The gastrointestinal (GI) tract is covered with harmless bacteria, bacteria which are somehow able to evade the immune system cells that heavily populate this area. These bacteria are commensal, meaning they that both the bacteria and the organism they reside in are able to benefit from their presence in the gut. It has previously been shown that children who have increased diversity of bacteria in their GI tract during infancy are less prone to developing allergies when they reach school age 1. It is also known that these bacteria play an important role in helping with the digestion of food, providing vitamin K, helping protect the colon from the invasion of harmful bacteria, and helping to educate the immune system to differentiate between harmless and harmful bacteria2. However, the mechanism employed by these bacteria that allows them to reside in the GI tract without being attacked by the hosts immune cells is not well understood.
One type of cell found in the immune system is the B cell, which secretes antibodies, or proteins that neutralize an infectious pathogen, stopping it from harming the host. After these cells encounter a pathogen, they mature into plasma cells and go through isotype switching, a process that allows the cells to change the type of antibody they secrete. Before this switch occurs, B cells secrete an antibody called IgG, but after the switch, they start creating an antibody that specifically targets the type of pathogen that they came in contact with. It is already known that plasma cells in the GI tract secrete the antibody IgA, but it is unknown what supports this class switching and its role in facilitating homeostatic balance between the bacteria in the gut and the host's immune system.
Jorg H. Fritz and associates found that nitric oxide (NO), which is produced by inducible nitric oxide synthase (iNOS) was necessary for the isotype switching of B-cells in the GI tract to IgA producing plasma cells. They had already found that mice who lack lymphotoxin, a chemical that activates the production of the iNOS, also lack IgA. So, they hypothesized that iNOS may cause the B-cell to isotype switch to IgA secreting plasma cells.
First, the scientists wanted to know if B-cells themselves were able to facilitate the production of iNOS in the intestine. They found that mice who were B-cell deficient had a decrease in iNOS. They then found that if they caused cells to start producing iNOS, mice that originally lacked IgA plasma cells were then found to have them. Later, they showed that a subset of these plasma cells were producing iNOS. To further bolster this observation, the scientists took three sets of cells found in the intestine of the mice and measured the amount of iNOS each of these cells produced. Two of these subsets did not produce IgA and the third did. Fritz found that only the IgA positive cells produced iNOS. However, Fritz notes that not all of the IgA positive cells produced iNOS, which he attributes to the pro-inflammatory nature of the molecule, implying that too much secretion of this molecule would wreak havoc on the sensitive intestinal mucosa.
To further understand the role of iNOS, the scientists measured the production of iNOS in mice who lacked bacteria in their intestines. They found that the IgA plasma cells in these mice did not produce iNOS, but when the intestines of these mice were populated with bacteria, their IgA plasma cells began producing it. These results show that iNOS plays a role in the presence of commensal bacteria in the gut.
Since iNOS is known to be an antimicrobial mediator, the investigators tested to see whether iNOS was necessary for the elimination of intestinal pathogens. After introducing the mouse pathogen Citrobacter rodentium, a pathogen found in their intestines after infection, the scientists discovered that mice lacking iNOS producing IgA plasma cells were not able to clear the infection as well as mice that had iNOS producing cells. These results showed that iNOS producing IgA plasma cells also have an important role in regulating the organisms found in the intestine.
Fritz concludes that iNOS is necessary for homestasis in the gut through its role in both maintaing the population of commensal bacteria in the gut and eliminating pathogens. While it is not well understood understood precisely how this is done, this research provides another step in the direction of understanding how the gut is able to support bacterial growth. These results could play important roles in helping combat intestinal diseases in people by facilitating the growth of beneficial bacteria and fighting off harmful ones.
Fritz, J. H., Rojas, O. L., Simard, N., McCarthy, D. D., Hapfelmeier, S., Rubino, S., Robertson, S. J., et al. (2011). Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut. Nature, 1-7. doi:10.1038/nature10698
1. Bisgaard, H., Li, N., Bonnelykke, K., Chawes, B. L. K., Skov, T., Paludan-Müller, G., Stokholm, J., et al. (2011). Reduced diversity of the intestinal microbiota during infancy is associated with increased risk of allergic disease at school age. The Journal of allergy and clinical immunology. doi:10.1016/j.jaci.2011.04.060
2. Guarner Fand Malagelada JR, 2003. Gut flora in health and disease. Lancet 361, 512–9