If the interplay of factors that regulate the intestinal immune system tips out of balance, this could result in allergic reactions or serious inflammatory intestinal diseases. Professor Dr. med. Stefan Meuer, Managing Director of the Institute for Immunology at the University Hospital in Heidelberg, is focusing on the molecular mechanisms of mucosal immune regulation.
The intestinal mucosa, with which the human organism absorbs food, forms the largest surface of the human body. It occupies an area of between 300 to 500 m2, which makes it considerably larger than a tennis court (260 m2), an example that is often used to illustrate just how big the human mucosa is. It is also the biggest barrier between the body and the outside world, and is much larger than the surface area of the human lungs, which is around 80 m2 including all the fine branches, and the human skin, which barely covers an area of 2 m2.
The huge surface area of the intestinal wall is due to the presence of tiny projections (villi) that protrude from the epithelial lining of the intestingal wall and the microvilli-coated brush border. Similar to the bristles of a brush, the apical plasma membrane of the intestinal epithelial cells is invaginated, which results in numerous microvilli. The mucosa also harbours a large proportion of human immune cells. It is inhabited by around 100 trillion (1014) bacteria, around ten times more than the total number of cells that make up a human body. The major benefit for humans of these commensal microorganisms is the supply of energy through the degradation of polysaccharides into short-chain fatty acids and lactic acid. The bacteria also degrade cellulose for which humans do not have an enzyme.
The immune cells of the intestine are located in the lamina propria, a connective tissue layer supplied by blood and lymph vessels and located immediately beneath the epithelium. The intestinal immune cells are thus exposed to the huge number of antigens (of bacteria and food constituents) that enter the human body, thereby providing an effective line of defence. Under normal circumstances these defence mechanisms do not lead to the chronic inflammations that result from the permanent stimulation of the immune cells of the blood and lymph systems. Professor Dr. med. Stefan Meuer, Managing Director of the Institute for Immunology at the University Hospital of Heidelberg, explains that chronic inflammation arises from the interplay of numerous factors. Meuer's major research focus is the molecular mechanisms of mucosal immune regulation.
On the one hand, the direct contact between immune cells and commensal microorganisms or food antigens is to a large degree prevented by a dense mucosal layer and the epithelial cell layer. The mucus contains bactericidal proteins such as lysosymes and defensins, as well as immunoglobulin A (IgA), which is produced as a dimer by the plasma cells of the lamina propria and which binds to a poly-Ig receptor (known as a secretory component) of the basolateral plasma membrane of the intestinal epithelial cells. The dimeric IgA is internalised by the cells as part of a complex with the secretory component and subsequently released as secretory IgA (sIgA) at the apical plasma membrane (microvilli of the brush border), where the sIgAs help to prevent antigens from crossing the epithelial barrier.
In this way more than 60 per cent of all antibodies produced every day by the human body are secreted by the intestinal mucosa. On the other hand, Prof. Meuer and his team have shown that the lamina propria macrophages (LPMO) and T-lymphocytes (LTP) are in a state of "hyporesponsiveness" (reduced ability to react) that differs considerably from the differentiation state of the monocytes and T-lymphocytes in the peripheral blood (see box).
Hyporesponsiveness of intestinal immune cells
In contrast to blood monocytes (macrophage precursor cells), the human lamina propria macrophages (LPMO) hardly ever or never express the surface antigen CD14. CD14 is a so-called "pattern recognition receptor" (TLF) that recognises lipopolysaccharides in bacterial cell walls. In addition, the expression of different adhesion molecules (CD4, CD80/86, CD58) required for the costimulation of T-cells and of Fc and complement receptors is strongly reduced or missing altogether, preventing the LPMO from effectively recognising bacteria and generating an adaptive immune response.
In contrast to blood T-lymphocytes which are virtually unable to undergo clonal expansion, the hyporesponsiveness of lamina propria (LPT) T-lymphocytes is, in the large part, due to their clonal expansion when stimulated by their CD3-antigen-receptor complex. In contrast to adaptive immune responses, this process does not lead to strong cellular proliferation (cell division). The synthesis of glutathione (an important reducing molecule consisting of the three amino acids glutamate, cysteine and glycine and necessary for maintaining the intracellular redox balance) by T-lymphocytes depends on the presence of monocytes in their vicinity that produce and secrete cysteine. Prof. Meuer's team has been able to show that LPT have a glutathione concentration that is around 50% lower than that of blood lymphocytes, due to the insufficient supply of cysteine through LPMO. Monocytes do not produce cysteine spontaneously; cysteine production needs to be induced by certain plasma membrane receptors, including CD14 and CD58, which are not expressed by LPMO. Prof. Meuer's team had also previously shown that the intestinal mucosa is characterised by a pro-oxidative microenvironment that is inhibited by the proliferation of T-lymphocytes.
As outlined above, the majority of antigens absorbed by the human intestine do not lead to a specific immune response. Antigens that are taken up orally are normally tolerated by the intestinal immune system and no antibodies are produced to counteract them. Of course, it is immediately clear that defence reactions must not be activated against food. Pathogenic bacteria are however effectively destroyed by the intestinal immune system. It is not yet clear how the hyporesponsiveness of lamina propria T-lymphocytes is compensated and how an immune response of mucosal LMPO and LPT can be initiated. This issue is currently subject to intensive research.
The immunological balance maintained by healthy intestines therefore depends on a number of factors, including the barrier function of the intestinal epithelium, the protective function of secretory IgA antibodies and the hyporesponsiveness of LPMO and LPT. In addition, the point in time and the extent of the contact with commensal microorganisms and food antigens as well as an individual's genetic disposition all play a role in maintaining the immunological balance. An unbalanced interplay of these factors might lead to allergic reactions against food constituents that are normally harmless. Such allergic reactions tend to occur early on in a person's life. This topic will be looked at in detail in the article entitled "Development of food allergies".
The regulation of the intestinal immune system is also defective in people suffering from chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis. These are serious diseases that tend to occur for the first time in people between 20 and 30 years of age, subsequently recurring at intervals or becoming chronic. Up until now, no curative therapies have been made available to treat these diseases. Prof. Meuer's team has developed a human intestinal organ culture model for investigating the molecular mechanisms that induce inflammatory reactions in the immune cells of the intestinal flora. The researchers from Heidelberg have been able to show that the detachment of the epithelial cell layer induces a strong inflammatory reaction that is accompanied by the activation of resident macrophages and T-lymphocytes and the production of inflammatory cytokines and chemokines. Intestinal inflammatory reactions are characterised by the expression of a surface molecule known as ALCAM (activated leukocyte cell adhesion molecule) on activated immune cells. The function of ALCAM is currently being investigated in an ongoing research project.
In November 2010, the German Research Foundation (DFG) announced the establishment of a new collaborative research centre (SFB 938) coordinated by Prof. Meuer. The SFB 938 on “Environment-specific control of immunological reactivity” will be funded with around 10 million euros for four years. It comprises 16 research projects that are being carried out at the University of Heidelberg and at the German Cancer Research Center (DKFZ) to investigate factors that contribute to the hyperactivity of immune cells, induce chronic inflammatory diseases and the factors in the vicinity of immune cells that make the latter lose control. The researchers expect that the insights gained into the interactions between immune cells and their environment will help them develop new innovative strategies to specifically modulate immune processes. Prior to this new SFB, another SFB, which was also coordinated by Prof. Meuer, led to successful insights into “immunological tolerance and its disorders” and received funding from the DFG for the maximum period of twelve years.