stomach disorders, respiratory illnesses and other inflammatory malfunctions - caused due to the entry of pathogens through the linings of the gut (the intestine), the tonsils, nose and lungs - are common in India. So is the knowledge of their causative factors. What most of us are unaware of is that the mucosal surfaces of these organs (mucus-secreting membranes which line the gut, for instance) are rich in immune cells and thus play a significant role in immune defence responses of the body. In recent years, the study of these surfaces has gained importance, leading to the emergence of mucosal immunology as a separate branch of medical research during the last decade. The Ninth International Congress of Mucosal Immunology, sponsored by the us-based Society for Mucosal Immunology and held at Sydney, Australia, in January, marked another milestone in the consolidation of developments in this field.
Though immunologists are not a rarity in India, study of mucosal immunity has not yet attracted sufficient attention. Several immunologists in various hospitals, universities and research institutions in New Delhi confess that though they have heard of this exciting area of research, they are not working on it themselves, nor are they aware of any of their peers in India specialising in the field.
Gut issues In the developed world, however, immunity studies are getting down to gut issues, as scientists are beginning to digest how the intestinal tract plays an important role in the body's defences against harmful agents, as well as in inducing tolerance towards less harmful ones. The gut is permanently under surveillance by the immune system to prevent invasion by pathogens that may sneak in along with food. This is necessary because, unlike the skin, the intestinal lining is more permeable, as its essential function is facilitating the digestion and absorption of food. The risk of attack is enhanced because the surface area of the inner lining of the intestine is 60-fold larger - due to the presence of innumerable folds such as the plicae, villi and crypts - than that of the skin.
The inner lining of the gut is rich in lymphocytes, a class of white blood cells that play a major role in immune functions of the body. They are organised in groups, collectively known as gut-associated lymphoid tissue, or galt. Though their presense was first described in rats more than 300 years ago by the 17th century Swiss anatomist Johann Konrad Peyer and, therefore, are popularly called Peyer's patches, much of the knowledge of their significance has started trickling in only recently.
Peyer's patches are present all along the length of the intestine in most mammals, including humans. Each Peyer's patch is a small bulging of the intestinal wall lining the gut cavity. The surface (dome) of this bulge contains specialised cells called m cells, which are involved in sampling and inward transport of antigens (the molecular 'labels' based on which pathogens are recognised) that accompany food. Once inside the Peyer's patch, antigens are handled by the defence apparatus of the immune system consisting of lymphocytes, macrophages (large white blood cells) and other cells, for an appropriate immune response.
Nutrition and immunity
Recent findings point out that malnutrition may weaken galt and suppress the local as well as systemic (whole body's) immune functions, increasing the vulnerability to enteric diseases such as cholera, while over-feeding may lead to certain complications in people undergoing surgery. The type of nutrition and the method of feeding may also alter the immune capacity of the body.
These findings could have significant implications for public health and hospital care in developing countries. For example, artificial (intravenous) nutrition has become an essential part of hospital care for traumatised and surgical patients. While this is generally preferred as a matter of convenience, several studies have shown that the oral/nasal route is much more beneficial to the patient, as it stimulates gut immunity and improves the local and systemic immune responses. This not only results in faster recovery, but also reduces the chances of infection.
The role of nutrition in enhancing gut immunity seems much more significant in infants. Scientists now believe that several stomach disorders in the newborn are at least partially related to the poor development of their gut immunity. Some of these problems can be eliminated by breast-feeding infants; according to an update published in Advances in Paediatrics (1995), mother's milk contains some growth factors that are crucial to the accelerated development of an infant's gut immunity.
Immune tolerance to a variety of bacterial and dietary antigens coming from the gut cavity is another speciality of the intestinal immune system. This is believed to have evolved so that the helpful (symbiotic) bacteria inside the gut and other harmless antigens routinely encountered by the intestine, do not lead to inflammation and fever. The immune cells of Peyer's patches play a crucial role in bringing about oral tolerance. Scientists are now examining the possibility of inducing such tolerance not only in the gut but in the whole body by giving antigens orally.
This could have interesting implications in therapy, not only in countering a whole range of allergic disorders, but also to cure autoimmune diseases such as rheumatoid arthritis, which are caused when the immune system goes wrong and begins to recognise 'self' as 'foreign'. According to a review published in the Annual Review of Immunology (1994), clinical trials to induce oral tolerance in cases of autoimmune diseases have shown positive results. Oral administration of antigens prevents the rejection of transplanted organs as 'foreign' and prolongs the survival of the organ, according to H L Weiner and other scientists, the authors of the review.
Influenced by intestines
Intestinal immunity also plays an important role in immune responses associated with other parts of the body. In a study of the role of intestinal immunity in respiratory tract infections, C Ruedl and colleagues of the Institute for General and Experimental Pathology, University of Innsbruck Medical School, Austria, fed laboratory mice with a potion containing extracts from seven different bacteria that cause common respiratory disorders. After immunisation for five consecutive days, they found that rats which were 'primed' by oral immunisation elicited an enhanced immune response in the lung as compared to control animals. Their results were reported in Clinical Diagnostics and Laboratory Immunology (1994).
Scientists are now trying to develop model systems to study possible interactions between the mucosal immune systems of the lung and intestine, and their implications for local and systemic immune responses. For example, H C Bellum and colleagues of the department of microbiology and immunology, Medical University of South Carolina, Charleston, us, have recently reported in Laboratory Investigation (1996) about the possibility of working with a strain of reovirus (a virus that infects mucosal tissues in mice) that evokes immune responses from the gut as well as the lung. Some of these studies also seem to offer interesting implications for developing vectors (carriers) for oral vaccines. This can be achieved by using harmless or inactivated viruses as vehicles to carry antigens or vaccines that induce immunity in the hosts when infected.
Scientists now believe that there is a common mucosal immune system that involves gut as well as other mucosal tissues. These tissue subsystems not only seem to interact between themselves, but also with systemic immunity by exchanging immune cells and information through blood circulation. These interactions seem to strongly determine the nature and intensity of the body's immune responses. Says A Ferguson, president of the Society for Mucosal Immunology, "An appreciation of the special immune processes in the mucosal organs and their interactions, combined with a measure of constructive lateral thinking, can open up new avenues to explore in physiology and pathology. The imaginative application of such new approaches to the pharmaceutical and biological manipulation of the immune system could revolutionise our management of some diseases."
Listen to your gut response
By and large, the immune responses of the gut have been most extensively studied by scientists, though the mucosal tissues of tonsils, nose and lungs probably play an equally important role in the body's immunity. The gut's role becomes important because a lot depends on how antigens are dealt with and transported in the intestine. Defective handling of antigens in the gut predisposes the body to a whole range of intestinal and other disorders. The opposite also seems to be true; frequent infections and surgery may hamper the gut immune function.
The side-effects of some medicines seem to help the intestine handle the antigens in a desirable manner, while others may do just the opposite. For example, steroid drugs which suppress or stimulate body immune functions, also affect the immune responses of the gut and its symbiotic bacteria that live in the gut. Similarly, several non-steroidal anti-inflammatory drugs increase the permeability of the gut mucosal barrier. However, very little is known on this front as yet, and there are no medicines that specifically stimulate or suppress gut immune function. The underlying message of these findings is that modern medicine cannot ignore the gut responses of the body, or its relationship with nutrition.
In contrast, traditional medicinal systems seem to rely much more on the body's own defence responses, often with clear stipulations on dietary restrictions; simultaneous treatment of more than one disorder is usually discouraged. Is it possible that they are much more in tune with gut responses?