune induction and these strategies can be adapted to both respiratory and oral delivery systems depending on the vaccine.

We are only now beginning to see the outcome of current research into mucosal immunity and vaccines. Disrupting the close relationship between pathogens and the mucosa is paramount in preventing the millions of deaths worldwide from mucosal-borne infections and the concurrent development of novel targeting and vaccination strategies we may well witness the generation of highly effective, easily administered and most importantly safe vaccines for the most dangerous known diseases: AIDS; cholera; and influenza.

Azizi A, Kumar A, Diaz-Mitoma F, Mestecky J (2010) Enhancing Oral Vaccine Potency by Targeting Intestinal M Cells. PLoS Pathog 6(11): e1001147. doi:10.1371/journal.ppat.100114