Self and non self - The immune system may be regarded as a guardian of our self. The outer world, or the non-self, presents itself to our organism as antigens whose images are stored in the immune system memory, and manifested as receptors or antibodies. Antigens are sampled by a special sensory organ, the mucosa-associated lymphoid tissue, or MALT. Since our body is covered by an impermeable horny layer that prevents antigen intrusion, antigens are sampled only by mucosae, particularly by the gut-associated lymphoid tissue, or GALT. The gastro-intestinal mucosa is covered by two types of epithelia: enterocytes responsible for absorption and secretion, and M-cells, which sample antigens. M-cells are located above lymphoid follicles, or Peyer's patches (1). Figure 1 depicts the relationship between the different cells. Enterocytes cover crypts and villi, and M-cells occur in dome areas above the lymphoid follicles.
The relationship between enterocytes and M-cells is depicted in Figure 2. The two cell types are glued together by tight junctions, (zonula occludens), and form the mucosal barrier. Small molecules, e.g., haptens, amino acids, sugar units and lipids are absorbed by enterocytes. Larger particles, e.g., bacteria, viruses, lectins, and yeast, are taken in by M-cells. After crossing the M-cell, they are ingested by macrophages, and presented by them to local lymphocytes which continue to the nearest lymphoid follicle. From there they reach the entire lymphatic system. The epi-follicular dome and its covering epithelium is the gut antigenic sense organ. Similar sense organs exist in the bronchus-associated lymphoid tissue, BALT, in the nasal cavity, tonsils, and salivary gland excretory ducts.
Bacterial translocation - M-cells actively ingest all particular matter in their vicinity, e.g., bacteria, viruses, yeast, or endotoxin. The occurrence of live bacteria beyond the mucosal barrier is known as bacterial translocation. This a physiological process that does not lead to disease: "portal vein endotoxinemia of gut origin in minute amounts is a normal physiological phenomenon", and "the mesenteric lymph node is the most reliable site to culture for the purposes of monitoring bacterial translocation" (2). Translocated bacteria, even pathogens, continue living in our organism for a while without causing overt harm. Their pathogenicity depends, among other things, upon the host-pathogen balance. A compromised host, on one hand and a vigorous pathogen, on the other, tip the balance in favor of the invader, which is manifested by clinical infection. Some pathogens may damage the mucosal barrier, and cross it directly, causing clinical infections, e.g., enteritis. Compared with the ongoing bacterial translocation, this occurs relatively rarely. Bacterial translocation may also be influenced by the gut eco-system. Anaerobes that adhere to the mucosa probably control the entry of enterobacteria (2) (3).
Immunological memory - Immunological memory is carried by memory lymphocytes. Since they are relatively short-lived, the immune system may lose its memory when they are gone. They might transfer their memory to their progeny; however, the memory response to non replicating protein antigens decays rapidly. By 30-40 days after transfer of lymphocytes to adoptive recipient mice, the relative memory response dropped to 10%. Immunological memory might be refreshed by persisting antigens. Some postulate that "memory cells do not really exist; what we call memory cells are just cells that are maintained in a state of activation (4). Apparently, bacterial translocation provides the necessary antigenic stimulus for memory persistence. Translocated bacteria may be vital to our health.
The intestinal eco-system - Microbes are everywhere, and inhabit our skin and intestine. The newborn baby receives its microbial flora, which already infects it at birth, from its mother. The development of our personal microbial community, known as primary succession, involves an ordered sequential change in the microbial populations of the community. Succession ends when the community consists of up to 400 different species, and attains homeostasis. It is stable, resists any change in its content, and repels unwelcome microbes like the hospital strain (3). Eco-system evolution is a complex process that repeats itself in every growing child. By infecting the baby, its mother transmits to it the best microbial populations that she has gathered. This is a vertical inheritance of a protecting eco-system that is adapted later to the needs of the adult. The child also inherits the translocated bacteria that mold its immunological memory.
Eco-system and translocated bacteria may be manipulated by diet. This fascinating facet of nutrition is still a mystery. It forms a rationale for alternative medical treatments, e.g., herbal medicine, juice therapy, and various diets. Imagine "immunizing" a population against pathogens by a suitable diet.
Latent viruses might boost immunological memory - Bacterial translocation should turn our attention to the possibility of viral translocation. Viruses may also maintain immunological memory. Take, for instance, the herpes virus that is incorporated into the host DNA. Its products might activate lymphocytes to keep recognizing herpes viruses. Only when the host becomes compromised, do they gain strength and produce blisters. Even retroviruses may play a similar role, and protect us against retrovirus-induced cancer.
1. Gebert A, Rothkotter HJ, Pabst R. M cells in Peyer's patches of the intestine. Internat Rev Cytol 157, 91-149, 1996.
2. Van Leeuwen PAM, Boermeester MA, Houdijk APJ et al. Clinical significance of translocation. Gut suppl 1 S28-S34, 1994.
3. Zajicek G. Antibiotic resistance and the intestinal flora. The Cancer J 9, 214, 1996.
4. Gray D. Immunological memory: a function of antigen persistence.Trends in Microbiol. 1, 39-41, 1993.